Therapeutic agent composition and method of use, for treatment of mild cognitive impairment, depression, and psychological disorders

Abstract

To provide a method of regenerating neurons and glia cell loss as a result of an insult from injury or disease.SOLUTION: This method comprises: a) providing a subject in need of regenerating neurons and glia cell loss; and b) administering to the subject cyclic Prolyl Glycine (cPG) or its analogues (cyclic(tri(Prolyl Glycine) or cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline or cyclic Glycyl-2-Methyl-Proline (cPMeG)) (collectively called a cPG compound), or a combination thereof, in an effective amount to regenerate new neurons and glia cells. Therein: the neurons are regenerated and the glia cell loss is regenerated in the subject; further the cPG compound serves as a neurogenesis agent in the central nervous system; and further the neurons and glia cell loss as a result of an insult from injury or disease are regenerated.SELECTED DRAWING: Figure 3

Description

Cross - reference to related applications

[0001] This application claims the benefit of priority of U.S. Patent Application No. 62 / 674,855, filed May 22, 2018 , U.S. Patent Application No. 62 / 671,485, filed May 15, 2018, and U.S. Patent Application No. 62 / 671,466, filed May 15, 2018, each of which is hereby incorporated by reference in its entirety The inventor, Lloyd Han Roy Tran, reflects the change of legal name from Roy H to this.

Technical Field

Technical Field

[0002] The present invention generally relates to novel cyclic dipeptide compounds structurally related to diketopiperazine and methods for their therapeutic use. In particular, the present invention relates to the neuro protective activity and neurogenic activity of such compounds. In particular, the present invention relates to the use of cyclic prolylglycine ( "cyclic GP" or "cPG") and cPG analogs, and cPG compounds, pharmaceutically effective analogs thereof , and the use of their pharmaceutical compositions in the treatment and prevention of cognitive impairment and related neurodegenerative diseases and mental disorders. The present invention also generally relates to materials and methods for regenerating nerve cells and glial cells, or methods for repairing damaged nerve cells and glial cells .

Background Art

[0003] Mild cognitive impairment (MCI) refers to a state in which cognitive function has declined more than expected according to age and educational background . Mild cognitive impairment refers to a state in which there is a disorder in cognitive functions such as memory, and although it exceeds the age standard , it does not reach dementia, which is a characteristic of dementia. The morbidity rate of MCI ​varies by age. The prevalence of MCI by age is as follows: 6.7 % for those aged 60 - 64, 8.4% for those aged 65 - 69, 10.1% for those aged 70 - 74, 14.8% for those aged 75 - 79, and 25.2% for those aged 80 - 84. More than half of people with MCI will develop dementia within 5 years (Non - patent literature: 10.1212 / WNL.0000000000004826.:https: / / en.wikipedia.org / w iki / PubMed_Identifier “\o” PubMed Identifier 29282327.).

[0004] Dementia is an umbrella term that describes a group of symptoms associated with a decline in memory and other thinking abilities, and is severe enough to reduce a person's ability to perform daily activities. Alzheimer's type dementia accounts for 60 - 80% of dementia cases. Vascular dementia, which occurs after a stroke, is the second most common type of dementia. However, there are many other diseases that can cause dementia symptoms, including reversible ones such as thyroid problems and vitamin deficiencies. The symptoms of dementia are varied, but a person cannot be diagnosed with dementia unless at least two of the following core mental functions are significantly impaired: memory, communication, language, concentration and attention, reasoning and judgment, and visual perception. In 2018, more than 5.5 million people in the United States and over 50 million people worldwide were living with Alzheimer's disease. Reference: Alzheimer's Disease International World Alzheimer Report 2018) The increasing prevalence of Alzheimer's disease over the next few decades is expected to

[0005] place a significant pressure on social and healthcare systems, regardless of whether they are developed or developing countries. There has long been an unmet need for therapies that halt, substantially retard, or slow the progression and symptoms of diseases associated with this illness, or otherwise improve or provide comfort and palliative care. The pioneering researcher Ramón y Cajal, at the beginning of the 20th century, wrote as follows: "The functional specialization of the brain imposed two great cleavages on the neurons. It is for this reason that, at the end of development, the sources of growth and regeneration of axons and dendrites become irreversibly depleted." (Non-Patent Document 2 (New Ideas on the Microscopic Anatomy of the Central Nervous System)).

[0006] This hypothesis, which was previously considered a fundamental principle of neuroscience dating back from the late 19th century to the mid-20th century, has now been proven invalid. "The functional specialization of the brain imposed two great cleavages on the neurons. At the end of development, the sources of growth and regeneration of axons and dendrites become irreversibly depleted, for this reason." (Non-Patent Document 2 (New Ideas on the Microscopic Anatomy of the Central Nervous System)). This is why the sources of growth and regeneration of axons and dendrites become irreversibly depleted once development is complete. (Non-Patent Document 2 (New Ideas on the Microscopic Anatomy of the Central Nervous System)). This hypothesis, which was previously considered a fundamental principle of neuroscience dating back from the late 19th century to the mid-20th century, has now been proven invalid. (Non-Patent Document 2 (New Ideas on the Microscopic Anatomy of the Central Nervous System)).

[0007] In 1966, Altman and Gopal demonstrated the evidence of adult mammalian neurogenesis in other regions of the brain, including the hippocampus of rodents. They reported autoradiography and histological studies of postnatal neurogenesis, with cell proliferation and migration seen in the anterior forebrain, particularly referring to the persistence of neurogenesis in the olfactory bulb (Non-Patent Document 3 (https: / / doi.org / 10.1002 / cne.901240303)). In Altman's experiment, in the intact adult mammalian brain, neuroregeneration maintains the function and structure of the central nervous system (CNS). Thymidine-H3 was intraperitoneally injected into 6-day-old and 13-day-old rats, and then they were allowed to survive for 1 hour to 60 days. Autoradiography data obtained from animals that survived for a short period were used to estimate the local cell proliferation rate. Animals with a long survival period were at the reproductive site In Altman's experiment, in the intact adult mammalian brain, neuroregeneration maintains the function and structure of the central nervous system (CNS). Thymidine-H3 was intraperitoneally injected into 6-day-old and 13-day-old rats, and then they were allowed to survive for 1 hour to 60 days. Autoradiography data obtained from animals that survived for a short period were used to estimate the local cell proliferation rate. Animals with a long survival period were at the reproductive site In Altman's experiment, in the intact adult mammalian brain, neuroregeneration maintains the function and structure of the central nervous system (CNS). Thymidine-H3 was intraperitoneally injected into 6-day-old and 13-day-old rats, and then they were allowed to survive for 1 hour to 60 days. Autoradiography data obtained from animals that survived for a short period were used to estimate the local cell proliferation rate. Animals with a long survival period were at the reproductive site (Non-Patent Document 3 (https: / / doi.org / 10.1002 / cne.901240303)).

[0008] In Altman's experiment, in the intact adult mammalian brain, neuroregeneration maintains the function and structure of the central nervous system (CNS). Thymidine-H3 was intraperitoneally injected into 6-day-old and 13-day-old rats, and then they were allowed to survive for 1 hour to 60 days. Autoradiography data obtained from animals that survived for a short period were used to estimate the local cell proliferation rate. Animals with a long survival period were at the reproductive site In Altman's experiment, in the intact adult mammalian brain, neuroregeneration maintains the function and structure of the central nervous system (CNS). Thymidine-H3 was intraperitoneally injected into 6-day-old and 13-day-old rats, and then they were allowed to survive for 1 hour to 60 days. Autoradiography data obtained from animals that survived for a short period were used to estimate the local cell proliferation rate. Animals with a long survival period were at the reproductive site In Altman's experiment, in the intact adult mammalian brain, neuroregeneration maintains the function and structure of the central nervous system (CNS). Thymidine-H3 was intraperitoneally injected into 6-day-old and 13-day-old rats, and then they were allowed to survive for 1 hour to 60 days. Autoradiography data obtained from animals that survived for a short period were used to estimate the local cell proliferation rate. Animals with a long survival period were at the reproductive site In Altman's experiment, in the intact adult mammalian brain, neuroregeneration maintains the function and structure of the central nervous system (CNS). Thymidine-H3 was intraperitoneally injected into 6-day-old and 13-day-old rats, and then they were allowed to survive for 1 hour to 60 days. Autoradiography data obtained from animals that survived for a short period were used to estimate the local cell proliferation rate. Animals with a long survival period were at the reproductive site To infer the migration of new cells from the migration channel to the target site and determine their differentiation pattern were used. The formation and differentiation of micro neurons continue during infancy, but in most structures, the rate has decreased. In the external granular layer of the cerebellar cortex, cell proliferation continues at an unusually high rate, and cells migrate from there to the molecular layer and the internal granular layer.

[0009] It has been shown that adult regenerative neurons are integrated into existing brain circuits and contribute to the improvement of neuropathy (Non-Patent Document 4).

[0010] Interestingly, neurogenesis has been observed not only at the levels of the olfactory bulb and hippocampus, but also at the level of nerve cells. In this regard, this process has been suggested to occur in the substantia nigra of adult mice, opening up a new field of research for the treatment of neurodegenerative diseases (Non-Patent Document 5).

[0011] According to the review paper by Guo-li Ming, since the discovery of neural precursors in the postnatal rat hippocampus, researchers have firmly established that active neural precursors from neural precursors continue throughout life in scattered regions of the central nervous system (CNS) of all mammals, including humans (Non-Patent Document 6).

[0012] Regarding the developmental process and regulation of adult neurogenesis, great progress has been made in understanding processes such as proliferation, fate specification, neuronal maturation, targeting, and synaptic integration of newborn neurons.

[0013] Although the exact mechanism for maintaining functional neural stem cells (NSCs) in these regions has not been elucidated, NSCs have the ability to restore neurons and glia in response to specific pathological conditions. ​​​​​​​​​​is shown.

[0014] Depression is a mental health disorder characterized by a persistently low mood and a diminished interest in activities, which causes significant impairment in daily life. Many factors, such as genes, stress , and the chemical nature of the brain, may cause depression. According to John Geddes, a professor of epidemiological psychiatry at the University of Oxford, "Depression is the single largest contributor to the global disorder we have, and a major problem for humanity." It affects approximately 350 million people worldwide and has increased by nearly 20% from 2005 to 2015 (World Health Organization (WHO) and Centers for Disease Control).

[0015] In recent years, a lot of research efforts have been devoted to the study of mental depression and its treatment methods. Many commercially available drugs can improve depression, but they all have undesirable side effects. Recently, suicide has been reported as one of the serious side effects of depression, and this has virtually become the only cause of death due to mental illness.

[0016] The present invention provides a method for treating depression without severe side effects. According to this method, cyclic prolylglycine and its pharmaceutically effective analogs have been demonstrated as potential treatments for patients suffering from depression.

Prior Art Documents

Non-Patent Documents

[0017]

Non-Patent Document 1

Non - Patent Document 5

Non - Patent Document 6

Summary of the Invention

Means for Solving the Problems

[0018] One aspect of the present invention provides cyclic prolylglycine compounds suitable for the treatment and prevention of diseases and injuries in animals and humans. Cyclic PGs are selected from the group including cPG, cPG analogs, cPG peptidomimetics, and related compounds that promote or cause the formation of cPG or cPG analogs in vivo.

[0019] ​​​An example of a cPG analog is cyclic (glycyl-L-prolyl-L-prolyl), or is abbreviated as cyclic or c(PG)3 as referred to herein. Another example of a CPG analog is cyclic glycyl-2

[0020] -allylproline, or cyclic glycyl-alkylproline, referred to herein as "cGAL".

[0021] Collectively, cPG, c(PG)3, cGAL, and cyclic glycyl-2-methyl-proline, as well as their pharmaceutically acceptable salts, are referred to herein as "cPG compounds".

[0022] In addition, cyclic glycyl-2-methyl-proline is a compound belonging to the group of cyclic glycyl-2-alkyl prolines of the compound.

[0023] Furthermore, any of the c PG compounds, their derivatives, their analogs, and the like disclosed herein or otherwise known in the art can be provided in the form of pharmaceutically acceptable salts.

[0024] Preferably, the cPG compound is administered in a pharmaceutically acceptable composition such as a pharmaceutically acceptable carrier.

[0025] More preferably, the composition further comprises a therapeutically effective amount of the cPG compound in combination with a compound selected from growth factors and related derivatives (insulin-like growth factor-I ( IGF-I), insulin-like growth factor-II (IGF-II), GPE, transforming growth factor -II). Activin, growth hormone, nerve growth factor, growth hormone binding protein, JQF binding protein Proteins (especially JGFBP-3), basic fibroblast growth factor, acidic fibroblast growth factor , hst / Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-induced growth factor. Additional members of the FGF family include, for example, int-2, fibroblast growth factor homologous factor-1 (FHF-1), FHF-2, FHF-3 and FHF-4, keratinocyte growth factor 2, glia activating factor, FGF-10 and F GF-16, ciliary neurotrophic factor, brain-derived growth factor. Neurotrophin 3, neuro trophin 4, bone morphogenetic protein 2 (BMP-2), glial cell line-derived neurotrophic factor, activity-dependent neurotrophic factor, cytokine leukemia inhibitory factor, oncostatin M, interleukin), β, α, χ or consensus interferon, TNF -α. Cromethiazole; kynurenic acid, max, FK506 [tacrolimus], L-s reo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, an drenocorticotropin-(4-9_analog [ORG2766] and dizolcipine MK-801], selegiline; glutamic acid ali, for example, NPSl 5O6, GV15 05 260, MK-801, GV150526. 2,3-dihydroxy-6-nitro- 7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070 and L Y300164-like AMPA ali; anti-MAdCAM-1lmAb MECA-367 such as addressin MAdCAM-1 and / or integrin α4 receptor (α4β1 and α4β7)-directed anti-inflammatory agents (ATCC accession number HB-9478) , interferon βLb and interferon alpha con-1 including interferon Ron.

[0026] Preferably, the cPG compound can be used for the treatment or prevention of cell damage or cell death resulting from septic shock, ischemia, cytokine administration, cytokine overexpression, ulcers, gastritis, ulcerative colitis, Crohn's disease, and diseases and injuries caused thereby. Diabetes arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, liver cirrhosis, transplant rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis glomerulonephritis, uveitis, glaucoma, blepharitis, chalazion, allergic eye diseases, corneal ulcers, corneal inflammation, cataracts, retinal disorders, age-related macular degeneration, optic neuritis, ileus, inflammation due to overproduction of inflammatory cytokines hemorrhagic shock, anaphylactic shock, burns, infections leading to overproduction of inflammatory cytokines induced by bacteria, viruses, fungi, parasites, hemodialysis, chronic fatigue syndrome, stroke, cancer, cardiovascular diseases associated with overproduction of inflammatory cytokines heart disease, cardiopulmonary bypass, ischemia-reperfusion injury, ischemia associated with overproduction of inflammatory cytokines · reperfusion, toxic shock syndrome, adult respiratory distress syndrome, cachexia, myocarditis, autoimmune diseases eczema, psoriasis, heart failure, dermatitis, hives, cerebral ischemia, systemic lupus erythematosus, AIDS, AIDS dementia, chronic neurodegenerative diseases, chronic pain, priapism, cystic fibrosis, amyotrophic lateral sclerosis, schizophrenia, depression. Premenstrual syndrome, anxiety, poisoning, migraine, Huntington's disease epilepsy, gastrointestinal motility disorders, obesity, dysphagia, neuroblastoma, malaria, blood cancer, bone myelofibrosis, lung injury, graft-versus-host disease, head injury, central nervous system trauma, hepatitis, renal failure, chronic type C hepatitis, paraquat poisoning, transplant rejection and preservation, enhanced reproductive capacity, bacterial translocation, circulatory shock, and type C chronic hepatitis, paraquat poisoning, transplant rejection and preservation, enhanced reproductive capacity, bacterial translocation, circulatory shock, Traumatic shock, hemodialysis, hangover, and combinations of two or more thereof.

[0027] Preferably, the cPG compound can be used for the recovery of myelination of axons in mammals in which myelin has been depleted due to nerve damage or disease. It can be used for the recovery of myelination that has been depleted due to traumatic injury, toxin exposure, asphyxia or hypoxia-ischemia, perinatal hypoxic-ischemic injury, injury or disease to the central nervous system white matter, acute brain injury, chronic neurodegenerative diseases including multiple sclerosis, and demyelinating diseases and disorders including acute disseminated encephalomyelitis, optic neuritis, polymyositis, Devic's disease, leukodystrophy. Diseases such as non-inflammatory lesions, progressive multifocal leukoencephalopathy, and central pontine myelinolysis.

[0028] Preferably, the cPG compound can be administered in combination with IGF-1 or interferon. Another related aspect is that the present invention relates to a method for treating or preventing cell damage or cell death in response to injury and disease by administering at least one cPG compound. Preferably, the cPG compound can be administered at a dose between about 1 μg and about 150 mg per kilogram of body weight. Suitable dosages for the administration of cPG are, for example, preferably between about 0.1 mg and about 100 mg per kilogram of body weight, between about 1 mg and about 100 mg per kilogram of body weight, between about 5 mg and about 70 mg per kilogram of body weight, between about 10 mg and about 50 mg per kilogram of body weight, or between about 20 mg and

[0029]

[0030]

[0031] ​​​​​​​​​​​It can be administered in an amount ranging from about 40 mg, but is not limited thereto. cP The dosage, route of administration, and dosing regimen of G may vary depending on the disease, disorder, or condition. As an example, in mild cognitive impairment, the dosage using the same or different routes of administration may be lower than in the case of Alzheimer's disease. For example, a typical dosage for a patient with mild cognitive impairment can be administered orally between about 0.2 mg and about 1 mg per day (e.g., taking 1 capsule of 20 mg or 2 capsules per day based on a doctor's prescription). On the other hand, patents for more severe Alzheimer's disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. The determination of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally, or for a specific subject or patient, be evaluated.

[0032] For example, a typical dosage for a patient with mild cognitive impairment can be administered orally between about 0.2 mg and about 1 mg per day (e.g., taking 1 capsule of 20 mg or 2 capsules per day based on a doctor's prescription). On the other hand, patents for more severe Alzheimer's disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. The determination of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally, or for a specific subject or patient, be evaluated. For example, a typical dosage for a patient with mild cognitive impairment can be administered orally between about 0.2 mg and about 1 mg per day (e.g., taking 1 capsule of 20 mg or 2 capsules per day based on a doctor's prescription). On the other hand, patents for more severe Alzheimer's disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. The determination of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally, or for a specific subject or patient, be evaluated. disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. The determination of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally, or for a specific subject or patient, be evaluated. disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. The determination of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally, or for a specific subject or patient, be evaluated. disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. The determination of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally, or for a specific subject or patient, be evaluated. disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. The determination of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally, or for a specific subject or patient, be evaluated. For example, a typical dosage for a patient with mild cognitive impairment can be administered orally between about 0.2 mg and about 1 mg per day (e.g., taking 1 capsule of 20 mg or 2 capsules per day based on a doctor's prescription). On the other hand, patents for more severe Alzheimer's disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. The determination of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally, or for a specific subject or patient, be evaluated.

[0033] A further aspect of the present invention is a method for restoring myelination of axons in a mammal that requires remyelination due to nerve injury or disease, comprising administering a therapeutic amount of a cPG compound, where the cPG compound consists of cPG. Biologically active cPG analogs such as c(PG)3 and cGAL, biologically active cPG peptidomimetics, compounds that increase the concentration of cPG, or compounds that increase the concentration of cPG analogs are effective in restoring myelination of axons in mammals. In one aspect of the present invention, the method for restoring myelination of axons, which comprises administering a therapeutic amount of a cPG compound, consists of stimulating astrocytes to promote remyelination. A further aspect of the present invention is a method for restoring myelination of axons in a mammal that requires remyelination due to nerve injury or disease, comprising administering a therapeutic amount of a cPG compound, where the cPG compound consists of cPG. Biologically active cPG analogs such as c(PG)3 and cGAL, biologically active cPG peptidomimetics, compounds that increase the concentration of cPG, or compounds that increase the concentration of cPG analogs are effective in restoring myelination of axons in mammals. In one aspect of the present invention, the method for restoring myelination of axons, which comprises administering a therapeutic amount of a cPG compound, consists of stimulating astrocytes to promote remyelination. A further aspect of the present invention is a method for restoring myelination of axons in a mammal that requires remyelination due to nerve injury or disease, comprising administering a therapeutic amount of a cPG compound, where the cPG compound consists of cPG. Biologically active cPG analogs such as c(PG)3 and cGAL, biologically active cPG peptidomimetics, compounds that increase the concentration of cPG, or compounds that increase the concentration of cPG analogs are effective in restoring myelination of axons in mammals. In one aspect of the present invention, the method for restoring myelination of axons, which comprises administering a therapeutic amount of a cPG compound, consists of stimulating astrocytes to promote remyelination. A further aspect of the present invention is a method for restoring myelination of axons in a mammal that requires remyelination due to nerve injury or disease, comprising administering a therapeutic amount of a cPG compound, where the cPG compound consists of cPG. Biologically active cPG analogs such as c(PG)3 and cGAL, biologically active cPG peptidomimetics, compounds that increase the concentration of cPG, or compounds that increase the concentration of cPG analogs are effective in restoring myelination of axons in mammals. In one aspect of the present invention, the method for restoring myelination of axons, which comprises administering a therapeutic amount of a cPG compound, consists of stimulating astrocytes to promote remyelination. A further aspect of the present invention is a method for restoring myelination of axons in a mammal that requires remyelination due to nerve injury or disease, comprising administering a therapeutic amount of a cPG compound, where the cPG compound consists of cPG. Biologically active cPG analogs such as c(PG)3 and cGAL, biologically active cPG peptidomimetics, compounds that increase the concentration of cPG, or compounds that increase the concentration of cPG analogs are effective in restoring myelination of axons in mammals. In one aspect of the present invention, the method for restoring myelination of axons, which comprises administering a therapeutic amount of a cPG compound, consists of stimulating astrocytes to promote remyelination. A further aspect of the present invention is a method for restoring myelination of axons in a mammal that requires remyelination due to nerve injury or disease, comprising administering a therapeutic amount of a cPG compound, where the cPG compound consists of cPG. Biologically active cPG analogs such as c(PG)3 and cGAL, biologically active cPG peptidomimetics, compounds that increase the concentration of cPG, or compounds that increase the concentration of cPG analogs are effective in restoring myelination of axons in mammals. In one aspect of the present invention, the method for restoring myelination of axons, which comprises administering a therapeutic amount of a cPG compound, consists of stimulating astrocytes to promote remyelination. A further aspect of the present invention is a method for restoring myelination of axons in a mammal that requires remyelination due to nerve injury or disease, comprising administering a therapeutic amount of a cPG compound, where the cPG compound consists of cPG. Biologically active cPG analogs such as c(PG)3 and cGAL, biologically active cPG peptidomimetics, compounds that increase the concentration of cPG, or compounds that increase the concentration of cPG analogs are effective in restoring myelination of axons in mammals. In one aspect of the present invention, the method for restoring myelination of axons, which comprises administering a therapeutic amount of a cPG compound, consists of stimulating astrocytes to promote remyelination. A further aspect of the present invention is a method for restoring myelination of axons in a mammal that requires remyelination due to nerve injury or disease, comprising administering a therapeutic amount of a cPG compound, where the cPG compound consists of cPG. Biologically active cPG analogs such as c(PG)3 and cGAL, biologically active cPG peptidomimetics, compounds that increase the concentration of cPG, or compounds that increase the concentration of cPG analogs are effective in restoring myelination of axons in mammals. In one aspect of the present invention, the method for restoring myelination of axons, which comprises administering a therapeutic amount of a cPG compound, consists of stimulating astrocytes to promote remyelination. In another aspect of the invention, a method of restoring myelination of axons, which consists of administering a therapeutic dose of a cPG compound, is to stimulate oligodendrocytes to produce myelin. or consists of.

[0034] In yet another aspect of the invention, a method of repairing myelination of axons is further to administer a therapeutic amount of a cPG compound in combination with a compound selected from IGF-I or interferon to a mammal in need of restored myelination. In one aspect of the invention, a method of restoring myelination of axons consists of administering a therapeutic dose of a cPG compound in combination with IGF-I or interferon to stimulate astrocytes to promote remyelination. In another aspect of the invention, a method of restoring myelination of axons consists of administering a therapeutic dose of a cPG compound in combination with IGF-I or interferon to stimulate oligodendrocytes to produce myelin. In a preferred embodiment, the interferon consists of interferon β1b (Betaseron). In a further most preferred embodiment, the interferon consists of consensus interferon (Infergen® (registered trademark), interferon alphacon-1). In yet another aspect of the invention, a method of treating or preventing cell damage and death in response to injury and disease is to administer a therapeutic dose of a cPG compound, preferably an amount of cPG between about 10 μg and about 150 mg per kg of body weight of the mammal, but not limited thereto. A suitable amount for administration of cPG is, for example, preferably 1 k g of body weight of the body weight. In a more preferred embodiment, the interferon consists of consensus interferon (Infergen® (registered trademark), interferon alphacon-1). consists of.

[0035] In yet another aspect of the invention, a method of treating or preventing cell damage and death in response to injury and disease is to administer a therapeutic dose of a cPG compound, preferably an amount of cPG between about 10 μg and about 150 mg per kg of body weight of the mammal, but not limited thereto. A suitable amount for administration of cPG is, for example, preferably 1 k g of body weight per kg of body weight, preferably Between about 0.1 mg and about 100 mg per g, between about 1 mg and about 100 mg per kg of body weight, between about 5 mg and about 70 mg per kg of body weight, between about 10 mg and about 50 mg per kg of body weight, or between about 20 mg and about 40 mg per kg of body weight, but not limited to these. The dosage, route of administration, and dosing regimen of cPG may vary depending on the disease, disorder, or condition. As an example, in mild cognitive impairment, the dosage using the same or a different route of administration may be lower than in the case of Alzheimer's disease. For example, a typical dosage for a patient with mild cognitive impairment is about 10 mg to about 50 mg per day by oral administration (1 capsule of 20 mg taken 1 capsule per day or 2 capsules per day as prescribed by a physician). On the other hand, patents for more severe Alzheimer's disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. Details of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally or specifically be evaluated for a given subject or patient. Between, but not limited to these. The dosage, route of administration, and dosing regimen of cPG may vary depending on the disease, disorder, or condition. As an example, in mild cognitive impairment, the dosage using the same or a different route of administration may be lower than in the case of Alzheimer's disease. For example, a typical dosage for a patient with mild cognitive impairment is about 10 mg to about 50 mg per day by oral administration (1 capsule of 20 mg taken 1 capsule per day or 2 capsules per day as prescribed by a physician). On the other hand, patents for more severe Alzheimer's disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. Details of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally or specifically be evaluated for a given subject or patient. Between about 10 mg and about 50 mg per kg of body weight, or between about 20 mg and about 40 mg per kg of body weight, but not limited to these. The dosage, route of administration, and dosing regimen of cPG may vary depending on the disease, disorder, or condition. As an example, in mild cognitive impairment, the dosage using the same or a different route of administration may be lower than in the case of Alzheimer's disease. For example, a typical dosage for a patient with mild cognitive impairment is about 10 mg to about 50 mg per day by oral administration (1 capsule of 20 mg taken 1 capsule per day or 2 capsules per day as prescribed by a physician). On the other hand, patents for more severe Alzheimer's disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. Details of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally or specifically be evaluated for a given subject or patient. In another aspect of the present invention, a method for restoring axonal myelination in a mammal in need thereof comprises administering to the mammal a therapeutically effective amount of a cPG compound in combination with IGF-I at about 1 mg to about 100 mg per kg of body weight of the mammal, or in combination with an interferon of IGF-I at about 1.0 μg to about 10 μg per kg of body weight of the mammal. In a preferred embodiment, the interferon is interferon β. A dosage suitable for administration of cPG is, for example, preferably about 0.1 mg to about 1 g per kg of body weight. In mild cognitive impairment, the dosage using the same or a different route of administration may be lower than in the case of Alzheimer's disease. For example, a typical dosage for a patient with mild cognitive impairment is about 10 mg to about 50 mg per day by oral administration (1 capsule of 20 mg taken 1 capsule per day or 2 capsules per day as prescribed by a physician). On the other hand, patents for more severe Alzheimer's disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. Details of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally or specifically be evaluated for a given subject or patient. In mild cognitive impairment, the dosage using the same or a different route of administration may be lower than in the case of Alzheimer's disease. For example, a typical dosage for a patient with mild cognitive impairment is about 10 mg to about 50 mg per day by oral administration (1 capsule of 20 mg taken 1 capsule per day or 2 capsules per day as prescribed by a physician). On the other hand, patents for more severe Alzheimer's disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. Details of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally or specifically be evaluated for a given subject or patient. In mild cognitive impairment, the dosage using the same or a different route of administration may be lower than in the case of Alzheimer's disease. For example, a typical dosage for a patient with mild cognitive impairment is about 10 mg to about 50 mg per day by oral administration (1 capsule of 20 mg taken 1 capsule per day or 2 capsules per day as prescribed by a physician). On the other hand, patents for more severe Alzheimer's disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. Details of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally or specifically be evaluated for a given subject or patient. (1 capsule of 20 mg taken 1 capsule per day or 2 capsules per day as prescribed by a physician). On the other hand, patents for more severe Alzheimer's disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. Details of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally or specifically be evaluated for a given subject or patient. On the other hand, patents for more severe Alzheimer's disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. Details of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally or specifically be evaluated for a given subject or patient. On the other hand, patents for more severe Alzheimer's disease or severe traumatic brain injury can be administered intravenously in the range of about 50 mg to about 300 mg per day. Details of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally or specifically be evaluated for a given subject or patient. Details of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally or specifically be evaluated for a given subject or patient. Details of the dosage, route of administration, and regimen for a specific disease, disorder, or condition can generally or specifically be evaluated for a given subject or patient.

[0036] In yet another aspect of the present invention, a method for restoring axonal myelination in a mammal in need thereof comprises administering to the mammal a therapeutically effective amount of a cPG compound in combination with IGF-I at about 1 mg to about 100 mg per kg of body weight of the mammal, or in combination with an interferon of IGF-I at about 1.0 μg to about 10 μg per kg of body weight of the mammal. In yet another aspect of the present invention, a method for restoring axonal myelination in a mammal in need thereof comprises administering to the mammal a therapeutically effective amount of a cPG compound in combination with IGF-I at about 1 mg to about 100 mg per kg of body weight of the mammal, or in combination with an interferon of IGF-I at about 1.0 μg to about 10 μg per kg of body weight of the mammal. In yet another aspect of the present invention, a method for restoring axonal myelination in a mammal in need thereof comprises administering to the mammal a therapeutically effective amount of a cPG compound in combination with IGF-I at about 1 mg to about 100 mg per kg of body weight of the mammal, or in combination with an interferon of IGF-I at about 1.0 μg to about 10 μg per kg of body weight of the mammal. In yet another aspect of the present invention, a method for restoring axonal myelination in a mammal in need thereof comprises administering to the mammal a therapeutically effective amount of a cPG compound in combination with IGF-I at about 1 mg to about 100 mg per kg of body weight of the mammal, or in combination with an interferon of IGF-I at about 1.0 μg to about 10 μg per kg of body weight of the mammal. In yet another aspect of the present invention, a method for restoring axonal myelination in a mammal in need thereof comprises administering to the mammal a therapeutically effective amount of a cPG compound in combination with IGF-I at about 1 mg to about 100 mg per kg of body weight of the mammal, or in combination with an interferon of IGF-I at about 1.0 μg to about 10 μg per kg of body weight of the mammal. In a preferred embodiment, the interferon is interferon β. A dosage suitable for administration of cPG is, for example, preferably about 0.1 mg to about 1 g per kg of body weight. 00mg, 1mg to 100mg per kg of body weight, 5mg to 7mg per kg of body weight 0 mg, about 10 mg to about 50 mg per kg of body weight, or about 20 mg per kg of body weight The dose of cPG may be, but is not limited to, about 40 mg. The route and administration regime may vary depending on the disease, disorder, or condition. Cognitive impairment may be more pronounced than in Alzheimer's disease, using the same or different routes of administration. For example, the dose may be lower than that typical for patients with mild cognitive impairment. Dosages may range from about 10 mg to about 40 mg per day administered orally (as prescribed by a physician). (For more information, take one or two 20 mg capsules per day.) Patents with more severe Alzheimer's disease or severe traumatic brain injury should take approximately 50 mg per day. The dose ranges from about 100 mg to about 300 mg intravenously. The specific dosage, route of administration, and regime for each individual may be determined generally or for a specific subject or can be assessed for the patient.

[0037] and the administration of cPG compounds to treat or inhibit cell damage and death in response to injury and disease. In a further preferred embodiment of the method of administering or preventing a cPG compound to a mammalian ventricle, It is administered to the mammal via the shunt.

[0038] and the administration of cPG compounds to treat or inhibit cell damage and death in response to injury and disease. In a further preferred embodiment of the method for preventing or administering a cPG compound to the mammalian host by peripheral administration. Administered to dairy animals.

[0039] The present invention provides a method for the treatment of myelinemia by inducing the production of myelin in mature astrocytes after hypoxic-ischemic injury. A method of stimulating, comprising increasing the active concentration of cPG and / or the concentration of an analog of c PG in the mammalian CNS, provides a therapeutic method.

[0040] Most preferably, it is an effective amount of IGF-I itself increased within the mammalian CNS. This can be achieved by direct administration of a cPG compound such as cPG, c(PG)3 or cGAL or cGMeP, and this is actually preferred. However, it is not possible to rule out the administration of compounds that indirectly increase the effective amount of IGF -I (for example, prodrugs that are cleaved in the patient to release cPG). -I (for example, prodrugs that are cleaved in the patient to release cPG). -I (for example, prodrugs that are cleaved in the patient to release cPG).

[0041] The active compound (IGF-I or an analog or mimetic thereof) can be administered alone or, preferably as part of a pharmaceutical composition.

[0042] The composition can be administered directly to the CNS. The latter route of administration can include, for example, lateral cerebral vein injection, local injection, or a shunt surgically inserted into the lateral cerebral vein of the patient's brain. injection, local injection, or a shunt surgically inserted into the lateral cerebral vein of the patient's brain.

[0043] Advantageously, in the prevention or treatment of demyelinating diseases such as multiple sclerosis, administration of a cPG compound stimulates and promotes myelin production in oligodendrocytes, and supports, stimulates and promotes remyelination by mature astrocytes.

[0044] As generally described in U.S. Patent Application Publication US201002 47483A1, which is hereby incorporated by reference in its entirety, cyclic prolylglycine (``cyclic PG'' or ``cPG'') has the following structure. [Chemistry] (This structure and compound are also known as NA-831, and these terms are used interchangeably in this specification.)

[0045] The present invention includes novel diketopiperazines structurally related to cPG.

[0046] One aspect of the present invention provides a novel cyclic compound having the structural formula and substituents described below. [Chemistry] (Referred to herein as "cGAL".)

[0047] In the formula, R can be "alkyl" which refers to a saturated branched, straight-chain or cyclic hydrocarbon radical. Exemplary alkyl groups include methyl, ethyl, isopropyl, cyclopropyl, tert-butyl, cyclopropylmethyl, hexyl, and the like.

[0048] In the formula, R can be allyl which refers to a group, having the structural formula H 2 C=CH-CH 2 R, where R is the remainder of the molecule.

[0049] When R is methyl, one aspect of the present invention comprising cycloglycyl-2-alkylproline is (8as)-methyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione which is referred to as cycloglycyl-2-methylprolym or cyclogMeP or c GMeP.

[0050] [Chemistry] (This is available from a supplier of polypeptides, e.g., Bachem Americals, Inc. (Torrance, California, USA)).

[0051] Generally, c(PG)3 and cGAL can be prepared by methods well known to those of ordinary skill in the art of peptide and modified peptide synthesis as will be apparent. See, for example, Bodanzsky. Principles of Peptide Synthesis , Berlin, New York. Springer-Verlag 1993. The synthesis of the diketopiperazine compounds of the present invention may be by solid-phase synthesis as discussed in the examples or, Merrifield et al. (1963 J. Amer. Chem. Soc .:85,2149-2156. Specific examples of diketopiperazine synthesis are described in Fischer, 2 003, J. Peptide Science. 9:9-35 and the references cited therein . Those of ordinary skill in the art will have no difficulty in developing one or more suitable synthetic methods for the compounds of the present invention in view of the technology and available knowledge and this disclosure.

[0052] In the present application, the names and structures and abbreviations of the compounds are not particularly limited to this section where they are provided but various compounds can be used in all aspects of the invention included herein . For example, if cPG is described herein, all other compounds of this section (and the entire application), such as cPG compounds and related derivatives such as cGAL are not limited to the various methods of treatment described herein but are described herein It is not limited to the treatment methods of various states, and is included in that part and other descriptions. are included.

[0053] [Chemical formula] (One possible structure)

[0054] The chemical synthesis of cyclo(glycyl-L-prolyl-L-prolyl) was carried out as described in Israel Journal of Chemistry, Vol. 12, Nos. 1-2, 1974 by Charles M. Deber and Elkan R. Boutrous. and Elkan R. Boutrous, pp. 15-29 “CYCLIC Peptides VII: The Synthesis and Characterization of Cyclic Peptides with Repeating Pro-Gly Sequences”. was carried out as described therein.

[0055] Synthesis of Cyc / o(glycyl-L-prolyl-glycyl-L-prolyl) A solution of p-nitrophenyl ester hydrochloride (500 mg) dissolved in dimethylformamide (DMF) (20 mL, dried over sodium sulfate) was added dropwise with stirring to 500 mL of reagent-grade pyridine over 6 hours at room temperature. The bright yellow mixture was stirred continuously at room temperature for 48 hours. The solvent was removed by a rotary evaporator high-vacuum pump system at 45°. The residue was washed with 20 ml of acetone, which dissolved p-nitrophenol and pyridine hydrochloride but left the peptide fraction insoluble. The insoluble material and acetone were transferred to a flask and the acetone was evaporated at 45°. The material was then dissolved in the minimum amount of DMF. The white microcrystalline precipitate was Cyc / o that formed a complex with DMF. -nitrophenyl ester hydrochloride (500 mg) in while stirring over 6 hours at room temperature. The bright yellow mixture was stirred continuously at room temperature for 48 hours. The solvent was removed by a rotary evaporator high-vacuum pump system at 45°. The residue was washed with 20 ml of acetone, which dissolved p-nitrophenol and pyridine hydrochloride but left the peptide fraction insoluble. The insoluble material and acetone were transferred to a flask and the acetone was evaporated at 45°. The material was then dissolved in the minimum amount of DMF. The white microcrystalline precipitate was Cyc / o that formed a complex with DMF. (Glycyl-L-prolyl-glycyl-L-prolyl) (155 mg, yield 28%) was shown to be. By crystallization of 100 mg of this substance from methanol-ether, crystalline cyclo(Pro-Gly) without DMF 3 (55 mg) was obtained. Chemical analysis C 21 H 30 N 6 O 6 H 2 was calculated for. C, 52.49; H, 6 .71; N, 17.49. In the elemental analysis, C, 52.60; H, 6.81; N, 17.3 8 was found.

[0056] In still other embodiments, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a therapeutically effective amount of a cyclic GP or an analog thereof having the structural formula given above for treating a disease, disorder, or condition, such as Alzheimer's disease and related conditions including, but not limited to, cognitive impairment. In yet another aspect, the present invention provides a method of treating an animal having cognitive impairment, the method comprising administering to the animal an effective amount of a composition comprising a cyclic GP or an analog thereof. In a further aspect, the animal to be treated is a human. In one aspect of the invention, it is generally directed to the therapeutic treatment of neurological diseases and injuries. Explicitly, without wishing to be limited to any mechanism of action, merely proposing any mechanism of action, the inventor(s) propose that the present invention can be based, in part, on inducing neurogenesis, particularly the proliferation of neural stem cells or progenitor cells. According to one aspect of the present invention

[0057]

[0058] ​ It is said that cyclic prolylglycine and its analogs (the "cPG compounds") act as important regulators of neurogenesis that promote and induce proliferation and / or differentiation in nerve cells.

[0059] "Neurogenesis" is defined herein to mean the proliferation, differentiation, migration, or survival of nerve cells in vivo or in vitro. In a preferred embodiment of the present invention, the nerve cells can be adult, fetal, or embryonic neural stem cells or progenitor cells. Neural progenitor cells also refer to a net increase in cell number or a net increase in cell survival rate. As used herein, "N SC" will include at least all brain stem cells, all brain progenitor cells, and all brain progenitor cells.

[0060] It has been shown that an increase in the levels of cAMP and / or Ca 2+ induces the proliferation of adult neural stem cells . In some cases, this induction follows the activation of G protein -coupled receptors (GPCRs). Increasing the intracellular levels of cAMP and / or Ca 2+ via a GPCR ligand can induce the proliferation of adult neural stem cells .

[0061] G protein-coupled receptors (GPCRs), also known as G protein-linked receptors (GPLRs), constitute a large family of receptors that detect extracellular molecules, activate intracellular signaling pathways, and ultimately activate cellular responses.

[0062] Ligands that bind to and activate these receptors include photosensitive compounds, odors, pheromones They range in size from small molecules to peptides and large proteins. GPCRs in the mammalian brain are involved in the regulation of serotonin, dopamine, GABA, Binds several different neurotransmitters, including glutamate; G protein-coupled receptors It is involved in many diseases of the body and is also the target of approximately 34% of all modern medicines.

[0063] One embodiment of the present invention is, but is not limited by the proposed mechanism, and its analogs, 2+ Neurodevelopmental regulation of intracellular levels of cPG can act as a bioregulator, increasing cAMP (e.g., synthesis by increasing or decreasing the decomposition of Ca 2+ Increase It is possible to increase the flow rate (e.g., by increasing the inflow or decreasing the outflow). This has been shown chemically and biologically.

[0064] One aspect of the present invention describes a novel method for promoting the regeneration of damaged nerve tissue. The method reduces the growth rate of glial cells to promote the growth of neural tissue. and administering an effective amount of cycloprolylglycine (cPG) and its analogs to the patient. It consists of:

[0065] Neurons are closely surrounded by glial cells or astrocytes. One of the difficulties in achieving regeneration of neurons after they have been damaged or severed is the lack of glial The cells proliferate and form a barrier to regenerating neurons. Further migration of neurons to the adhesion sites is inhibited, and regeneration of structure and function ceases. The formation and progressive necrosis of stroite and connective tissue scars have an adverse effect on the functional regeneration of nerve cells. This has been observed.

[0066] Accordingly, one aspect of the present invention is a method for promoting the regeneration of damaged nerve tissue in a mammal (e.g., a human), comprising administering an effective amount of a cPG compound (cPG and its analogs) to the damaged site. This consists of administering an effective amount of a cPG compound (cPG and its analogs) to the damaged site. This consists of administering an effective amount of a cPG compound (cPG and its analogs) to the damaged site.

[0067] Some of the purposes of the experiments provided herein are to provide an enabling for methods of regenerating neurons and glial cells, or repairing damaged neurons and glial cells as claimed. Some of the purposes of the experiments provided herein are to provide an enabling for methods of regenerating neurons and glial cells, or repairing damaged neurons and glial cells as claimed. This is to provide an enabling for methods of regenerating neurons and glial cells, or repairing damaged neurons and glial cells as claimed.

[0068] One aspect of the present invention involves the use of cyclic prolylglycine (cPG) and its pharmaceutically active analogs as regulators of nerve cells for the treatment of depression and other psychological disorders. This involves the use of cyclic prolylglycine (cPG) and its pharmaceutically active analogs as regulators of nerve cells for the treatment of depression and other psychological disorders. The N-methyl-D-aspartic acid receptor (the "NMDA receptor") is a glutamate receptor and ion channel protein found in nerve cells. The NMDA receptor is a glutamate receptor and ion channel protein found in nerve cells. The NMDA receptor is one of three ionotropic glutamate receptors, the other two being the AMPA receptor and the kainate receptor. The NMDA receptor is activated when glutamate and glycine bind, and when activated, positively charged ions flow through the cell membrane. The NMDA receptor is activated when glutamate and glycine bind, and when activated, positively charged ions flow through the cell membrane. [Furukawa, Hiroyasu; Singh, Satinder K; Mancussol, Romina; Gouaux, Eric (Nov ember 2005). “Subunit arrangement and function in NMDA. Receptors”. Nature. 43 8 (7065): 185 - 92. doi: 10.1038 / nature04089. PMID 16281028.]

[0069] The NMDA receptor channel plays an important role in synaptic plasticity and synaptogenesis during the development of the central nervous system (CNS). When the NMDA receptor is overactivated, an excessive influx of Ca 2+ occurs, causing excitotoxicity and being implicated in neurodegenerative diseases. Therefore, blocking the NMDA receptor is theoretically considered useful for the treatment of such diseases.

[0070] The NMDA receptor is an ion channel protein receptor that is activated when glycine and glutamate bind. The receptor is a heteromeric complex that interacts with multiple intracellular proteins through three different subunits. It is a heteromeric complex that interacts with multiple intracellular proteins through three subunits: NR1, NR2, and NR3. NR1 has eight different subunits generated by alternative splicing from one gene. There are four different NR2 subunits (A - D) for the NR2 subunit, and NR3A and NR3B subunits have been reported. Six separate genes encode NR2 and NR3. [Loftis J. M., Janowsky A. (2003). “The N - methyl - D - aspartate re ceptor subunit NR2B: localization, functional properties, regulation, and clinic “all implications”. Pharmacol Ther. 97 (1): 55-85. doi: l 0. 016 / sO 163-7258(02)0 0302-9.]。

[0071] Agonists or allosteric modulators of the NMDA receptor, particularly channels containing the NR2B subunit, are being studied as therapeutic agents for major depressive disorders (G. Sanacora, 2008, Nature Rev. Drug Disc. 7: 426-437). The NR2B subunit is involved not only in regulating activities such as learning, memory, processing, and feeding behavior, but also in the number of human disorders. The basic structure and function related to the NMDA receptor are thought to be due to the NR2B subunit.

[0072] In addition, an allosteric and non-competitive binding site has been identified in the N-terminal domain of NR2B. The NR2 subunit functions as a binding site for glutamate, one of the major excitatory neurotransmitter receptors in the mammalian brain. [Yoshimura Y, Ohmura T, Komatsu Y (July 2003). “Two forms of synaptic plasticity with distinct dependence on ag e, experience, and NMDA receptor subtype in rat visual cortex”. The Journal of Neuroscience. 23 (16): 6557-66. PMID 12878697]。

[0073] NR2B is associated with plasticity that depends on age and visual experience in the rat neocortex. In conclusion, the increase in the NR2B / NR2A ratio directly correlates with the strength of excitatory LTP in young animals. This may contribute to the experience-dependent refinement of developing cortical circuits.

[0074] The role of the NR2B subunit of the NMDA receptor in the action of various antidepressants It has been demonstrated. [Poleszak E, Wlaz P, Szewczyk B, Wlaz A, Kasperek R, Wrobel A, N owak G (2011) A complex interaction between glycine / NMDA receptors and serotoner gic / noradrenergic antidepressants in the forced swim test in mice. J Neural Tran sm 1 18: 1535-1546].

[0075] G protein-coupled receptors (GPCRs) are G protein-linked receptors (GPLRs) Also known as phospholipase A (GPA), they detect extracellular molecules and activate intracellular signaling pathways, They constitute a large protein family of receptors that ultimately activate cellular responses. .

[0076] GPCRs in the mammalian brain are involved in the regulation of serotonin, dopamine, GABA, glutamate, and other They bind several different neurotransmitters. G protein-coupled receptors are involved in many diseases. They are involved in the development of new drugs and are the targets of approximately 34% of all modern pharmaceuticals.

[0077] One aspect of the present invention is the use of cyclic prolylamine to treat depression and other psychological disorders. Glycine (cPG) and its pharmacologic active analogues act as neuronal modulators. including. Although not explicitly limited to any mechanism, one possible mechanism is , the regulation of the intracellular levels of cAMP and / or Ca 2+ . Here, cPG increases c AMP (e.g., by increasing synthesis or decreasing degradation) and / or Ca 2+ (e.g., by increasing influx or decreasing efflux) has been shown chemically and biologically.

[0078] In addition, cyclic prolylglycine and its pharmaceutically active analogs have been shown to selectively bind to the N-terminal domain of NR2B, and may have the potential to sustain an antidepressant response in humans.

[0079] The present invention provides the technical advantages of cyclic prolylglycine ("cPG") and its pharmaceutically active analogs, which together are ligands for the NR2B receptor and are known as cPG compounds that may be useful in the treatment of various disorders of the central nervous system. Further, c PG compounds offer advantages for pharmaceutical use with respect to, for example, one or more of their mechanism of action, binding, inhibitory potency, target selectivity, solubility, safety profile, or bioavailability.

[0080] In practicing the methods of the present invention, a patient with depression is administered a combination of substances at a pharmaceutically effective dosage level using an appropriate route of administration and regimen. The substances may be administered in the form of a single dosage unit in which the active substance is combined with a suitable carrier, or the active substances may be administered in separate dosage units individually combined with suitable carriers. When administered separately Administration may be simultaneous or at selected time intervals.

[0081] Administration is preferably oral, and the carrier or carriers are selected taking this into account. This is the case, but other modes of administration of the two substances, as well as modes of mixing with the individual materials, are considered to be part of the present invention.

[0082] The dosage levels of the materials will vary depending on the particular materials used and the severity of the condition of the patient being treated. Cyclic prolylglycine (cPG) is used in an amount of about 0.1 mg to about 10 mg per kg of body weight. It is recommended to administer orally at a dosage of about 20 mg to about 80 mg per day, and in some severe cases, up to about 100 mg per day can be administered according to a physician's prescription.

[0083] The pharmaceutical compositions of the present invention are prepared using the active ingredients in association with the pharmaceutically acceptable carriers conventionally employed. The compositions of the present invention are generally intended to be administered orally to achieve an antidepressant effect. This can be in any of the dosage forms such as tablets, capsules, powders, suspensions, solutions, syrups, etc., including sustained-release formulations. As used herein and in the claims, the term dosage form refers to physically discrete units administered in single or multiple doses, each unit containing a predetermined amount of the active substance in association with the necessary diluent, carrier or vehicle. The amount of the active substance is an amount calculated to produce the desired therapeutic effect upon administration of one or more of such units.

[0084] Powders are prepared by grinding the active substance to a suitable container size and a pharmaceutically acceptable carrier of a similarly ground diluent. It is prepared by mixing with an edible carbohydrate material such as starch. Sweeteners, fragrances, preservatives, dispersants, and colorants may also be present.

[0085] The capsules are manufactured by preparing the powder mixture as described above and filling the formed gelatin sheath. Lubricants such as talc, magnesium stearate, and calcium stearate may be added to the powder mixture as adjuvants before the filing operation, and lubricants such as colloidal silica may be added to improve fluidity. Disintegrants or solubilizers may also be added to improve the usefulness of the drug when the capsules are ingested.

[0086] Tablets are prepared by preparing a powder mixture, granulating or slugging it, adding lubricants and disintegrants, and pressing it into tablets. The powder mixture is prepared by appropriately pulverizing the active substance and mixing it with a diluent or base such as starch, sucrose, kaolin, or dicalcium phosphate. The powder mixture can be moistened with a binder such as syrup, starch paste, acacia mucilage, or a solution of a cellulose-based or polymer-based material and forced through a screen to granulate it. As an alternative to granulation, the powder mixture can be passed through a tablet machine and the resulting incompletely formed slug can be crushed into granules. The granules can be lubricated by the addition of stearic acid, stearates, talc, or mineral oil to prevent adhesion to the tablet-forming die. The lubricated mixture is then compressed into tablets.

[0087] The drug can also be combined with a free-flowing inert carrier and subjected to the steps of granulation or slugging. ​​​​​​​​​​​​It can be compressed directly into tablets without going through the step. The shellac sealing coat , a coating of sugar or polymer material, and a wax polishing coat can provide a protective coating. To distinguish different unit doses, dyes can be added to these coatings.

[0088] Oral liquid preparations such as syrups and elixirs can be prepared in unit dose form so that a predetermined amount, for example, one teaspoonful contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution of sucrose while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be prepared by dispersing the drug in a non-toxic vehicle in which it is insoluble.

[0089] In one important embodiment of the present invention, pharmaceutically acceptable non-toxic acid addition salts of the active drug are used, especially for preparing solid pharmaceutical preparations. Such pharmaceutically acceptable non-toxic acid addition salts include those derived from both organic and inorganic acids, for example, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, lactic acid, succinic acid, malic acid, maleic acid, aconitic acid, phthalic acid, tartaric acid, embonic acid, enenenic acid and the like.

[0090] Although the present invention mainly contemplates oral administration, other modes are certainly not excluded. Ampoules for parenteral application can be prepared, preferably containing a water-soluble salt of the active substance and, if possible, a buffering substance in an aqueous solution.

[0091] In a liquid composition designed for oral or parenteral administration containing an active substance care must be taken to ensure the stability of the active substance.

[0092] When the active substances are administered separately, the individual compositions are prepared by the above method. These individual compositions are then administered in such a way, while maintaining their separate identities, for example, in a multilayer tablet or single capsule containing both components among a plurality of discrete particles, or they can be administered in combination in a single dosage unit.

[0093] A better understanding of the present invention will be obtained by reference to the following examples and drawings.

Brief Description of the Drawings

[0094]

Figure 1

Figure 2

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Figure 9

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Figure 15

Mode for Carrying Out the Invention

[0095] The present invention is described with reference to its specific embodiments. Other aspects of the present invention can be understood with reference to the drawings. The drawings are also provided in the above text and the attached drawings, and are further provided below, where their descriptions are provided. With reference to the drawings, it can be understood. The drawings are also provided in the above text and the attached drawings, and are further provided below, where their descriptions are provided. And are further provided below, where their descriptions are provided.

[0096] The following examples are given for illustrative purposes only and should not be taken as limiting the scope of the present invention. Should not be taken as limiting the scope of the present invention.

[0097] The process by which IGF1 is metabolized into the tripeptide GPE and des IGF has surprisingly been found to be only a part of it. Has been found to be only a part of it.

[0098] The cis isomer of GPE further decomposes to form cyclic prolylglycine and glutamic acid. It can be done. This is shown in Figure 1.

[0099] The cyclic PG structure is small enough to cross the blood-brain barrier.

[0100] Also, as shown in Figure 2, Mg 2+ , Ca 2+ , Co 2+ It is possible to provide ligands for binding metal ions such as, and it has a molecular structure that can function as a chelating agent.

[0101] The possible role of cPG as an agent is further supported by the companion degradation product, glutamate.

[0102] Glutamate is known to be associated with brain diseases. (Johnston, G.A.R. in Roberts P.J. et al Editors, Glutamate: Transmitter in the Central Nervous System , John Wiley & Sons, 1981, pp.77-87).

[0103] As used herein, a cPG compound is a compound having a biological activity similar or identical to that of cPG, and the cPG compound consists of cPG, a biologically active cPG analog, a biologically active cPG mimetic, and a compound that increases the concentration of cPG and cPG analogs in mammals. CPG compounds include cPG molecules such as the truncated portion of the IGF-I compound, and other chemical and biological analogs and mimetics.

[0104] As used herein, a "cPG analog" refers to an mGluR receptor in the CNS Effectively bind to the body and can promote an equivalent neuroprotective effect on CNS neurons refers to any analog of cPG, a naturally occurring cPG analog, or a variant thereof. Examples of CPG analogs include c(PG)3 and cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline. are included.

[0105] The term "cPG molecule" includes peptide fragments and truncated portions of longer IGF-I compounds, as well as other chemical and biological analogs and mimetics, and cPG compounds can be used for the treatment of mammals suffering from neutral injuries or diseases. In particular, cPG compounds can be used for the treatment of human patients suffering from nerve damage or diseases. More generally, the compositions and methods of the present invention are found to be useful for the treatment of mammals such as human patients suffering from nerve damage or potential apoptosis and / or necrosis due to injuries or diseases such as septic shock, ischemia. It has also been found that the administration of cytokines, overexpression of cytokines, ulcers, gastritis, ulcerative colitis, Crohn's disease, diabetes, rheumatoid arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, cirrhosis, transplant rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis, glomerulonephritis, uveitis, glaucoma, blepharitis, cardion, allergic eye diseases, corneal ulcers, keratitis, cataracts, retinal disorders, age-related macular degeneration, optic neuritis, ileus. Inflammation due to overproduction of inflammatory cytokines, hemorrhagic shock, anaphylactic shock, burns, overproduction of inflammatory cytokines caused by bacteria, viruses, fungi, parasites leading to ​​​​​infectious diseases, hemodialysis, chronic fatigue syndrome, stroke cancer, associated with overproduction of inflammatory cytokines cardiovascular diseases, heart diseases, cardiopulmonary bypass, ischemia-reperfusion injury, overproduction of inflammatory cytokines ischemia-reperfusion associated with, toxic shock syndrome, adult respiratory distress syndrome cachexia, myocarditis, auto immune diseases, eczema, psoriasis, heart failure, dermatitis, hives, cerebral ischemia, systemic lupus erythematosus, AIDS, AIDS dementia, chronic neurodegenerative diseases, chronic pain, priapism, cystic fibrosis, amyotrophic lateral sclerosis. Schizophrenia, depression, premenstrual syndrome, anxiety, addiction, migraine, han tington's disease, epilepsy, gastrointestinal motility disorders, obesity, dysphagia, neuroblastoma, malaria, blood is, myelofibrosis, lung injury, graft-versus-host disease head trauma, central nervous system trauma, hepatitis, renal failure, C type chronic hepatitis, paraquat poisoning, transplant rejection and preservation, enhanced reproductive ability, bacterial translocation, circulatory sho ck, traumatic shock, hemodialysis, hangover, and combinations of two or more of these.

[0106] Furthermore, cPG and its analogs, such as c(PG)3 and cGMeP, are suffering from white matter injury (insult) as a result of acute brain injury such as perinatal low oxygen-ischemic injury, and can be used to treat mammals suffering therefrom, but are not limited thereto. Or, neurodegenerative diseases such as chronic nerve injury or multiple sclerosis, or other demyelinating diseases including inflammatory involvement such as acute disseminated encephalomyelitis, optic neuritis, polymyositis, Devic's disease, leukodystrophy, etc. and disorders, non-inflammatory involvement, progressive multifocal leukoencephalopathy, central pontine myelinolysis. Patients suffering from such diseases and injuries can obtain great benefits through a treatment protocol that can initiate remyelination.

[0107] The present invention is applicable to the induction of myelin production following injury in the form of trauma, toxin exposure, asphyxia or hypoxia-ischemia, and is applicable to the treatment or prevention of apoptosis in response to injury or disease in the form of cancer, viral infections, autoimmune diseases, neurological diseases and injuries, cardiovascular diseases. Treatment with cPG or analogs thereof, including but not limited to c(PG)3 and cGAL, can be carried out before injury (not only to modify), for example, before elective surgery. Examples of related elective procedures include neurosurgery where retraction of brain lobes may lead to cerebral edema, or cardiac procedures such as valve replacement where a small unavoidable embolism is said to lead to a detectable impairment of brain function in some 75% of cases.

[0108] cPG can act as anti-necrotic and anti-apoptotic during the process of cell death. Its anti-apoptotic activity and anti-necrotic activity in vivo can be measured by cell count. cPG can also be measured in vitro (Gudasheva T.A. et al. FEBS Letters, Vol. 391, Issues 1-2, 5 August 1996, pp. 149-152). CNS injury can be clinically measured, for example, by the degree of permanent neurological deficit cognitive function and / or the tendency to seizure disorder. (Rakic L.J et al, in Rakic L.J et al Peptide and Amino Acid Transport Mechanisms in The Central Nervous System, 1988, The MacMillan Press

[0109] Pharmacology and Efficacy ​ Ltd. Press Ltd. (London) pp.167-181)

[0110] Pharmaceutical Composition and Its Administration cGP itself, as part of the present invention, can be used to prevent or treat cell damage and programmed death, as well as the induction of murin production. Usually, this is done by direct administration of cGP to the patient. If desired, a combination of cPG compounds and their analogs can be administered in a pharmaceutically acceptable composition.

[0111] One skilled in the art will understand that the applicant does not intend to exclude other forms of administration of cPG and its analogs. By way of example, administering a prodrug of cPG consisting of cPG and a carrier can increase the effective amount of cPG in the CNS, and the cPG and the carrier are linked by a linkage that is readily cleaved or digested within the patient. Any suitable linker that is cleaved or digested to release cPG after administration can be employed. after administration can be employed.

[0112] Furthermore, it is envisioned that the cPG level can be increased via an implant containing cell lines capable of expressing active cPG within the patient's CNS.

[0113] Prodrugs of cPG and its analogs can also be administered. In that case, the prodrug is metabolized or otherwise changed within the subject to form cPG. CPG and its analogs, for example, c(PG)3 and cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or cyclic glycyl-2-methylprolym, etc. Examples include, but are not limited to, administration as part of a pharmaceutical or pharmaceutical preparation. This includes combining cPG with a pharmaceutically suitable carrier, adjuvant or excipient. The choice of carrier, adjuvant or excipient will, of course, ordinarily depend on the route of administration employed.

[0114] The route of administration can be varied and can be any suitable route of administration. An advantage of cPG is that it can be administered peripherally. That is, it is not necessary to administer directly to the patient's CNS in order to be effective in the CNS.

[0115] Any peripheral route known in the art can be employed. These include, for example, injection into the peripheral circulation, subcutaneous injection, intraorbital injection, ophthalmic injection, intrathecal injection, intravesical injection, topical injection, infusion (e.g., using a mini-pump such as a controlled release device or an osmotic pump or a skin patch), transplantation, aerosol, inhalation, scarification, intraperitoneal injection, intracapsular injection, intramuscular injection, intranasal injection, oral injection, buccal injection, pulmonary injection, rectal injection or vaginal injection, but are not limited to these. The compositions of the present invention can be formulated for parenteral administration to humans or other mammals in a therapeutically effective amount (e.g., an amount that eliminates or alleviates the patient's condition) for the treatment of the above-described neurological diseases.

[0116] Preferred routes of administration include, but are not limited to, subcutaneous injection (e.g., dissolved in 0.9% sodium chloride) or oral administration (in capsules).

[0117] In some cases, it will also be understood that there are situations where it is desirable to administer the cPG compound directly to the patient's CNS. Again, this can be achieved by any suitable direct administration route. Examples include administration by lateral cerebral vein injection or administration via a shunt surgically inserted into the lateral cerebral vein of the patient's brain. Here too, this can be achieved by any suitable direct administration route. Examples include administration by lateral cerebral vein injection or administration via a shunt surgically inserted into the lateral cerebral vein of the patient's brain.

[0118] Calculating the effective amount of the cPG compound to be administered is within the scope of the ordinary skill in the art and will be routine for those skilled in the art. Needless to say, the ultimately administered amount depends on the administration route and the nature of the neuropathy or condition to be treated. Preferably, the cPG compound is administered at a dose of between about 1 μg and about 100 mg per kg of body weight when the dose is administered centrally. Suitable doses for cPG administration are, for example, between about 0.1 mg and about 10 mg per kilogram of body weight, or between about 1 mg and about 5 mg per kilogram of body weight. Calculating the effective amount of the cPG compound to be administered is within the scope of the ordinary skill in the art and will be routine for those skilled in the art. Needless to say, the ultimately administered amount depends on the administration route and the nature of the neuropathy or condition to be treated. Preferably, the cPG compound is administered at a dose of between about 1 μg and about 100 mg per kg of body weight when the dose is administered centrally. Suitable doses for cPG administration are, for example, between about 0.1 mg and about 10 mg per kilogram of body weight, or between about 1 mg and about 5 mg per kilogram of body weight. Suitable doses for cPG administration are, for example, between about 0.1 mg and about 10 mg per kilogram of body weight, or between about 1 mg and about 5 mg per kilogram of body weight.

[0119] For inclusion in a pharmaceutical, the cPG compound can be obtained from a suitable commercial source such as Bachem AG of Bubendorf, Switzerland. Alternatively, cPG can be synthesized by the stepwise solid-phase synthesis method of Merrifield et al. (1963 J. Amer. Chem. Soc.: 85, 2149-2156). Alternative syntheses can involve the use of a commercially available peptide synthesizer such as the Applied Biosystems model 430A. For inclusion in a pharmaceutical, the cPG compound can be obtained from a suitable commercial source such as Bachem AG of Bubendorf, Switzerland. Alternatively, cPG can be synthesized by the stepwise solid-phase synthesis method of Merrifield et al. (1963 J. Amer. Chem. Soc.: 85, 2149-2156). Alternative syntheses can involve the use of a commercially available peptide synthesizer such as the Applied Biosystems model 430A.

[0120] cGAL can be prepared by methods well known to those skilled in the synthesis of peptides and analogs. For example, according to "Principles of Peptide Synthesis" by E. G. Creighton. cGAL can be prepared by methods well known to those skilled in the synthesis of peptides and analogs. ​​​Published by Verlag in 1993.

[0121] C(PG)3 can be prepared by the method published in Israel Journal of Chemistry, Vol. 12, Nos. 1-2, 1974, pp. 15-29, “CYCLIC Peptides V II: The Synthesis and Characterization of Cyclic Peptides with Repeating Pro-Gly Sequences” by Charles M. Deber and Elkan R. Blout. pu can be prepared by the method published in Israel Journal of Chemistry, Vol. 12, Nos. 1-2, 1974, pp. 15-29, “CYCLIC Peptides V

[0122] Generally speaking, the total pharmaceutically effective amount of the cPG compound administered parenterally per single dose will be in the range measurable by the dose-response curve. One can administer increasing amounts of the cPG compound to a patient and confirm the patient's serum level for cPG. The amount of the cPG compound to be employed can be calculated on a molar basis based on these serum levels of cPG. Specifically, one method for determining the appropriate dosage of a compound involves measuring the cPG level in a biological fluid such as a body fluid or blood plasma. Measurement of such levels can be performed by any means including RIA and ELISA. After measuring the cPG level, the fluid is contacted with the compound using a single dose or multiple doses. After this contacting step, the cPG level in the fluid is re-measured. If the cPG level in the fluid has decreased by an amount sufficient to provide the desired efficacy at which the molecule should be administered, the dosage of the molecule can be adjusted to provide maximum efficacy. This method can be practiced in vitro or in vivo. The amount of the cPG compound to be employed can be calculated on a molar basis based on these serum levels of cPG.

[0123] Specifically, one method for determining the appropriate dosage of a compound involves measuring the cPG level in a biological fluid such as a body fluid or blood plasma. Measurement of such levels can be performed by any means including RIA and ELISA. After measuring the cPG level, the fluid is contacted with the compound using a single dose or multiple doses. After this contacting step, the cPG level in the fluid is re-measured. If the cPG level in the fluid has decreased by an amount sufficient to provide the desired efficacy at which the molecule should be administered, the dosage of the molecule can be adjusted to provide maximum efficacy. This method can be practiced in vitro or in vivo. If the cPG level in the fluid has decreased by an amount sufficient to provide the desired efficacy at which the molecule should be administered, the dosage of the molecule can be adjusted to provide maximum efficacy. This method can be practiced in vitro or in vivo. Preferably, the method is carried out in vivo, i.e., in a mammal. Fluid is extracted from the subject and cPG levels are measured, after which a compound of the present invention is administered either at a single dose or Multiple doses are administered to the mammal (i.e., the contacting step is performed by administering to the mammal). (This is accomplished by measuring the cPG levels again from the fluid extracted from the mammal. .

[0124] The compounds of the present invention may also be suitably administered by sustained release compositions. Suitable examples of compositions include shaped articles, such as films, or semi-solid articles in the form of microcapsules. Permeable polymer matrices are available. Sustained release matrices include polylactide (US Patent No. 3,773,919; EP58,481), L-glutamic acid and γ-ethyl copolymers of 2-hydroxy-L-glutamic acid (Sidman et al., 1983), poly(2-hydroxy diethyl methacrylate) (Langer et al., 1981), ethylene vinyl acetate ( Langer et al., supra), or poly-D-(-)-3-hydroxybutyrate (EP133, No. 988. Sustained release compositions also include compounds entrapped in liposomes. Liposomes containing the compound are prepared by methods known per se. DE Patent 3,218 ,121; Epstein et al., 1985; Hwang et al., 1980; EP Patent 52,3 No. 22; EP Patent No. 36,676; EP Patent No. 88,046; EP No. 143,949; E P142,641; Japanese Patent Application No. 83-118008; U.S. Patent No. 4,485, 045 and 4,485,045; and EP 102,324. The lipid content of the mixture is about 30 mol percent or more cholesterol, and the selected The ratio is adjusted for the most effective treatment and is of a small (from about 200 angstroms to about 800 angstroms at most) single-membrane type.

[0125] PEGylated peptides with longer lifetimes can also be employed, for example, based on the conjugation techniques described in WO95 / 32003 published on November 30, 1995. It is possible.

[0126] When parenteral administration is preferred, the compound is generally in a unit-dose injectable form (solution, suspension, or emulsion), each at the desired concentration, and is formulated by mixing with a pharmaceutically or parenterally acceptable carrier, i.e., a carrier that is non-toxic to the recipient at the doses and concentrations employed and is compatible with the other ingredients of

[0127] the formulation. Generally, the formulation is prepared by contacting the compound with a liquid carrier or a divided solid carrier or both. Then, it is shaped into the desired formulation as necessary. Preferably, the carrier is a parenteral carrier, more preferably a solution isotonic with the recipient's blood. Examples of such carrier vehicles include water, physiological saline, Ringer's solution, buffer solutions, glucose solutions, etc. Also, non-aqueous vehicles such as

[0128] fixed oils and ethyl oleate may be used. The carrier may further contain additives such as substances that enhance isotonicity and chemical stability. Such substances are non-toxic to the recipient at the doses and Antioxidants such as ascorbic acid; low molecular weight (less than about 10 residues) polypeptides, e.g., polyarginine or tripeptides; proteins such as serum albumin, gelatin, or immunoglobulins ; proteins such as hydrophosphates; at the doses and concentrations used are non-toxic to the recipient. Polyarginine or tripeptides; proteins such as serum albumin, gel atin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone ; glycine; amino acids such as glutamic acid, aspartic acid, histidine, or arginine. Monosaccharides, disaccharides, and other carbohydrates such as cellulose or its derivatives, glucose, mannose, trehalose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; nonionic surfactants such as polysorbate, poloxamer, or polyethylene glycol (PEG); and / or neutral salts such as, e.g., the following. Na Cl, KCl, MgCl ; CaCl 2 ; etc. 2

[0129] cPG compounds are typically formulated in such vehicles at a pH between about 5.5 and about 8.0. Typical adjuvants that may be incorporated into tablets, capsules, etc. include binders such as acacia, corn starch, gelatin; excipients such as microcrystalline cellulose; disintegrants such as corn starch and alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose and lactose; flavors such as peppermint, wintergreen, cherry, etc. When the dosage form is a capsule, in addition to the above materials, a liquid carrier such as an oilIt may also contain. Additionally, various types of materials may be used as coating agents and may be used as modifiers of the physical form of the dosage unit. Syrup or elixir may contain an active compound, a sweetening agent such as sucrose, a preservative such as propylparaben, a coloring agent, and a flavor such as cherry. A sterile composition for injection can be formulated according to conventional pharmaceutical practices. For example, dissolution or suspension of the active compound in a vehicle such as water or a natural vegetable oil such as sesame oil, peanut oil, or cottonseed oil , or a synthetic fatty vehicle such as ethyl oleate may be desired. Buffering agents, preservatives, antioxidants, etc. can be incorporated according to accepted pharmaceutical practices. The compounds used for therapeutic administration must be sterile. Sterility can be easily achieved by filtration through a sterile filtration membrane (e.g., a 0.2 micron membrane). The therapeutic composition is generally placed in a container having a sterile access port, such as an intravenous solution bag or a vial having a stopper pierceable by a hypodermic needle

[0130] . The compounds are usually stored in unit dose or multi-dose containers, such as sealed glass ampoules or vials, as aqueous solutions or lyophilized formulations for reconstitution. As an example of a lyophilized formulation, a 5 mL sterile filtered 1% (w / v) aqueous solution of the compound is filled into a 10 mL vial and the resulting mixture is lyophilized. Infusions are prepared by reconstituting the lyophilized compound with bacteriostatic injection water.

[0131] The compounds are usually stored in unit dose or multi-dose containers, such as sealed glass ampoules or vials, as aqueous solutions or lyophilized formulations for reconstitution. As an example of a lyophilized formulation, a 5 mL sterile filtered 1% (w / v) aqueous solution of the compound is filled into a 10 mL vial and the resulting mixture is lyophilized. Infusions are prepared by reconstituting the lyophilized compound with bacteriostatic injection water.

[0132] The cPG compounds herein, whether increasing total cPG in the blood or enhancing the effect of cPG Combination therapies with one or more other suitable reagents that enhance are also contemplated. These reagents generally enable the release of cPG produced by the cPG compounds of the present specification.

[0133] Furthermore, in one aspect of the invention, for treating a mammal, when the cPG compound is a peptide, using gene therapy with a nucleic acid encoding the cPG compound is included. Generally, gene therapy is used to increase (or overexpress) cPG levels in a mammal. Nucleic acids encoding cPG peptides can be used for this purpose. Once the amino acid sequence is known, multiple nucleic acid molecules can be generated using the degeneracy of the genetic code and one can be selected for use in gene therapy.

[0134] There are two main approaches for introducing nucleic acids (optionally contained in a vector) into a patient's cells for gene therapy purposes: in vivo and ex vivo. For in vivo introduction, the nucleic acid is injected directly into the patient, usually at the site that requires the cPG compound. For ex vivo therapy, the patient's cells are removed, the nucleic acid is introduced into these isolated cells, and the modified cells are administered to the patient, either directly or encapsulated, for example, within a porous membrane that is transplanted into the patient. See, for example, U.S. Pat. Nos. 4,892,538 and 5,283,187.

[0135] There are various techniques available for introducing nucleic acids into germ cells. The techniques vary depending on whether the nucleic acid is introduced into cultured cells in vitro or introduced in vivo into the cells of the intended host. Suitable for introducing nucleic acids into mammalian cells in vitro Techniques include liposomes, electroporation, microinjection, and cells. fusion, DEAE-dextran, calcium phosphate precipitation, etc. A commonly used vector for ex vivo delivery is a retrovirus.

[0136] The currently preferred in vivo nucleic acid transfer technique is the use of viral vectors (e.g., adenovirus, Transfection with herpes simplex virus type I or adeno-associated virus and lipid-based systems (useful lipids for lipid-mediated transfer of genes are, for example, DO In some circumstances, the nucleic acid source may include , agents that target target cells, e.g., agents specific for cell surface membrane proteins or target cells. It may be desirable to provide an antibody, a ligand for a receptor on a target cell, etc. When using endocytosis-related proteins, proteins that bind to cell surface membrane proteins are used. To target and / or enhance uptake of proteins, for example, transfectants may be introduced into specific cell types. Selected capsid proteins or fragments thereof, proteins that undergo internalization during cycling These include the use of targeted antibodies to target the subcellular localization and proteins that increase intracellular half-life. The technique of receptor-mediated endocytosis is described, for example, in Wu et al., 1987; Currently known gene markings and For a review of gene therapy protocols, see Anderson 1992. See also WO93 / 25673 and the references cited therein.

[0137] Kits are also contemplated by the present invention. A typical kit includes a pharma- ceutically acceptable buffer solution. A container, preferably a vial, containing a cPG compound formulation consisting of the cPG compound therein, and instructions such as a product insert or label that instructs the user to use the formulation. It will consist of.

[0138] Certain aspects of the invention include the use of cPG in the treatment of age - associated cognitive impairment with neurodegenerative conditions, and also in situations where cognitive impairment without obvious neurodegeneration is found.

[0139] Such other agents can be selected from the non - limiting group consisting of, for example, growth factors and related derivatives such as insulin - like growth factor - I (IGF - I), insulin - like growth factor - II (IGF - II), growth hormone, nerve growth factor, growth hormone binding protein, and / or IGF binding protein.

[0140] Application to Treatment The compositions and methods of the invention find use in the treatment of animals such as human patients suffering from cognitive impairment. More generally, the compositions and methods of the invention are used in the treatment of memory impairment, mild cognitive impairment, Alzheimer's disease, Lewy body disease, frontotemporal lobar degeneration, vascular dementia, dementia including that caused by cerebral atrophy associated with head trauma, Huntington's disease, Parkinson's disease, and also in the treatment of mammals such as human patients and subjects suffering from Down syndrome, but are not limited thereto.

[0141] Pharmaceutical Composition and Its Administration The cyclic PG compound can be administered as part of a medicament or pharmaceutical formulation. This involves combining the compounds of the invention with any pharmaceutically suitable carrier, adjuvant or excipient. It can include. The selection of the carrier, adjuvant or excipient usually depends, of course, on the route of administration employed.

[0142] Generally, the compounds of the present invention are administered in a therapeutically effective amount, either alone or in combination with other conventional therapeutic agents for the disease being treated, by any of the usual modes known in the art. The therapeutically effective amount can vary depending on the disease or injury being treated, its severity, the age and relative health of the animal being treated, the potency of the compound(s), and other factors. The therapeutically effective amount of cyclic prolylglycine can range from 0.01 to 10 milligrams per kilogram of the animal's mass, and lower doses such as 0.01 to 0.1 mg / kg are suitable for administration via the cerebrospinal fluid, for example, by intracerebral venous administration, while higher doses such as 0.1 to 10 mg / kg are suitable for administration by methods such as oral administration, systemic administration (e.g., transdermal administration), or parenteral administration (e.g.,

[0143] intravenous administration). Those skilled in the art of ordinary skill can determine the therapeutically effective amount of the compounds of the present invention for a given disease or injury without undue experimentation, considering their skill and this disclosure. Cyclic prolylglycine and cPG compounds can be administered orally or This can include, but is not limited to, routes.

[0144] For the convenience of the patient, the cyclic prolylglycine compounds and cPG compounds of the present invention are administered orally. The amount of the compound of the present invention in the composition may vary depending on the type of composition, the amount of the unit dose, and the amount of the compound. Size, type of excipient, and other factors well known to those of ordinary skill in the art. Generally, the final composition is for a typical adult with a body weight of 50-120 kg. For adults, 5 mg to 50 mg of cPG or 1× 10 -5 %~3×10 -4 It may be composed of % by weight (%w).

[0145] Other convenient routes of administration are subcutaneous injection or intravenous infusion (e.g., active cPG is 0.9% Dissolved in a physiologically compatible carrier such as sodium chloride or dextrose ), or directly into the CNS. Using a stereotaxic device and a precise map of the animal's CNS, The compound can then be injected directly at the site of nerve injury.

[0146] An effective amount of a compound in the central nervous system is determined by administering to the patient a prodrug comprising a compound of the present invention and a carrier. The increase in activity can be achieved by administration of a compound in the form, where the carrier is cleaved or is attached to the compound of the invention by a digestible linkage. Any suitable linker may be employed.

[0147] However, the applicants have no intention of excluding other forms of administration.

[0148] In other embodiments of the invention, the restoration of neurological function in an animal is selected from, for example, It can include administering a therapeutic amount of cyclic prolylglycine or a cPG compound in combination with another neuroprotective agent. Growth factors and related derivatives (insulin-like growth factor -I (IGF-I), insulin-like growth factor-II (IGF-II), transforming growth factor-β1, activin, growth hormone, nerve growth factor, growth hormone-binding protein, IGF-binding protein, keratinocyte growth factor, androgen-induced growth factor. Additional members of the FGF family include, for example, fibroblast growth factor homolog-1 (FHF -1), FHF-2, FHF-3 and FHF-4, keratinocyte growth factor 2, brain-derived growth factor, neurotrophin 3, and neurotrophin 4. Other embodiments of neuroprotective therapeutic agents are crometazole, kynurenic acid, semax, tacrolimus; glutamate agonists such as NPS1506, GV1505260, MK-801, GV150526; AMPA ari such as 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f ) quinoxaline (NBQX). Anti-MAdCAM-1 mAb MECA-367 (ATCC accession number HB-9478) and the like. )

[0149] The cyclic prolylglycine compound can preferably be administered by a sustained-release composition. Suitable examples of sustained-release compositions include, for example, shaped articles, films, or microcapsules in the form of a semipermeable polymeric matrix.

[0150] For parenteral administration, in one embodiment, the cyclic prolylglycine or cPG compound is generally in an injectable form of unit dose (solution, suspension, or an emulsion), pharmaceutically or parenterally acceptable carriers, for example, those employed in the amounts and concentrations that are non-toxic to the recipient and compatible with the other components of the formulation are formulated by mixing with a carrier.

[0151] Generally, the cyclic prolylglycine or cPG compound is brought into intimate contact with a liquid carrier or a subdivided solid carrier or both to prepare the formulation. Then, if desired, it is shaped into the desired formulation. Preferably, the carrier is a parenteral carrier and the vehicle is preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, physiological saline, Ringer's solution, buffer solutions, glucose solutions, etc. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein.

[0152] The cyclic prolylglycine or cPG compound is typically incorporated into such vehicles at a pH of from 4.5 to about 8. It will be understood that the specific use of the excipients, carriers, or stabilizers described above may result in the formation of salts of the compound. The final preparation may be a stable liquid or a lyophilized solid.

[0153] The formulation of the cyclic prolylglycine or cPG compound in the pharmaceutical composition may also contain adjuvants. Representative adjuvants that can be incorporated into tablets, capsules, etc. include binders such as acacia, corn starch, gelatin; excipients such as microcrystalline cellulose; disintegrants such as corn starch and alginic acid; lubricants such as magnesium stearate; sweeteners such as sucrose and lactose; flavors such as peppermint, wintergreen, cherry, etc. Examples include spices. When the dosage form is a tablet, the cyclic prolylglycine or cPG compound and composition can include a binder and optionally a smooth coating. When the dosage form is a capsule, in addition to the above materials, it may also contain a liquid carrier such as a fatty oil. Various other types of materials may be used as coatings or as modifiers of the physical form of the dosage form. Syrups or elixirs may contain the active compound, a sweetener such as sucrose, a preservative such as propylparaben, a coloring agent, and a flavor such as cherry. The sterile composition for injection can be formulated according to conventional pharmaceutical practices. For example, dissolution or suspension of the active compound in a vehicle such as water or a naturally occurring vegetable oil such as sesame oil, peanut oil, or cottonseed oil, or a synthetic fatty vehicle such as ethyl oleate may be desired. For injection, intravenous administration and other invasive routes of administration, the cyclic prolylglycine or cPG compound is preferably sterile. Sterilization can be achieved by any method known in the art, for example, by filtration through a sterile filtration membrane (e.g., a 0.2 micron membrane). The therapeutic composition is generally placed in a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a subcutaneous injection needle. The first aspect of the present invention includes a method of regenerating the loss of neurons and glial cells as a result of injury or damage due to a disease, and includes the following steps. a) The regenerated neurons

[0154]

[0155] Preferred Embodiment of the Present Invention ​​​​​​​​​​​​​​​and providing a subject in need of loss of neurons and glial cells, and b) administering to said subject an amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycy l-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof ) that is effective to regenerate new neurons and glia, steps, a method comprising: wherein in said subject, neurons are regenerated and loss of glial cells is regenerated; wherein further, said cPG compound functions as a neurogenic agent in the central nervous system; and neurons and loss of glial cells as a result of injury or damage due to disease are regenerated, a further method.

[0156] Neuronal regeneration generally refers to the regeneration or repair of neurons, glia, axons, myelin, or synapses. Researchers are developing new tools to effectively control the process of nerve injury and degeneration, enhance the natural repair ability, and create a microenvironment that enhances the effectiveness of other regeneration strategies such as nerve cell replacement and nerve rehabilitation. Experiments 7 and Experiment 8 describes methods for regenerating nerve cells and glial cells lost as a result of injury or disease.

[0157] Another aspect of the invention includes the case where the administration is in the form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

[0158] A further aspect of the invention includes that the effective amount of the cPG compound is from about 1 μg to about 100 mg per kg of body weight.

[0159] ​​​​​​ A further aspect of the present invention includes the case where administration is carried out in combination with artificial cerebrospinal fluid.

[0160] Another aspect of the present invention includes the case where administration is intravenous administration.

[0161] A further aspect of the present invention includes the case where administration is combined with a neuroprotective agent, insulin-like growth factor-II (IGF -I) or insulin-like growth factor-III (IGF-II). Including.

[0162] A further aspect of the present invention where administration is combined with an anti-inflammatory agent and an anti-integrin α4 subunit reagent. Aspect.

[0163] A second aspect of the present invention includes a method for repairing the loss of neurons and glial cells damaged as a result of injury or disease, including the following steps. a) Providing a subject in need of regeneration of the neuron and glial cell loss; and b) Administering to the subject cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or, collectively referred to as cPG compounds or a combination thereof) in an amount effective to regenerate new neurons and glia; including. Here, the neurons are regenerated and the loss of the glial cells is regenerated in the subject; where the cPG functions as a neurorescue agent in the central nervous system, and further here, the loss of neurons and glial cells damaged as a result of injury or disease is repaired, method. Including the following steps. a) Providing a subject in need of regeneration of the neuron and glial cell loss; and b) Administering to the subject cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or, collectively referred to as cPG compounds or a combination thereof) in an amount effective to regenerate new neurons and glia; including. Here, the neurons are regenerated and the loss of the glial cells is regenerated in the subject; where the cPG functions as a neurorescue agent in the central nervous system, and further here, the loss of neurons and glial cells damaged as a result of injury or disease is repaired, method. Including the following steps. a) Providing a subject in need of regeneration of the neuron and glial cell loss; and b) Administering to the subject cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or, collectively referred to as cPG compounds or a combination thereof) in an amount effective to regenerate new neurons and glia; including. Here, the neurons are regenerated and the loss of the glial cells is regenerated in the subject; where the cPG functions as a neurorescue agent in the central nervous system, and further here, the loss of neurons and glial cells damaged as a result of injury or disease is repaired, method. Including the following steps. a) Providing a subject in need of regeneration of the neuron and glial cell loss; and b) Administering to the subject cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or, collectively referred to as cPG compounds or a combination thereof) in an amount effective to regenerate new neurons and glia; including. Here, the neurons are regenerated and the loss of the glial cells is regenerated in the subject; where the cPG functions as a neurorescue agent in the central nervous system, and further here, the loss of neurons and glial cells damaged as a result of injury or disease is repaired, method. Including the following steps. a) Providing a subject in need of regeneration of the neuron and glial cell loss; and b) Administering to the subject cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or, collectively referred to as cPG compounds or a combination thereof) in an amount effective to regenerate new neurons and glia; including. Here, the neurons are regenerated and the loss of the glial cells is regenerated in the subject; where the cPG functions as a neurorescue agent in the central nervous system, and further here, the loss of neurons and glial cells damaged as a result of injury or disease is repaired, method. Including the following steps. a) Providing a subject in need of regeneration of the neuron and glial cell loss; and b) Administering to the subject cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or, collectively referred to as cPG compounds or a combination thereof) in an amount effective to regenerate new neurons and glia; including. Here, the neurons are regenerated and the loss of the glial cells is regenerated in the subject; where the cPG functions as a neurorescue agent in the central nervous system, and further here, the loss of neurons and glial cells damaged as a result of injury or disease is repaired, method. Cyclic Glycyl-2-Methylproline (cPMeG) Including the following steps. a) Providing a subject in need of regeneration of the neuron and glial cell loss; and b) Administering to the subject cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or, collectively referred to as cPG compounds or a combination thereof) in an amount effective to regenerate new neurons and glia; including. Here, the neurons are regenerated and the loss of the glial cells is regenerated in the subject; where the cPG functions as a neurorescue agent in the central nervous system, and further here, the loss of neurons and glial cells damaged as a result of injury or disease is repaired, method. Including the following steps. a) Providing a subject in need of regeneration of the neuron and glial cell loss; and b) Administering to the subject cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or, collectively referred to as cPG compounds or a combination thereof) in an amount effective to regenerate new neurons and glia; including. Here, the neurons are regenerated and the loss of the glial cells is regenerated in the subject; where the cPG functions as a neurorescue agent in the central nervous system, and further here, the loss of neurons and glial cells damaged as a result of injury or disease is repaired, method. Including the following steps. a) Providing a subject in need of regeneration of the neuron and glial cell loss; and b) Administering to the subject cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or, collectively referred to as cPG compounds or a combination thereof) in an amount effective to regenerate new neurons and glia; including. Here, the neurons are regenerated and the loss of the glial cells is regenerated in the subject; where the cPG functions as a neurorescue agent in the central nervous system, and further here, the loss of neurons and glial cells damaged as a result of injury or disease is repaired, method. Including the following steps. a) Providing a subject in need of regeneration of the neuron and glial cell loss; and b) Administering to the subject cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or, collectively referred to as cPG compounds or a combination thereof) in an amount effective to regenerate new neurons and glia; including. Here, the neurons are regenerated and the loss of the glial cells is regenerated in the subject; where the cPG functions as a neurorescue agent in the central nervous system, and further here, the loss of neurons and glial cells damaged as a result of injury or disease is repaired, method. Including the following steps. a) Providing a subject in need of regeneration of the neuron and glial cell loss; and b) Administering to the subject cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or, collectively referred to as cPG compounds or a combination thereof) in an amount effective to regenerate new neurons and glia; including. Here, the neurons are regenerated and the loss of the glial cells is regenerated in the subject; where the cPG functions as a neurorescue agent in the central nervous system, and further here, the loss of neurons and glial cells damaged as a result of injury or disease is repaired, method. Including the following steps. a) Providing a subject in need of regeneration of the neuron and glial cell loss; and b) Administering to the subject cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or, collectively referred to as cPG compounds or a combination thereof) in an amount effective to regenerate new neurons and glia; including. Here, the neurons are regenerated and the loss of the glial cells is regenerated in the subject; where the cPG functions as a neurorescue agent in the central nervous system, and further here, the loss of neurons and glial cells damaged as a result of injury or disease is repaired, method.

[0164] Restoring damaged neurons generally refers to reconstructive techniques or processes for preventing loss of neurons and glia and for restoring damaged neurons. The present invention describes methods that can repair neurons and glia damaged following traumatic, anoxic, infectious, and immunological insults. The old doctrine that axons cannot be regenerated and dead neurons cannot be replaced is no longer applicable. In particular, Experiments 7 and 8 describe the repair process by neurons, glia, and pharmacological intervention.

[0165] Another aspect of the present invention here includes that cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, or cyclic glycyl-2-alkylproline, or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof) is from about 1 μg to about 100 mg per kg of body weight.

[0166] A further aspect of the present invention includes the case where the administration is in the form of a pharmaceutical composition comprising its pharmaceutically acceptable carrier.

[0167] A further aspect of the present invention includes the case where the administration is carried out in combination with artificial cerebrospinal fluid.

[0168] Another aspect of the present invention includes the case where the administration is combined with a neuroprotective agent, insulin-like growth factor-I (IGF-I) or insulin-like growth factor-III (IGF-II).

[0169] A further aspect of the present invention includes that in this specification, the administration is combined with an anti-inflammatory agent. ​​​​​​​​​​​​

[0170] A third aspect of the present invention includes a method for alleviating or reducing cognitive dysfunction resulting from a disease, injury or condition in a mammal in need thereof, the method comprising the following steps including: a) providing a mammal in need of alleviation or reduction of cognitive dysfunction caused by a disease, injury or condition; and b) administering to the mammal a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine ), or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof). Here, the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, and multi-infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or corticobasal degeneration, and the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, and multi-infarct dementia. The injury is selected from the group consisting of neurotoxic injury, cerebral hypoxia / ischemia, traumatic brain injury, coronary artery bypass surgery, and when the condition is normal aging, age-related memory loss, memory impairment, cholinergic hypofunction, stenosis or occlusion of intracerebral blood vessels, nerve inflammation, mild cognitive impairment, brain atrophy, frontotemporal lobe degeneration, Pick's disease, HIV infection, Down syndrome, and loss of synaptic plasticity. Further, when the mammal is selected from the group consisting of, the mammal is selected from the group consisting of age-related memory loss, memory impairment, cholinergic hypofunction, stenosis or occlusion of intracerebral blood vessels, nerve inflammation, mild cognitive impairment, brain atrophy, frontotemporal lobe degeneration, Pick's disease, HIV infection, Down syndrome, and loss of synaptic plasticity, and further, when the mammal is , Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, Alzheimer's -related neurodegeneration, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia , senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or corticobasal degeneration for the alleviation or reduction of cognitive impairment caused by a disease, injury or condition wherein.

[0171] The alleviation of cognitive impairment generally refers to a method capable of alleviating symptoms related to memory, thinking, language, and other thought processes. Furthermore, it may also be useful for mood, anxiety, and other behavioral problems.

[0172] Another aspect of the present invention is now that said cyclic prolylglycine (cPG) or its analog (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-2-alkylproline, or cyclic glycyl-2-methylproline (cPM eG), collectively referred to as cPG compounds, or combinations thereof) is combined with an aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers, or adjuvants and includes that. Including.

[0173] A further aspect of the present invention is that said cyclic prolylglycine (cPG) or its analog (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds), or combinations thereof, further includes one or more excipients, carriers, additives, adjuvants or binders in tablets or capsules and includes that. Including that. Including that.

[0174] A further aspect of the invention, here, the disorder is mild cognitive impairment, Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or corticobasal degeneration.

[0175] Another aspect of the invention is that cyclic prolylglycine (cPG) or an analogue thereof (cyclic (tri (prolylglycine) or cyclic glycyl-2-allylproline, or cyclic glycyl- 2-alkylproline, or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof) are administered by oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, intraocular, intraspinal, intravesical, topical, drip, implantation, aerosol, inhalation, scarring, intracapsular, intramuscular, nasal, buccal, transdermal, pulmonary, rectal, vaginal, or combinations thereof.

[0176] Another aspect of the invention is that a pharmaceutically effective amount has a lower limit of about 0.001 milligrams and an upper limit of about 100 mg / kg per kilogram body mass (mg / kg) of the mammal

[0177] A further aspect of the invention includes the case where the cognitive impairment is caused by cholinergic hypofunction.

[0178] A further aspect of the invention includes that the cognitive impairment is caused by a decrease in glutamate receptors in the granular cell layer (CA1 ) of the hippocampus of the mammal.

[0179] Another aspect of the present invention is that cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri (prolylglycine) or cyclic glycyl-2-allylproline, or cyclic glycyl- 2-alkylproline, or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof) causes an increase in AMPA receptors in the granule cell layer (CA1) of the hippocampus of the mammal.

[0180] A further aspect of the present invention is that here, cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, or cycl ic glycyl-2-alkylproline, or cyclic glycyl-2-methylproline (cPM eG)) is included. Collectively referred to as cPG compounds or combinations thereof, in the granule cell layer (CA1) and the pyramidal cell layer (CA3) region of the hippocampus of the mammal, the cPG compound causes an increase in the plasticity of nerve cells.

[0181] A further aspect of the present invention includes cerebral hypoxia / ischemia caused by traumatic brain injury .

[0182] In another aspect of the present invention, here, it includes that cognitive impairment is caused by multi-infarct dementia .

[0183] A further aspect of the present invention is that here, it includes that cognitive impairment is caused by coronary artery bypass grafting (CABG) .

[0184] A further aspect of the present invention is that here, cognitive impairment, memory loss, resulting from Alzheimer's disease, Attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, mixed Dementia of vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, Parkinson Dementia associated with disease, progressive supranuclear palsy or corticobasal degeneration.

[0185] A fourth aspect of the present invention is a method for preventing in a mammal in need thereof symptoms of mild cognitive impairment caused by or associated with a disease, injury, or condition comprising the following. a) providing a mammal in need of prevention of cognitive impairment caused by a disease, injury or condition; b) administering to the mammal a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMe G), collectively referred to as cPG compounds or combinations thereof). Here, the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, and multi-infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, mixed vascular origin dementia, degenerative origin Dementia, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive nuclear Supranuclear palsy or corticobasal degeneration.

[0186] Preventing symptoms of mild cognitive impairment generally refers to actions taken to prevent the stage of symptoms and primarily reduce the risk of disease . Generally, prevention in dementia is referred to as primary prevention, Secondary prevention, tertiary prevention.

[0187] ​​​​In neurodegenerative dementia, the secondary prevention stage corresponds to the stage of mild cognitive impairment. At this stage there are symptoms, but they are not severe enough to constitute dementia. Therefore, the treatment of cPG compounds for subjects with MCI is considered a secondary prevention trial.

[0188] Tertiary prevention refers to a treatment method aimed at stopping the progression of a disease that has already occurred. It aims to reduce the impairment of people with mild cognitive impairment and improve the long-term prognosis.

[0189] A fifth aspect of the present invention includes a method of treating, in a mammal in need of treatment, mild cognitive impairment symptoms caused by or related to a disease, injury, or condition, comprising: a) providing a mammal in need of treatment for cognitive impairment caused by a disease, injury, or condition; b) administering to the mammal a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (collectively referred to as cPG compounds or combinations thereof), such as cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline, or cyclic glycyl-2-methylproline (cPMeG). Here, the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, and multi-infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy, or corticobasal degeneration.

[0190] Treating the symptoms of mild cognitive impairment generally means treating cognitive function, i.e., the process of thinking, including, but not limited to, the abilities of learning, reading comprehension, conversation, writing, etc. Patients with mild cognitive impairment (MCI) retain these important cognitive abilities necessary to manage their daily activities, but have difficulty remembering recent events and recently acquired information. Long-term memory tends to remain intact. In particular, see Clinical Trial 12, which was conducted on patients with Alzheimer's type dementia having mild cognitive impairment.

[0191] Neurons are among the oldest of all specialized animal cells. Their structure is unlike that of other classes of cells. A central challenge in neural growth and development is how to grow axons and dendrites, find appropriate partners, and selectively form synapses with them to build a functional network.

[0192] A sixth aspect of the present invention includes a method for increasing neuron growth or synapse formation in a mammal caused by, associated with, or in need of a disease, injury, or the like. a) Providing a mammal in need of increasing neuron growth or synapse formation; b) Administering to the mammal a pharmaceutically effective amount of a composition comprising cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (collectively referred to as cPG)) or a combination thereof. Here, the disease is Alzheimer's disease, Huntington's disease, Related to Lewy body disease, dementia, and multi-infarct dementia, memory loss, Alzheimer's disease Attention deficit symptoms, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin Dementia, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear Selected from the group consisting of paralysis or corticobasal degeneration

[0193] The seventh aspect of the present invention includes a method of providing a mammal in need of a method for reducing or alleviating a cognitive impairment caused by a disease, injury, or condition, including the following. a) Providing a mammal in need of reducing or alleviating a cognitive dysfunction caused by a disease, injury, or condition; and b) Administering to the mammal a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (collectively referred to as cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof). Here, the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, and multi-infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear paralysis or corticobasal degeneration. The injury is selected from the group consisting of neurotoxic injury, cerebral hypoxia / ischemia, traumatic brain injury, coronary artery bypass surgery, and the condition is normal aging, in which case memory loss, memory impairment, cholinergic hypofunction, stenosis of intracerebral blood vessels or Reducing or alleviating A mammal ; And b) A pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (Cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl Alkyl proline or cyclic glycyl-2-methylproline (cPMeG), collectively Referred to as cPG compounds or combinations thereof) to the mammal Animal administration. Here, the disease is Alzheimer's disease, Huntington's disease, Lewy body Disease, dementia, and multi-infarct dementia, memory loss, attention deficit disorder associated with Alzheimer's disease Symptoms, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, Pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear paralysis or Selected from the group consisting of corticobasal degeneration. The injury is selected from the group consisting of neurotoxic injury, cerebral hypoxia / ischemia , Traumatic brain injury, coronary artery bypass surgery, and the state is normal aging In the case of, age-related memory loss, memory impairment, cholinergic hypofunction, stenosis of intracerebral blood vessels or Obstruction, neuroinflammation, mild cognitive impairment, brain atrophy, frontotemporal lobe degeneration, Pick's disease, AIDS infection, Down syndrome, and loss of synaptic plasticity, and when selected from the group consisting of, further further, said mammal is for the alleviation or reduction of cognitive impairment caused by Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile cognitive impairment, senile cognitive impairment, dementia associated with Parkinson's disease, progressive supranuclear palsy or cortico basal degeneration including diseases, injuries or conditions. It is for the alleviation or reduction of cognitive impairment caused by an injury or condition.

[0194] Another aspect of the present invention is here, cyclic prolylglycine (cPG) or an analogue thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, or cyclic glycyl -alkylproline, or cyclic glycyl-2-methylproline (cPMeG ), collectively called cPG compounds, or combinations thereof) is composed of an aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers, or adjuvants. Including that.

[0195] A further aspect of the present invention is cyclic prolylglycine (cPG) or an analogue thereof (cyclic ( tri(prolylglycine) or cyclic glycyl-2-allylproline, or cyclic glycy l-alkylproline, or cyclic glycyl-2-methylproline (cPMeG), collectively called cPG compounds), or combinations thereof, further comprising one or more excipients, carriers, additives, adjuvants or binders in tablets or capsules. Including that. Including that.

[0196] A further aspect of the present invention is where the disorder is mild cognitive impairment, Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or corticobasal degeneration.

[0197] Another aspect of the present invention is where cyclic prolylglycine (cPG) or an analogue thereof (cyclic (tri (prolylglycine) or cyclic glycyl-2-allylproline, or cyclic glycyl- 2-alkylproline, or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof) are administered by oral, intraperitoneal, intravascular, peripheral circulation, subcutaneous, intraorbital, intraocular, intraspinal, intravesical, topical, drip, implantation, aerosol, inhalation , scarification, intracapsular, intramuscular, nasal, buccal, transdermal, pulmonary, rectal, vaginal, or combinations thereof.

[0198] A further aspect of the present invention is where the pharmaceutically effective amount has a lower limit of about 0.001 milligrams and an upper limit of about 100 mg / kg per kilogram mass (mg / kg) of the mammal.

[0199] A further aspect of the present invention includes the case where the cognitive impairment is caused by cholinergic hypofunction.

[0200] Another aspect of the present invention includes the case where the cholinergic hypofunction is caused by scopolamine.

[0201] A further aspect of the present invention is where the cognitive impairment is age-related memory loss, cognitive impairment, MCI ( "mild cognitive impairment", Alzheimer's disease, memory loss, attention deficit disorder associated with Alzheimer's disease conditions, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or corticobasal degeneration, including cases where it is the latter.

[0202] A further aspect of the invention includes that the cognitive impairment is caused by a decrease in glutamate receptors in the granular cell layer (CA1) of the hippocampus of the mammal.

[0203] Another aspect of the invention includes that the cPG compound causes an increase in AMPA receptors in the granular cell layer (CA1) of the hippocampus of the mammal.

[0204] A further aspect of the invention is here cyclic prolylglycine (cPG) or an analogue thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-2-alkylproline, or cyclic glycyl-2-methylproline (cPM eG)). Collectively referred to as cPG compounds or combinations thereof, in the granular cell layer (CA1) and pyramidal cell layer (CA3) regions of the hippocampus of the mammal, the cPG compound causes an increase in the plasticity of nerve cells caused thereby.

[0205] A further aspect of the invention includes cerebral hypoxia / ischemia caused by traumatic brain injury.

[0206] In another aspect of the invention, here the cognitive impairment is caused by multi-infarct dementia is included.

[0207] ​​​​A further aspect of the present invention now includes that the cognitive impairment is caused by coronary artery bypass grafting (CABG).

[0208] A further aspect of the present invention now includes cognitive impairment, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or corticobasal degeneration.

[0209] An eighth aspect of the present invention includes a method of preventing in a mammal in need thereof mild cognitive impairment symptoms caused by or associated with a disease, injury, or condition, comprising: a) providing a mammal in need of prevention of cognitive dysfunction caused by a disease, injury or condition; and b) administering to the mammal a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPM eG), collectively referred to as cPG, or a combination thereof). Here, the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, and multi-infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or corticobasal degeneration.

[0210] ​​​​A ninth aspect of the present invention is a method for treating symptoms of mild cognitive impairment caused by or associated with a disease, injury, or condition in a mammal in need of treatment, and includes the following: a) providing a mammal in need of treatment for cognitive dysfunction caused by a disease, injury, or condition; and b) administering to the mammal a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof). Here, the disease is selected from the group consisting of Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, and multi-infarct dementia, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or corticobasal degeneration. A tenth aspect of the present invention includes a method for increasing neuron growth or synaptogenesis in a mammal caused by, associated with, or in need of a disease, injury, or the like, and includes the following: a) providing a mammal in need of increasing neuron growth or synaptogenesis; and b) cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)

[0211] ​​​​​​​​​​​​​​​​, from a pharmaceutically effective amount of cPG compounds or combinations thereof, collectively referred to as administering an effective amount of the composition to a mammal. Here, the disease is Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, and multi-infarct dementia, memory loss, Alzheimer's attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, mixed vascular origin dementia, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease selected from the group consisting of progressive supranuclear palsy or corticobasal degeneration.

[0212] The 11th aspect of the present invention is a neurodegenerative disorder, an ischemic disorder, a neurological trauma, learning and memory disorders, or a method of modulating neurogenesis in the neural tissue of a patient exhibiting at least one symptom of a central nervous system disorder that is a combination thereof. administering cyclic prolylglycine (cPG) or an analog thereof ( cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline)) or cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or a combination thereof thereof, or a functional or active analog, variant, derivative, and combinations thereof having the same, substantially the same, or similar functions as cPG, wherein the agent modulates neurogenesis in the patient, thereby modulating neurogenesis in the neural tissue of the patient.

[0213] Neurogenesis is the process by which new neurons are generated, mature, specialize, and become integrated into the neuronal network and become functional from neural stem cells and progenitor cells. In neural tissue regulation of neurogenesis generally refers to modulating or controlling the growth of nerve cells in the human brain Refers to a method.

[0214] Another aspect of the present invention is where the neurological disorder is Alzheimer's disease, Parkinson's disease and and Parkinson's disorder, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Shy-D rager syndrome, progressive supranuclear palsy, Lewy body type, spinal cord ischemia, ischemic stroke, cerebral infarction, spinal cord injury, cancer-related brain and spinal cord injury, multi-institutional dementia, senile dementia, mild cognitive impairment, depression, including cases of traumatic injury.

[0215] A further aspect of the present invention includes that the regulation of the neurogenesis is performed by activation of GPCR receptors in the nerve tissue.

[0216] A further aspect of the present invention is that in a further aspect of the present invention, the agent is in an amount of cyclic prolylgly sin (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl -2-allylproline, or cyclic glycyl-alkylproline or cyclic glycyl-2 -methylproline (cPMeG), collectively called cPG compounds, or combinations thereof ) from about 0.1 mg to about 10 mg / kg / day, from about 0.5 mg to about 20 m g / kg / day, from about 0.2 mg to about 40 mg / kg / day, from about 5 mg to about 50 mg / kg / day, or from about 10 micrograms to about 100 mg / kg / day.

[0217] A twelfth aspect of the present invention includes a method for regulating neurogenesis in the nerve tissue of a patient showing at least one symptom of a central nervous system disorder that is a neurodegenerative disorder, an ischemic disorder, a neurological trauma, a learning and memory disorder, or a combination thereof. The patient is administered the patient's adult nerve ​​Increase stem cells and administer an amount of cyclic pro rilglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl-2-alkylproline or cyclic gly ryl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof) to the patient to reduce at least one symptom of the disorder. The at least one symptom of the disorder can be reduced.

[0218] Another aspect of the invention herein is where the disorder is Alzheimer's disease, Parkinson's disease and Par kinson's disorder, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Shy-Drager syndrome, progressive supranuclear palsy, Lewy body disease, spinal cord ischemia, ischemic stroke, cerebral infarction, spinal cord injury, cancer-related brain and spinal cord injury, multi-bed dementia, senile dementia, cognitive impairment, depression, traumatic injury, or combinations thereof.

[0219] Another aspect of the invention herein is where cyclic prolylglycine (cPG) or an analog thereof (cyclic tri(prolylglycine) or cyclic glycyl-2-allylproline, or cyclic gly cyl-2-allylproline, or cyclic glycyl-alkylproline, or cyclic gly cyl-2-methylproline (cPMeG), collectively referred to as cPG compounds, or combinations thereof) are administered at about 0.01 mg / kg to about 100 mg per kilogram of body weight per day.

[0220] A thirteenth aspect of the invention is for treating depression or other psychological disorders in a subject. A method, comprising: a) providing a subject in need of treatment for depression or other psychological disorder; and b) administering to the subject a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl- alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cP G compounds or combinations thereof); wherein the subject is characterized by receiving treatment for depression or other psychological disorder.

[0221] The symptoms of depression vary from mild to severe and include: feeling sad, being in a depressed mood, losing interest or pleasure in activities once enjoyed, changes in appetite (weight loss or gain unrelated to dieting), sleep disturbances or excessive sleep, loss of energy or increased fatigue, thinking difficulties, reduced concentration, reduced decision-making ability, thoughts of death or suicide, etc.

[0222] Another aspect of the invention is where cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic gly cyl-2-alkylproline, or cyclic glycyl-2-methylproline (cPMeG ), collectively referred to as cPG compounds, or combinations thereof) consists of an aqueous solution and one or more pharmaceutically acceptable excipients, additives, carriers, or adjuvants.

[0223] A further aspect of the invention is cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic gly L-alkyl proline, or cyclic glycyl-2-methyl proline (cPMeG), collectively referred to as cPG compounds), or combinations thereof, are further included in one or more excipients, carriers, additives, adjuvants or binders in tablets or capsules.

[0224] A further aspect of the present invention is cyclic prolylglycine (cPG) or an analogue thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allyl proline, or cyclic glycy l-alkyl proline or cyclic glycyl-2-methyl proline (cPMeG), collectively referred to as cPG compounds or combinations thereof) is administered orally, intraperitoneally, intravascularly, peripherally circulated, subcutaneously, intraorbitally, intraocularly, intraspinally,

[0225] intravesically, topically, by infusion, implantation, aerosol, inhalation, scarring, intracapsularly, intramuscularly, nasally, buccally, transdermally, pulmonary, rectally, vaginally, or combinations thereof.

[0226] A further aspect of the present invention is that the pharmaceutically effective amount has a lower limit of about 0.1 milligram and an upper limit of about 10 milligrams / kg per kilogram body mass (mg / kg) of the mammal.

[0227] A 13th aspect of the present invention includes a method of preventing in a subject in need of preventing symptoms of depression or other psychological b) providing a subject in need of protection against cyclic prolylglycine (cPG) or its Analogues of cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, Cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG ), collectively referred to as cPG compounds or combinations thereof, administering to a subject; wherein the subject is prevented from developing symptoms of depression or other psychological disorder. This includes prevention.

[0228] Preventing depression symptoms generally negatively impacts the way a person feels, thinks, and behaves. Depression is a condition that causes feelings of sadness and the inability to do things you once enjoyed. Depression causes a variety of emotional and physical problems. and may impair functioning at work and at home. See especially Experiment 15.

[0229] A fourteenth aspect of the present invention relates to a method for treating depression or other psychological disorders in a subject in need of treatment. The present invention includes methods for treating symptoms of depression or other psychological disorders, comprising: a) administering to a patient a b) providing a subject in need of treatment for a cyclic prolyl glycol or other psychological disorder; cPG or its analogues (cyclic (tri(prolylglycine) or cyclic glycyl -2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methyl cPMeG, collectively referred to as cPG compounds or combinations thereof ), wherein the subject is suffering from depression or other psychological disorders. This includes receiving treatment for symptoms of a mental disorder.

[0230] The symptoms of depression vary from mild to severe and include the following: sadness feeling down or losing interest in and pleasure from activities that were once enjoyable changes in appetite (weight loss or gain unrelated to dieting), sleep disorders or excessive sleeping loss of energy or increased fatigue, thinking difficulties, reduced concentration, reduced decision-making ability, thoughts of death or suicide, etc.

[0231] The 15th aspect of the present invention includes a method for treating a patient in a mentally depressed state and includes the following. a) Providing a subject in need of treatment for depression or other mental disorders. b) Administering to a patient suffering from mental depression a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analogue thereof (collectively referred to as cPG compounds or combinations thereof, such as cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)), for example but not limited to, an amount not limited to 20 mg to 80 mg per day); where the subject is capable of receiving treatment for mental depression.

[0232] In the treatment of patients in a mentally depressed state, it was common to use commercially available antidepressants that increase the risk of suicidal thoughts and behaviors in short-term trials for children, adolescents, and young adults. However it has been demonstrated that the cPG of the present invention is an effective antidepressant with few side effects. In the present invention, it has been demonstrated that cPG functions as an effective antidepressant with few or no side effects see Experiment 15.

[0233] ​​The 16th aspect of the present invention is for reducing or alleviating the symptoms of depression or other psychological disorders, and includes the following method for reducing or alleviating the symptoms of a subject in need of depression or other psychological disorders. a) Providing a subject in need of reducing or alleviating the symptoms of depression or other psychological disorders; b) Administering to a mammal a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof); wherein the subject includes alleviating the symptoms of depression or other psychological disorders. The 17th aspect of the present invention includes a method for intervening or preventing in a subject in need of a cascade of depression or other psychological disorders, and includes the following. a) Providing a subject in need of intervening or preventing depression or other psychological disorders; b) Administering to a mammal a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof); wherein the subject includes preventing the symptoms of depression or other psychological disorders. Although treatment methods for depression are established, it is presumed and suggested that the majority of depression patients are not receiving appropriate care. Timely intervention is for people with major depressive episodes. a) Providing a subject in need of reducing or alleviating the symptoms of depression or other psychological disorders; b) Administering to a mammal a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof); wherein the subject includes alleviating the symptoms of depression or other psychological disorders. a) Providing a subject in need of intervening or preventing depression or other psychological disorders; b) Administering to a mammal a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof); wherein the subject includes preventing the symptoms of depression or other psychological disorders.

[0234] Although treatment methods for depression are established, it is presumed and suggested that the majority of depression patients are not receiving appropriate care. Timely intervention is for people with major depressive episodes. a) Providing a subject in need of intervening or preventing depression or other psychological disorders; b) Administering to a mammal a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof); wherein the subject includes preventing the symptoms of depression or other psychological disorders. Although treatment methods for depression are established, it is presumed and suggested that the majority of depression patients are not receiving appropriate care. Timely intervention is for people with major depressive episodes. a) Providing a subject in need of reducing or alleviating the symptoms of depression or other psychological disorders; b) Administering to a mammal a pharmaceutically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine)) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG), collectively referred to as cPG compounds or combinations thereof); wherein the subject includes alleviating the symptoms of depression or other psychological disorders.

[0235] Although treatment methods for depression are established, it is presumed and suggested that the majority of depression patients are not receiving appropriate care. Timely intervention is for people with major depressive episodes. Although treatment methods for depression are established, it is presumed and suggested that the majority of depression patients are not receiving appropriate care. Timely intervention is for people with major depressive episodes. It is an important element of the continuity model of care. In particular, refer to Experiment 15.

Example

[0236] The following in vitro and in vivo studies demonstrate the effectiveness of cyclic prolylglycine in reducing cognitive impairment. These are not intended to be limiting, and other compositions and methods of the present invention can be developed without performing unnecessary experiments. All of the following experiments were carried out using protocols developed under guidelines approved by the Animal Ethics Committee and the Institutional Review Board. Cyclic prolylglycine is available from commercial suppliers such as Bachem (Torrance, CA) and Sigma ( St. Louis, MO, USA).

[0237] :

[0238] Experiment 1. Cyclic PG prevents glutamate-induced neuronal cell death in a dose-related manner in vi tro. Materials and Methods : Preparation and Coating of Cerebellar Cell Culture Coverslips Ten cover slips were placed in a large petri dish and washed with 70% alcohol for 5 minutes, then washed with Millipore H2O. The cover slips were air-dried and coated with poly-D-lysine (P 1 mg / ml stock solution in BSS, 90 - 100 μl) and incubated at 34 °C for 2 hours.

[0239] Extraction Wistar rats on the 4th day after birth were used. The rats were placed in ice for 1 minute, decapitated at the head, and the cerebellum was removed on ice. The cerebellar tissue was placed in a large petri dish containing 0.65% glucose-supplemented PB Place it in 1 ml of S (10 μl of 65% stock D(+) glucose / 1 ml PBS), Cut into smaller sections and triturate with 1 ml of insulin via a 23G (0.4 mm) needle and return it to the glucose solution on a large petri dish and pipette. Shake the tissue through (a 125 μm pore size sieve), centrifuge twice (at 60 g for 2 minutes) and perform a medium exchange to serum-free BSA-supplemented START V medium (Biochrom). The second centrifugation step was performed with 1 ml of STARTART V medium. Microexplants were reconstituted in 500 μl of START V medium and placed on ice.

[0240] Culture and Fixation of Cerebellar Cells Two hours after PDL coating, the slides were washed with Milli-Q H 2 O and air-dried . Each slide was placed in a small 35 mm petri dish and 40 μl of V / cell suspension was added. The tissue was incubated at 34 °C (sedimentation period) for 2 hours. Then, START V medium (1 ml ) was added to the petri dish and cultured at 34 °C / 5% CO 2 / 100% humidity for 48 hours. The cells were washed with PBS and fixed with increasing concentrations of paraformaldehyde (500 μl of 0.4% PFA was applied, followed by 1.2% PFA, then 3% PFA and finally 4% PFA - all fixing solutions contain 0 .2% glutaraldehyde) for 2 - 3 minutes. Finally, the microexplants were rinsed with PBS. .2% glutaraldehyde) for 2 - 3 minutes. Finally, the microexplants were rinsed with PBS. The microexplants were rinsed with PBS.

[0241] Application of Drugs For Test 1, 10 μl of toxin (in L-glutamic acid-100 Milli-Q water) was added to cP G (manufactured by Bachem, prepared from a 10 mM stock in PBS to a final concentration between 1 - 100 nM (diluted) and applied simultaneously. For Test 2, the administration of c PG was delayed.

[0242] Results: Test 1: Glutamate treatment resulted in an 85% loss of cerebellar neurons. Cyclic PG, when administered simultaneously with glutamate, significantly decreased glutamate-induced neuronal cell death in a dose-responsive manner (Figure 3). Treatment with lower doses of cPG (10 - 100 nM) showed a significant recovery from glutamate-induced neurotoxicity.

[0243] Test 2: Cyclic PG, when administered 6 hours after glutamate treatment, showed a significant recovery from glutamate-induced neurotoxicity in the dose range of 1 - 10 0 nM compared to the vehicle-treated group (Figure 4). Furthermore, administration of even lower doses of cPG significantly increased the number of neurons compared to the normal control group,

[0244] suggesting a role of cPG in neuronal growth and differentiation.

[0245] Conclusion Excessive glutamate may cause excitotoxicity of neurons by active NMDA receptors. cPG acts as a direct or indirect NMDA agonist and, when administered immediately after or 6 hours after glutamate treatment, was able to completely prevent glutamate-induced neurotoxicity. Considering that cPG can agonize the mGlu2 / 3 receptors that can inhibit NMDA activity, GP E, the precursor hormone of cPG, probably promotes pCREB due to its antagonistic effect on the mGlu2 / 3 receptors. ​​It has been shown to be a partial NMDA receptor. cPG is effective as a delayed treatment and can promote the proliferation of nerve cells, so it can be involved in the prevention of neurons undergoing apoptosis. Since it is effective and can promote the proliferation of nerve cells, it can be involved in the prevention of neurons undergoing apoptosis.

[0246] Experiment 2. Cyclic (tri(prolylglycyl) or c(PG)3 inhibits glutamate-induced neuronal cell death in vitro in a dose-rel ated manner. Materials and Methods : (For Experiment 1 incorporated herein by reference, see the above.)

[0247] Application of Drugs 10 μl of the toxin (L-glutamic acid - 100 mM, Milli-Q water) was applied simultaneously with cyclic (tri(prolylglycyl)). (A 10 mM stock obtained from (Neurobiomed, San Jose, Ca lifornia) was prepared with PBS and diluted to a final concentration of 1 - 100 nM) was used in Test 1. For Test 2, the administration of cyclic (tri(prolylglycyl)) was delayed by 6 hours after glutamate treatment.

[0248] Results: Test 1: 85% of the cerebellar neurons disappeared due to glutamate administration. Cyclic (tri(prolylglycyl)), when administered simultaneously with glutamate, significantly reduced glutamate-induced neuronal cell death by 57% in a dose-responsive manner. Treatment with lower doses of cyclic (tri(prolylglycyl)) (10 - 100 nM) showed a significant recovery from glutamate-induced neurotoxicity.

[0249] Test 2: Cyclic (tri(prolylglycyl)) was administered 6 hours after glutamate treatment. In this case, in the dose range of 1 - 100 nM, about 43% significant recovery from glutamate-induced neurotoxicity was shown, and improvement was seen compared to the vehicle-treated group.

[0250] Even when administering a lower dose of cyclic (tri(prolylglycyl)), since the number of neurons significantly increased compared to the normal control group, the role played by cPG in the proliferation and differentiation of nerve cells was suggested.

[0251] Experiment 3 Cyclic Glycyl-2-Methylproline prevents glutamate-induced neuro nal cell death in a dose-related manner. Materials and Methods : (Regarding Experiments 1 and 2 incorporated herein by reference, see the above reference

[0252] Application of Drugs For Test 1, 10 μl of the toxin (L-glutamic acid - 100 mM in Millipore water) was applied simultaneously with cyclic glycyl-2-methylproline (obtained from Neurobiomed, San Jose Cali fornia), prepared as a 10 mM stock in PBS and diluted to a final concentration between 1 - 100 n M. For Test 2, the administration of cPG was delayed 6 hours after glutamate treatment.

[0253] Results: Test 1: Glutamate treatment resulted in an 85% loss of cerebellar neurons. Cyclic glycyl -2-methylproline, when administered simultaneously with glutamate, significantly reduced glutamate-induced neuronal death dose-dependently by 63%. Treatments with lower doses of cyclic glycyl-2-methyl proline (10 - 100 nM) showed significant recovery from glutamate-induced neurotoxicity. ​​​

[0254] Test 2: Cyclic glycyl-2-methylproline was administered 6 hours after glutamate treatment and showed a significant recovery of approximately 58% from glutamate-induced neurotoxicity in the dose range of 1 - 100 nM compared to the vehicle-treated group.

[0255] Furthermore, when a lower dose of cyclic glycyl-2-methylproline was administered, the number of neurons was significantly increased compared to the normal control group suggesting the role of cPG in the proliferation and differentiation of nerve cells.

[0256] Conclusion Excessive glutamate may cause excitotoxicity of nerve cells through active NMDA receptors. Cyclic PG analogs, cyclic (tri(prolylglycyl)) and cyclic glycyl-2-methylproline act as direct or indirect NMDA agonists and significantly prevent glutamate-induced neurotoxicity when administered immediately or 6 hours after glutamate treatment.

[0257] cPG compounds are effective as delayed treatment and can promote the proliferation of nerve cells, so they can be used for the prevention of nerve cells undergoing apoptosis, but are not limited to these, for example, cyclic PGs such as cyclic (tri(prolylglycyl)) and cyclic glycyl-2-methylproline and their analogs can be used.

[0258] Experiment 4. Effect of cPG after 6-OHDA-induced lesion. Materials and Methods Twenty male Wistar rats (280 - 310 grams) were used. The skull was exposed After that, 6-OHDA (8 μg in 2 μl of 0.9% physiological saline containing 1% ascorbic acid) was administered to the right medial forebrain bundle (MFB) using coordinates AP + 4.7 mm, R 1.6 mm v - 8 mm under 3% halogenated anesthesia. 6- OHDA was injected through a 25G needle connected via a polyethylene catheter to a 100 μl Hamilton syringe. 6-OHDA was injected at a rate of 0. 5 μl / min with a microdialysis infusion pump. The needle remained in the brain for an additional 3 minutes before being slowly withdrawn. The skin was sutured with 2.0 silk, and the rats were allowed to recover from anesthesia. The rats were housed in a holding room with free access to food and water at all times except during the behavioral tests.

[0259] cPG was dissolved in physiological saline. Four different doses of cPG (0, 0.1, 0.5, 1 mg / kg, Sigma) were administered intraperitoneally 2 hours after the lesion.

[0260] Seven days later, rats were injected with 0.1 mg / kg of apomorphine, and the number of contralateral rotations / hour was recorded and calculated using a computerized rotameter (San Diego Instruments). The experimenter was blinded to the treatment groups.

[0261] Results: The group administered 1 mg of cPG (n = 5, 154 ± 64) showed a tendency for a decrease in the number of rotations compared to the group administered the vehicle (n = 5, 290 ± 18). (Figure 5).

[0262] Experiment 5 Effect of cyclic (tri(prolylglycyl) after 6-OHDA-induced gliosis ​​​​​​Materials and Methods Conclusion (Refer to the above for Experiments 1, 2, 3, and 4).

[0263] Cyclic (tri(prolylglycyl)) was dissolved in physiological saline. Four different doses of cyclic (tri(prolylglycyl) 0, 0.1, 0.5, 1 mg / kg, Neurobiomed ) were intraperitoneally administered 2 hours after the lesion.

[0264] In the group treated with 1 mg of cyclohexyl(tri(prolylglycyl)) (n = 5, 172 ±69), there was a tendency for the rotation number to decrease compared to the vehicle-treated group (n = 5, 290 ± 18), suggesting the role of cyclic (tri(prolylglycyl)) in the improvement of functional recovery in 6-OHDA-induced ganglionic injury. Cyclic (tri(prolylglycyl)) dose-dependently improved the functional recovery of nerve-tilt disease after 6-OHDA induction.

[0265] Experiment 6. This data indicates that cyclic (tri(prolylglycyl)) can be used as a therapeutic agent for Parkinson's disease and other neurological disorders.

[0266]

[0267] Effect of cyclic glycyl-2-methylproly ne after 6-OHDA-induced gliosis Materials and Methods Conclusion

[0268] (Refer to Experiments 1 to 5 above).

[0268] Cyclic glycyl-2-methylproline (cGMeP) was dissolved in physiological saline. Four doses of cGMeP (0, 0.1, 0.5, 1 mg / kg, Neurobiomed) were administered 2 hours after the lesion. It was administered intraperitoneally after a certain time.

[0269] The group administered 1 mg of cGMeP (n = 5, 134 ± 69) showed a tendency for a significant decrease in the number of rotations compared to the group treated with the vehicle (n = 5, 292 ± 21). Although there was a tendency for a significant decrease in the number of rotations, cGMeP suggests a role in the improvement of functional recovery in 6-OHDA-induced ganglionic injury.

[0270] Experiment 7. Cyclic glycyl-2-methylproline improved the functional recovery of nerve-angulus lesions after 6-OHDA induction in a dose-related manner.

[0271] This data indicates that cycloglycyl-2-methylproline is effective as a therapeutic agent for Parkinson's disease.

[0272] The Morris water maze (MWM) model of learning and memory is used to evaluate the effect of cyclic prolylglycine on cognitive function. Methods Results When cPG is administered to animals with scopolamine-induced cognitive impairment, clinical improvements similar to those observed in people suffering from cholinergic hypofunction are obtained. Scopolamine is commonly used in animal models of cholinergic functional decline associated with Alzheimer's disease. The functional impairments observed after scopolamine treatment include those seen in human Alzheimer's disease patients. Thus, scopolamine treatment can reasonably predict the cognitive function impairments seen in human diseases. Furthermore, scopolamine treatment mimics cognitive function impairments in humans without neurodegenerative diseases.

[0273] The purpose of this study was to investigate cyclic prolylglycine and its effects on cognitive deficits and emotional states (depression). It was to evaluate

[0274] Experiment 8. The first part of the study was involved in the acute trial of cyclic prolylglycine in the Morris water maze memory model. The MWM test is one of the most frequently used tests to evaluate the spatial memory of rats and is generally well known for accurately predicting the effects of diseases and treatments on spatial memory. Therefore, the MWM test reflects the effects of diseases and treatments in human subjects.

[0275] Followed the standard procedure of MWM. A circular pool (water depth 80 cm × diameter 150 cm) filled with opaque water was used, and the temperature was maintained at 20°C. A platform was hidden 1 cm below the water surface, and a white flag (10 cm × 10 cm) was placed either 20 cm above the platform for visual cues or at the 3 o'clock position in relation to the starting position for spatial cues. From the first day to the fourth day of the experiment, rats received memory acquisition trials in 6 trials (60 seconds each) per day (habituation phase). The latency to reach the platform was recorded, and the daily decrease in the average latency was used to measure the ability to learn where the hidden platform was.

[0276] On the fifth day of the experiment, normal, non - aging Wistar rats were grouped and administered either saline (N = 12) or scopolamine (0.5 mg / kg, i.p., N = 12) to induce memory impairment. Scopolamine was administered 30 minutes before the start of the probe test.

[0277] Ten minutes after scopolamine treatment, cyclic prolylglycine was administered at 10 mg / kg (n = 16) Oral administration was performed, and the vehicle-treated animals were given the same treatment protocol (n = 15). The diluent was administered orally.

[0278]

Table 1

[0279] Next, the acute effects of cPG were tested using animals with scopolamine-induced memory impairment and control animals matched for age without memory impairment to determine the direct pharmacological effects on memory processing. The experimental groups are detailed in Table 1 below. On day 5, the probe MWM test was performed with the platform removed. The test was conducted 6 times, with a maximum duration of 60 seconds for each test, and at least a 5-minute rest was taken between tests. The time the rats spent swimming near the platform served as an indicator of how much they relied on visual and spatial cues to locate the platform, as opposed to using non-spatial strategies. The data were collected and analyzed using Any-maze (v4.2) software. The data generated from the behavioral tests were analyzed using one-way ANOVA to determine differences between age groups. To examine the progression of the results of the behavioral tests, two-way ANOVA was used with the time point as the dependent factor. GraphPad Prism version 3.02 was used for data analysis.

[0280] Treatment with scopolamine significantly impaired the acquisition of spatial memory in the treated animals (on day 4). The test was conducted 6 times, with a maximum duration of 60 seconds for each test, and at least a 5-minute rest was taken between tests (). The time the rats spent swimming near the platform served as an indicator of how much they relied on visual and spatial cues to locate the platform, as opposed to using non-spatial strategies. The data were collected and analyzed using Any-maze (v4.2) software. The time the rats spent swimming near the platform served as an indicator of how much they relied on visual and spatial cues to locate the platform, as opposed to using non-spatial strategies. In contrast to using non-spatial strategies, the time the rats spent swimming near the platform served as an indicator of how much they relied on visual and spatial cues to locate the platform. The data were collected and analyzed using Any-maze (v4.2) software. The data were collected and analyzed using Any-maze (v4.2) software.

[0281] The data generated from the behavioral tests were analyzed using one-way ANOVA to determine differences between age groups. To examine the progression of the results of the behavioral tests, two-way ANOVA was used with the time point as the dependent factor. GraphPad Prism version 3.02 was used for data analysis. GraphPad Prism version 3.02 was used for data analysis.

[0282] Determination of neurogenesis by testing cPG and its analogs c(PG)3 and cGMP Treatment with scopolamine significantly impaired the acquisition of spatial memory in the treated animals (on day 4). The time to the platform was about 208% of the control. Cyclic prolylglycine ( 20 mg / kg; daily) significantly reversed scopolamine-induced cognitive impairment (Figure 6).

[0283] From these results, NA-831 was confirmed to show cholinergic effects in the search for the skill of finding the learned submerged platform (spatial memory) and to be effective in patients with mild cognitive impairment.

[0284] using bromodeoxyuridine Purpose Experimental Methods Results The purpose of this experiment was to examine the effects of co-administering BrdU to rats with high neurogenic regions including the subventricular zone and the dentate gyrus of the hippocampus and intraperitoneally injecting cPG and its analogs c(PG)3 and cGMeP.

[0285] Conclusion . Male Wistar rats weighing approximately 250 - 270 g (not newborn) were used. All animal experiments were conducted in accordance with national and international guidelines. Care was taken to minimize the suffering of the animals. The animals were acclimated for one week before the start of the study. The animals were housed in groups of five per cage under standardized conditions of normal light and dark periods. The animals were allowed free access to food and water during the study period.

[0286] Three neurogenic regulators, cPG, c(PG)3, and cGMeP, were separately intraperitoneally administered to male Wistar rats (N = 10) at 10 mg / kg in 0.1% rat serum albumin (RSA). It was administered intracavity. For the negative control (n = 12), the vehicle group was injected with physiological saline (in 0.1% RSA). Bromodeoxyuridine (BrdU; 50 mg / kg) was co-administered with the compound. Intraperitoneal injections were performed at 12-hour intervals for 7 days. The animals were perfused on the 8th day. The rats were housed in a 12-hour light-dark regime. For perfusion, the animals were perfused transcardially with 50 ml of ice-cold phosphate-buffered saline (PBS) and then with 100 ml of 4% paraformaldehyde in PBS. The brain was fixed after removal with 4% paraformaldehyde in PBS at 4°C for 24 hours and at least 3 days before sectioning. The transcardial injection procedure consisted of the following steps.

[0287] The animals were weighed in 0.1-gram increments and administered sodium pentobarbital and ketamine / xylazine. The animals were placed in a heated cage for 10 - 15 minutes. The rats were fixed in a supine position (lying face up) with their forelimbs and hindlimbs fixed to the foamed styrene work surface in a chemical fume hood. An incision was made through the skin with surgical scissors just below the scaphoid process of the clavicle along the median sternal line of the thorax. Two additional skin incisions were made laterally from the rostral process along the base of the lateral thoracic wall of the abdomen. Please gently reflect the two flaps of skin rostrally and laterally to confirm complete exposure of the thoracic field. Grasp the soft bone of the anastomotic process with blunt forceps and gently lift it up to insert a pointed scissors. Cut through the pectoralis muscle and thorax between the sternum and the insertion of the inner rib, and extend the incision to the level of the clavicle for anastomosis. The diaphragm from both sides of the chest wall was separated by a zigzag cut. The reflected thorax was taped or pinned laterally with an 18G needle to expose the heart and other thoracic organs. The pericardium was gently grasped with blunt forceps. ​​​It was completely opened and torn. The beating heart was fixed with blunt forceps, and an incision of 1-2 mm was made into the left ventricle. The 24G X 25.4 mm animal feeding needle (Harvard apparatus cat. The feeding needle was threaded at the base of the aortic arch using a dissecting microscope. The base of the needle was clamped to the left ventricle over the incision site using a hemostatic plug The right atrium was immediately incised with scissors, and the injection of heparinized saline was initiated at the first sign of blood flow (Stage 1 perfusate), and continued until the fluid emerging from the right atrium became completely clear. The saline perfusate was changed to an aldehyde-based fixative (Stage 2 perfusate), and the total amount of fixative injected into the animal was changed to 20-30 ml. The animal was decapitated with large surgical scissors. The brain was removed and embedded in paraffin. Sections were prepared using a cryomicrotome and stored in cryoprotectant at -20°C prior to immunostaining for BrdU . Sections were immunostained for BrdU using mouse anti-BrdU paired with biotinylated goat anti-mouse IgG and visualized using an ABC elite kit (Vectorlab, following the manufacturer's instructions ). The total number of BrdU-positive cells in each section and related regions of the brain was counted using standard light microscopy techniques. Analysis and quantification were performed on proliferative brain regions, the subventricular zone, and the dentate gyrus of the hippocampus

[0288] . Other experimental details not described here are known to those skilled in the art, for example, as described in Pencea V et al. J. Neurosci Sep. 1 (2001). 21 (l 7): 6706-17. It should be noted that cPG, c(PG)3 and cGM at 10 mg / kg with 0.1% RSA

[0289] Experiment 9 ​​​ When eP was intraperitoneally injected into rats co-administered with BrdU twice a day, the number of newborn cells (BrdU-positive) in highly neurogenic regions including the subventricular zone and the dentate gyrus of the hippocampus significantly increased (non-parametric one-way ANOVA) (Figs. 7 and 8).

[0290] Determination of the regeneration of damaged nerve tissue using cPG From the above, it was revealed that cPG, c(PG)3, and cGMeP exhibit the proliferative effect on neural stem cells.

[0291] Results Conclusion Ten postpartum day 4 Wistar rats were used in the experiment. The rats were divided into two groups, one group of 5 rats treated with a chemical solution and the other group of 5 rats treated with a 0.9% sodium chloride (saline) solution. A chemical solution containing cPG (manufactured by Bachem, a 10 mM solution prepared in a 0.9% sodium chloride (saline) solution) was administered 4 times a day in a volume of 0.75 ml, and the injury site was thoroughly soaked in water. Two days after the spinal cord was crushed, the dura mater of the rat was opened, and a polyethylene tube was sutured to the soft tissue adjacent to the vertebral spine so that one end opening was directly lying on the injured part of the spinal cord.

[0292] The tube was brought through a subcutaneous tunnel so that the other end came out at the base of the skull. A syringe adapter was attached to the external opening for injecting the drug. All experiments were conducted in a double-blind manner in two groups: one group of 5 animals was treated with a chemical solution of 10 mM cPG in saline, and the other group was treated with a 0.9% sodium chloride (saline) solution. All animals were sacrificed and tissues After preparing histological sections, it was continued for 14 days.

[0293] Experiment 10 In the animals treated with the drug, compared with the animals treated with physiological saline, the infiltration of the lesioned area by nerve fibers was greater. In the animals treated with the drug, nerve fibers penetrated into the lesioned area in large numbers and no longer changed their orientation in the horizontal or vertical direction, but grew randomly in all directions. The fibers were often wavy and formed a venous shape, and often formed small bundles containing 3 to 6 axons. The size of the axons was very fine, and most of them were 3 to 7 microns in diameter. When the slides were coded and randomized, it was not difficult to distinguish between the specimens of the animals treated with the drug and those treated with physiological saline. The most vigorous nerve growth was observed in the animals treated with cPG.

[0294] Regeneration of damaged nerve tissue by cyclic (glycyl-L-prolyl-L-prolyl) This example showed that the regeneration of nerves was promoted by sufficiently bathing the composition in the injured site or contacting it by other methods. When the composition was directly administered to the injured site, the regeneration of the damaged nerve tissue was promoted.

[0295] Results Experiment 11 Ten postpartum day 4 Wistar rats were used in the test. The rats were divided into two groups, one group of 5 rats treated with the drug solution and the other group of 5 rats treated with a 0.9% sodium chloride (physiological saline) solution. The drug solution containing cyclic (glycyl-L-prolyl-L-prolyl) or c(PG)3 at 10 mM obtained from Neurobiomed (San Jose, California) was prepared with a 0.9% sodium chloride (physiological saline) solution at 10 m ​ The M solution was administered four times a day in a volume of 0.75 ml, and the injury site was thoroughly soaked in water.

[0296] Two days after the spinal cord was crushed, the dura mater of the rat was opened, and the polyethylene tube was sutured to the soft tissue adjacent to the vertebral spine so that one end opening lay directly over the injured part of the spinal cord. The tube was brought through a subcutaneous tunnel so that the other end emerged at the base of the skull. A syringe adapter was attached to the external opening for injecting the drug. All experiments were based on double - blind in two groups: one group of 5 animals was treated with a 10 mM c(PG)3 solution in saline, and the other group of 5 animals was treated with a 0.9% sodium chloride (saline) solution. The treatment of all animals continued for 14 days after sacrificing the animals and preparing histological sections. The results were similar to the above - mentioned experiments using cPG. In the animals treated with c(PG), the nerve fibers were no longer oriented longitudinally, but rather grew in a disorderly manner in all directions

[0297] Regeneration of damaged nerve tissue by cyclic glycyl-2-methylproline and grew in large numbers at the lesion site. The fibers often became serpentine and venous, and were often in small bundles containing 3 - 6 axons. The axons were very thin - diameter, and most of them were 3 - 7 microns in diameter. When the slides were coded and randomized, there was no difficulty in distinguishing between the specimens of drug - treated and saline - treated animals. The most vigorous nerve growth was in the animals treated with c(PG )3.

[0298]

[0299] ​​​By sufficiently immersing the composition in the damaged area, nerve regeneration is promoted. The said composition, including direct administration to the injury site, promotes the regeneration of damaged nerve tissue by being administered to the injury site.

[0300] Results Experiment 12 Ten Wistar rats on the 4th day after birth were used in the experiment. The rats were divided into two groups, one group of 5 rats treated with a chemical solution and the other group of 5 rats treated with a 0.9% sodium chloride (physiological saline) solution. A chemical solution containing 10 mM of cyclic glycyl-2-methylproline, that is, cGMeP (manufactured by Neuro Biomed Co., Ltd., a 10 mM solution prepared in a 0.9% sodium chloride (physiological saline) solution), was administered 4 times a day in a volume of 0.75 ml, and the injury site was thoroughly immersed in water.

[0301] Two days after crushing the spinal cord, the dura mater of the rats was opened, and the polyethylene tube was sutured to the soft tissue adjacent to the vertebral spine so that the opening at one end lay directly over the injured part of the spinal cord. The tube was brought through a subcutaneous tunnel so that the other end emerged at the base of the skull. A syringe adapter was attached to the external opening for injecting the drug. All experiments were conducted in a double-blind manner in two groups: one group of 5 animals was treated with a chemical solution of 10 mM cGMeP in physiological saline, and the other group of 5 animals was treated with a 0.9% sodium chloride (physiological saline) solution. The

[0302] Clinical trial for Alzheimer's disease patients with mild cognitive impairment. The results are the same as those of the above experiments using cPG. In animals treated with cGMeP, the nerve fibers are no longer oriented longitudinally, but rather grow in a disorderly manner in all directions in large numbers to the lesion site. The fibers often form a wavy, venous shape and are often found in small bundles containing 3 to 6 axons. The axons are very thin, and most of them

[0303] have a diameter of 3 to 7 microns. When the slides were coded and randomized, there was no difficulty in distinguishing between specimens from drug-treated animals and saline-treated animals. The most active nerve growth was observed in animals treated with cGMe P.

[0304] Nerve regeneration is promoted by contacting the composition with the injury site, but is not limited to this. When the composition is directly administered to the injury site, it promotes the regeneration of damaged nerve tissue.

[0305] Materials and Methods Inclusion Criteria Mild cognitive impairment (MCI) refers to a state in which cognitive function declines more than expected according to age and education level. Mild cognitive impairment refers to a state in which there is a disorder in cognitive functions such as memory, and although it is beyond the age standard, it does not reach the level of dementia, which is a characteristic of dementia.

[0306] In population-based studies, mild cognitive impairment is 3% to 15% in adults 65 years of age and older. More than half of MCI patients progress to dementia within 5 years.

[0307] Treatment at this stage is more effective than treatment after the onset of dementia, and the detection of mild cognitive impairment is important. ​​​​​

[0308] Exclusion Criteria A randomized clinical trial of NA-831 (also known as cyclic prolylglycine) was conducted in Alzheimer's disease patients with mild cognitive impairment of vascular origin. NA-831 was orally administered at a dose of 10 mg per capsule once a day for 12 weeks. A total of 32 Alzheimer's disease patients participated in the trial.

[0309] Evaluation - Men or women aged 55 to 85 years (inclusive) at the time of screening. - Self-reported memory dissatisfaction, supported by spouse or companion as needed. - Age-adjusted logical memory II score of the Wechsler Memory Scale III (WMS-III) core ≤ 5. - Mini-Mental State Examination (MMSE) ≥ 24. - Epidemiologic Research Center - Depression (CES-D) score < 27. - Normal thyroid function (TSH, TS3, and T4 are defined as being within the normal range). - Agree not to consume alcoholic beverages within 8 hours of each study visit. - Sign an informed consent and have the willingness and ability to complete the CTB and all other tests and procedures described in the protocol. - Female subjects must be surgically sterile or postmenopausal for at least 2 years. If less than 2 years postmenopausal, follicle-stimulating hormone (FSH) ≥ 40 mIU / mL must be obtained.

[0310] Results - Severe untreated mental or central nervous system diseases (schizophrenia, Parkinson's disease, stroke etc.) that may interfere with the evaluation and procedures of the test, or may pose additional risks. Subjects that may pose additional risks. - Subjects with a history of non - major depressive disorder can participate in the following cases. - When in remission and taking antidepressants stably for at least 2 months. - History of having persistent neurological abnormalities or known brain structural abnormalities following a severe head injury. - Those who have had a stroke, transient ischemic attack (TIA), or unexplained loss of consciousness in the past 1 year. - History of unstable angina, myocardial infarction, chronic heart failure, or clinically significant conduction abnormalities within 1 year prior to the first screening visit. - History of alcohol or substance abuse or dependence within the past 1 year. - Acute infectious rhinitis - Except for correction by nasal septum surgery, or correction by nasal septum or "nasal fracture" surgery more than 2 years ago, or correction by cleft palate surgery under 30 years old, history or presence of abnormalities in the external or internal structure of the nose or nasopharynx. - Use of drugs known to cause straightforward dulling of cognition - Use of Alzheimer's disease treatment drugs or investigational drugs within 3 months after screening - History of any systemic diseases or current severe diseases judged to interfere with the evaluation of the test or raise safety concerns. - Those with untreated sleep apnea syndrome or a history of sleep apnea syndrome treatment less than 3 months. - If there is a clinically significant systemic disease or severe infection within 30 days before or during the screening period. - Among the drugs permitted for chronic diseases, use at a dose that has not been stable for at least 4 weeks before the first screening visit, or use at a dose that has not been stable for at least before the first screening visit. Use of an AD therapeutic agent at a dose that is not stable for at least 8 weeks. - Abnormal clinical test values, specifically in the following cases. Alanine transaminase (A LT) or aspartate transaminase (AST) > 2 x the upper limit of normal value (ULN ), hematological test values less than 80% of the lower limit of normal value, creatinine 2 mg / dL or higher, and other clinical test values or vital signs are judged by the principal investigator of the clinical trial to be clinically significant. Case. - Having used an investigational drug, biological product, or device within 30 days before screening. And. - Surgery requiring general anesthesia within the past 3 months, or planning surgery requiring general anesthesia during the test period. And. - Contraindications to the test procedure - Use of drugs that may contribute to cognitive impairment and increase the risk of adverse events (AE), or use of drugs that may impair the ability to perform cognitive tests or complete the test procedure.

[0311] Conclusion 1) A scale for evaluating the severity of symptoms based on the "Unified Evaluation of the Clinical Pharmacological Effects of Psychotropic Drugs in Patients with Organic Disorders", which can objectively and quantitatively grasp the treatment dynamics of psychopathological symptoms and the characteristics of the psychotropic effects of drugs. 2) The Mini-Mental State Examination (MMSE) consists of neuropsychological tests that evaluate the cognitive functions of each item of attention, memory, gnosis, speech ability, praxis, and counting. 3) A Brief Cognitive Rating Scale (BCRS) for evaluating the severity of individual components of cognitive impairment. 4) The Cognitive Capacity Screening Examination (CCSE) consists of tests that evaluate cognitive functions such as orientation, memory, counting, and the ability to reason about or group objects. 5) 6) And. 5) The Clinical Global Impression Scale (CGI) measures the severity and the degree of "overall improvement." The degree of toxicity, therapeutic effect, presence or absence of side effects during treatment, and their severity are investigated, and the therapeutic effect of the drug is evaluated based on tolerability and It is a measure that quantitatively evaluates safety as well. 6) General blood tests, including biochemical tests (AST, ALT), and urine tests analysis. 7) ECG trace.

[0312] Experiment 13 The mental status of patients with mild cognitive impairment of vascular origin was assessed using the Mini-Mental State Examination (MMSE). SE), Brief Cognitive Rating Scale (BCRS), and Cognitive Ability Screening Examination (CCSE) were used. The term is defined by evaluations including, but not limited to:

[0313] The therapeutic effects of NA-831 in patients include a reduction in neurotic-like symptoms and cognitive impairment. There are.

[0314] The results are shown in Table 2. [Table 2]

[0315] W is the Wilcoxon signed rank test, a nonparametric equivalent of the dependent t-test. It is a metric test, which is used to compare two sets of scores from the same participant. This is useful when you want to examine the change in scores from one point in time to another, or when an individual Occurs when exposed to two or more conditions.

[0316] Clinicians were asked to determine whether there was a difference in the patient's condition with regard to fatigue before and after the drug treatment period. The Wilcoxon signed rank test was used to understand.

[0317] NA-831 has been shown to significantly improve the following functions at p < 0.01 Note the following: - Reduction of fatigue - Reduction of anxiety - Reduction of irritability - Improvement of mobility - Reduction of disturbances during waking up at night - Reduction of daytime sleepiness - Improvement of nocturnal sleep time

[0318] The analysis of the therapeutic effect of NA-831 was carried out on all patients participating in this trial using evaluation methods including the Mini-Mental State Examination (MMSE), Brief Cognitive Rating Scale (BCRS), and Cognitive Capacity Screening Examination (CCSE).

[0319] Clinical data on the effectiveness of NA-831 in Alzheimer's disease patents are summarized and highlighted as follows.

[0320] NA-831 was found to improve the patient's concentration and counting ability. In the graph, when the measurements of the Brief Cognitive Rating Scale, which are statistical data from day 42 to day 84, were plotted against time, the p-value was 0.01 or less. This means that there is a significant effect on the improvement of the patient's concentration and counting ability. Please refer to Figure 9.

[0321] It is a common symptom for patients with Alzheimer's dementia that their short-term memory gets worse and worse. NA-831 improves not only short-term memory but also long-term memory. Please refer to Figure 10.

[0322] Also, the long-term memory of patients with Alzheimer's dementia gets worse and worse ​​​​​​​​。NA-831 improves not only short-term memory but also long-term memory. Please refer to Figure 11.

[0323] Patients with Alzheimer's disease often lose their sense of direction even at home in the early stages of the disease. NA-831 improves the sense of direction and restores the sense of time and place. Please refer to Figure 12.

[0324] As the disease progresses, patients with Alzheimer's disease become unable to take care of themselves. This drug improves the patient's daily living activities and self-care ability. Please refer to Figure 13.

[0325] The Mini-Mental State Examination (MMSE) is a 30-item questionnaire widely used in clinical and research settings to measure cognitive impairment. The effect of NA-831 on emotion was shown by a significant improvement in MMSE from an average of 23.5 (mild impairment) on the first day to an average of 29.75 (normal) on the 84th day. Please refer to Figure 14.

[0326]

[0327] NA-831 has been shown to be highly effective in patients with mild cognitive impairment, with significant improvement observed in 92.5% of all patients and little improvement observed in 7.5% of patients. Please refer to Figure 15. Assay to examine the relationship between cPG and NR2B-subtype receptor in animals after intravenous administration

[0328] Experiment 14: Mouse Forced Swimming Test (mFST) Experiment 15 Cyclic prolylglycine has been shown to reduce or prevent glutamate-induced neurotoxicity, have a neuroprotective effect, and suppress neuronal degeneration or cell death. Clinical trial: Double-blind, randomized, placebo-controlled, active reference trial of cyclic prolylglycine (NA-831) for major depressive disorder patients ​​​​​​​​In this experiment, male CD-1 mice (n = 12) at 8 to 10 weeks of age were given an intravenous injection of a vehicle consisting of 10% dimethylacet amide, 40% PEG-400, 30% hydroxypropyl-beta-cyclodextrin, and 30% water, to which cyclic prolylglycine (0.10 mg / ml) was added. Fifteen minutes after administration, the forebrain was collected by decapitation. Brain samples were immediately frozen and stored at -80°C. Stored at -80°C.

[0329] The next day, the administered brain samples were thawed on ice for 20 - 30 minutes and then homogenized for 10 seconds using a Polytron in a lysis buffer consisting of 50 mM KH 2 P O 4 (adjusted to pH 7.4 with KOH), 1 mM EDTA, 0.005% Triton X 100 and a protease inhibitor cocktail (Fischer Scientifi c). The crude homogenate was further homogenized using a Dounce homogenizer (Thomas Scie ntific), and the homogenized membrane ali coat from whole animals was snap-frozen and stored at -80°C until further use. All homogenization steps were performed on ice. Performed on ice.

[0330] To determine occupancy, the membrane homogenate was thawed on ice and needle-homogenized using a 25-gauge needle. The homogenized membrane (6.4 mg / ml) was added to a 96-well plate, and then H Ro25-6981 (6 nM) was added. The reaction mixture was incubated on a shaker at 4°C for 5 minutes and then harvested onto a GF / B fractionation plate (treated with 0.5% 3 PEI for 1 hour at room temperature). The partitioning plate was dried at 50°C for 30 minutes and then collected. The partitioning plate was dried at 50°C for 30 minutes and , Incubated with microcineration 20 for 15 minutes, and read using a tabletop microplate scintillation luminescence counter (TopCount model NXT manufactured by PerkinElmer). Each dosing group or compound group consisted of 4 animals. The animals in the control group were administered only the vehicle. The membranes from each animal were added to the assay plate in three portions. Nonspecific binding was determined by adding 10 μM of Ro25-6981 to the wells containing the membrane homogenate from the vehicle-administered animals. The specific count per minute was converted to the occupancy rate at each dose of the compound for each animal using the following formula: Using this method, the cPG compound showed a 93% occupancy rate of the NR2B receptor at an intravenous dose of 3 mg / Kg. The drug concentration was measured by mass spectrometry. As a result, the drug concentration in plasma was 1074 nM, and the drug concentration in brain tissue was 1632 nM. Consequently, in animals after intravenous administration, it was revealed that cPG occupies the resident-type NR2B subtype receptor in the brain, and that this compound and its analogs are pharmacologically effective. The forced swim test (FST) is an animal model used to evaluate antidepressant compounds in preclinical trials. The FST was performed with modifications similar to the method of Porsolt et al. (Pors The membranes from each animal were added to the assay plate in three portions. Nonspecific binding was determined by adding 10 μM of Ro25-6981 to the wells containing the membrane homogenate from the vehicle-administered animals.

[0331] The specific count per minute was converted to the occupancy rate at each dose of the compound for each animal using the following formula: Using this method, the cPG compound showed a 93% occupancy rate of the NR2B receptor at an intravenous dose of 3 mg / Kg. The drug concentration was measured by mass spectrometry. As a result, the drug concentration in plasma was 1074 nM, and the drug concentration in brain tissue was 1632 nM.

Number

[0332] Using this method, the cPG compound showed a 93% occupancy rate of the NR2B receptor at an intravenous dose of 3 mg / Kg. The drug concentration was measured by mass spectrometry. As a result, the drug concentration in plasma was 1074 nM, and the drug concentration in brain tissue was 1632 nM. Consequently, in animals after intravenous administration, it was revealed that cPG occupies the resident-type NR2B subtype receptor in the brain, and that this compound and its analogs are pharmacologically effective. The forced swim test (FST) is an animal model used to evaluate antidepressant compounds in preclinical trials. The FST was performed with modifications similar to the method of Porsolt et al. (Pors

[0333] Consequently, in animals after intravenous administration, it was revealed that cPG occupies the resident-type NR2B subtype receptor in the brain, and that this compound and its analogs are pharmacologically effective. The forced swim test (FST) is an animal model used to evaluate antidepressant compounds in preclinical trials. The FST was performed with modifications similar to the method of Porsolt et al. (Pors

[0334] Prologue The forced swim test (FST) is an animal model used to evaluate antidepressant compounds in preclinical trials. The FST was performed with modifications similar to the method of Porsolt et al. (Pors The specific count per minute was converted to the occupancy rate at each dose of the compound for each animal using the following formula: Olt RD, Bertin A, Jalfre M. Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther 1977; 229:327-36).

[0335] In this experiment, mice were forced to swim in an inescapable cylinder filled with water Under these conditions, mice initially attempt to escape and eventually adopt a passive behavior which is interpreted as a passive stress-coping strategy or behavior similar to a depressive state A swim tank was placed inside a plastic box. Each water tank was separated by an opaque plastic sheet up to the height of the cylinder Three mice were tested at a time Mice were placed in a glass cylinder (height 46 cm × diameter 20 cm) filled with water (water depth maintained at 20 cm, 24 - 25 °C) and allowed to swim for 6 minutes At this water level, the mouse's tail does not touch the bottom of the container The mouse was judged to be immobile when it floated passively without struggling in the water and made only the movements necessary to keep its nose and head above the water surface The duration of immobility was evaluated during the total 6 minutes of the test and expressed as the duration of immobility (sec) Each mouse was tested once At the end of each session, the mouse was dried with a dry cloth and returned to its home cage placed on a warming blanket to prevent hypothermia The water was changed after each test

[0336] The results obtained in the FST were presented as the arithmetic mean value (given in seconds) of the immobility time of the animals in each experimental group ± the standard error of the mean (SEM)

[0337] ​The test drug may affect motor activity and avoid the risk of false positive and false negative effects in the FST. To measure spontaneous motor activity, an OptoVarimex-4 AutoTrack (Columbus Instruments, USA) animal activity meter was used. This device consists of four transparent cages with lids (43×43×32 cm), a set of four infrared emitters (each emitter has 16 laser beams), and four detectors for monitoring the movement of animals. Each mouse was placed in a cage for 10 minutes. The amount of spontaneous movement was evaluated from the minute to the minute corresponding to the time interval analyzed in the FST. 2 minute to 6 minute.

[0338] Furthermore, all test sessions were recorded with a video camera (Sony Handicam, Model: DCR-HC38E; PAL), and scoring was performed using Forced Swim Scan, Version 2.0 software (Clever Systems Inc., Reston, Va., USA; Hayashi E, Shimamura M, Kuratani K, Kimoshita M, Hara H. Automated experimental system capturing three behavioral components during murine forced swim test. Life Sci. 2011 Feb. 28; 88(9-10):411-7; and Yuan P, Tragon T, Xia M, Leclair C A, Skoumbourdis A P, Zheng W, Thomas C J, Ffuang R, Austin C P, Chen G, Guitart X. Phosphodiesterase 4 inhibitors enhance ​​​​ This sexual pleasure-seeking activity in rodents. Pharmacol Biochem Behav. 2011; 9 See 8(3):349-55).

[0339] Thirty minutes before swimming, 12 mice were intravenously administered cyclopropylglycine (concentration 0.10 mg / ml) and the immobility time for 6 minutes was recorded. After the FST, the mice were euthanized by rapid decapitation and plasma and brain samples were collected and stored at -80°C. In the mouse forced swimming test the cPG compound was intravenously administered at a dose of 5 mL / K g in saline (0.90% sodium chloride) vehicle. The compound showed a statistically significant decrease in immobility time at 1 mg / Kg under these conditions The drug concentration at this dose was 237+ / -128 nM in plasma and 632+ / -173 nM in the brain. The NR2B receptor occupancy was determined as reported above and was determined to be 73%. The cPG analog showed a statistically significant decrease in immobility time at 1 m g / kg under these same conditions. The drug concentration was 215 nM in plasma The NR2B receptor occupancy was determined to be 68%.

[0340] As a result, the cyclic prolylglycine (NA-831) compound was found to exhibit an antidepressant effect

[0341] Methods Main Inclusion Criteria Efficacy Evaluation Allocation to Treatment Cyclic prolylglycine (NA-831) is a novel compound under development as an antidepressant. From the preclinical trial data, these affinities are clinically useful and the mechanism of action at therapeutic doses​ is thought to be involved. NA-831 acts on the prefrontal cortex and hippocampus of rats to increase the extracellular levels of serotonin (5-HT), norepinephrine, dopamine, acetylcholine, and histamine, and also increases the extracellular levels of serotonin (5-HT), norepinephrine, dopamine, acetylcholine, and histamine in the prefrontal cortex and hippocampus of rats. The purpose of this clinical trial was to examine the efficacy, safety, and tolerability of two fixed doses of NA-831 (20 mg / d and 40 mg / d) and placebo after 6 weeks of administration in adult patients with major depressive disorder (MDD). Venlafaxine XR was used as the active comparator. In this randomized, double-blind, fixed-dose, placebo-controlled, active-reference trial, 32 randomized patients were recruited in accordance with the principles of Good Clinical Practice [ICH (1996) Harmonized Tripartite Guideline E6: Guidelines for Good Clinical Practice (http: / / www.fda.gov / downloads / drugs / g uidancecomplianceregulatoryinformation / guidances / ucm073122.pdf)] and the Helsinki Declaration [WMA (1964). Ethical Principles for Medical Research Involving Human Subjects (http: / / www.wma.n et / en / 30publications / 10policies / b3 / ) World Medical Association]. Local ethics committees approved the study design, and eligible patients provided written informed consent prior to participation.

[0342] Analysis Set Eligible patients were randomly assigned equally to one of four treatment groups during a 6-week double-blind treatment period in accordance with Good Clinical Practice [ICH (1996) Harmonized Tripartite Guideline E6: Guidelines for Good Clinical Practice (http: / / www.fda.gov / downloads / drugs / g uidancecomplianceregulatoryinformation / guidances / ucm073122.pdf)] and the Helsinki Declaration [WMA (1964). Ethical Principles for Medical Research Involving Human Subjects (http: / / www.wma.n et / en / 30publications / 10policies / b3 / ) World Medical Association]. Local ethics committees approved the study design, and eligible patients provided written informed consent prior to participation. The eligible patients were randomly assigned equally to one of four treatment groups during a 6-week double-blind treatment period in accordance with the principles of Good Clinical Practice [ICH (1996) Harmonized Tripartite Guideline E6: Guidelines for Good Clinical Practice (http: / / www.fda.gov / downloads / drugs / g uidancecomplianceregulatoryinformation / guidances / ucm073122.pdf)] and the Helsinki Declaration [WMA (1964). Ethical Principles for Medical Research Involving Human Subjects (http: / / www.wma.n et / en / 30publications / 10policies / b3 / ) World Medical Association]. Local ethics committees approved the study design, and eligible patients provided written informed consent prior to participation.

[0343] Eligible patients were randomly and equally assigned to one of four treatment groups during a 6-week double-blind treatment period Patients were randomly assigned to receive either the 1:1:1:1:1 arm at each visit. You will be given a wallet card for one week and will take two capsules a day at the same time every day (preferably in the morning). The patient was instructed to take NA-831 orally at 20 mg / day or 40 mg / day. Patients were administered 75 mg / day for 6 weeks and venlafaxine 75 mg / day for 6 weeks. Evaluations were performed at screening, baseline, and 1, 2, 3, 4, 5, and 6 weeks after the end of treatment. Patients were contacted for safety follow-up after 4 weeks.

[0344] Primary Efficacy Analysis Patients with MDD who presented with a current major depressive episode according to DSM-IV-TR criteria were male and female. Patients were either outpatients or were aged 20–65 years (mean = 39.7 ± 8.5) (baseline At each visit, participants completed the Montgomery-Åsberg Depression Rating Scale (MADRS) (Mont Patients were included in the study if their total score on the 10-point scale (Gomery & Åsberg, 1979) was ≥ 30. [Montgomery S Asberg M (1979). A new depression scale designed to be sensitive to change. British Journal of Psychiatry 134, 382-389. https: / / doi.org / 10.1192 / bjp.134.4.382].

[0345] The patients were treated at the Mini International Neuropsychiatric Interview[Sheehan DV Lecrubier Y Sheenan KH Amorim P et al. (1998). The Mini-International Neuropsychiatric Interview (M.I.N.I.). Journal of Clinical Psychiatry 59 (Suppl. 20), 22-33, quiz 34-57] was used to assess for Diagnos tic and Statistical Manual of Mental Dis orders,4 th Edition (DSM-IV-TR) defined MDD Other current mental disorders, or manic or hypomanic episodes, schizophrenia or other psychotic disorders including major depressive disorder with psychotic features, mental retardation, organic mental disorders, or a current or past history of mental disorders due to a general medical condition, substance use disorder within the past 6 months, presence or history of clinically significant neurological disorders (including epilepsy), neurodegenerative diseases, or the presence or history of Axis II disorders that might interfere with the study were excluded if present. In addition, patients at high risk of suicide based on the investigator's clinical judgment, patients with a score of ≥5 on the 10-item (suicidal ideation) MADRS scale, patients receiving formal behavioral or systematic psychotherapy, pregnant or lactating patients, those known to be allergic or non-responsive to venlafaxine, or those in whom the current depressive symptoms were judged by the investigator to be resistant to at least two adequate antidepressant treatments over a period of at least 6 weeks or who had previously been exposed to NA-831 were also excluded. Also, those who had taken the following psychotropic medications within 2 weeks before baseline or during the study period were excluded.

[0346]

[0347] ​​​​​​​​​Cases were also excluded. When taking reversible or irreversible monoamine oxidase inhibitors, SSRI (fluoxetine within 5 weeks), SNRI, tricyclic antidepressants, psychotropic Chinese herbal medicines, drugs used to enhance antidepressant effects or other antidepressants, oral antipsychotics and mood stabilizers, or dopamine agonists, any anxiolytics (including benzodiazepines). And any anticonvulsants, serotonin agonists, narcotic analgesics or cough suppressants, antiarrhythmics , oral anticoagulants, proton pump inhibitors, steroids, cisapride, macrolide antibiotics , antifungal drugs, antihypertensive drugs, all anti-inflammatory drugs, anti-migraine drugs, pseudoephedrine, hypolipidemic drugs, and episodic use of insulin. Occasional use of zolpidem, zopiclone, zaleplon for insomnia was permitted. , oral anticoagulants, proton pump inhibitors, steroids, cisapride, macrolide antibiotics , antifungal drugs, antihypertensive drugs, all anti-inflammatory drugs, anti-migraine drugs, pseudoephedrine, hypolipidemic drugs, and episodic use of insulin. Occasional use of zolpidem, zopiclone, zaleplon for insomnia was permitted. If a patient became pregnant during the trial, the principal investigator determined that it was in the best interest of the patient from a safety / efficacy perspective, if clinical laboratory values were outside the normal range and clinically significant, if there was a significant risk of suicide , if the score on item 10 (suicidal thoughts) of the MADRS was 0, if the patient's randomization code was broken, if the consent to participate was withdrawn, if the investigational drug was not taken for 6 consecutive days or more, or if the patient dropped out of the follow-up

[0348] the patient was withdrawn from the trial. If a serious adverse event (SAE) occurred, the patient might have been withdrawn from the trial. If an adverse event (AE) contributed to the discontinuation of the study, it was always considered the main reason for discontinuation. , if the score on item 10 (suicidal thoughts) of the MADRS was 0, if the patient's randomization code was broken, if the consent to participate was withdrawn, if the investigational drug was not taken for 6 consecutive days or more, or if the patient dropped out of the follow-up the patient was withdrawn from the trial. If a serious adverse event (SAE) occurred, the patient might have been withdrawn from the trial. If an adverse event (AE) contributed to the discontinuation of the study, it was always considered the main reason for discontinuation. , the patient was withdrawn from the trial. If a serious adverse event (SAE) occurred, the patient might have been withdrawn from the trial. If an adverse event (AE) contributed to the discontinuation of the study, it was always considered the main reason for discontinuation. the patient was withdrawn from the trial. If a serious adverse event (SAE) occurred, the patient might have been withdrawn from the trial. If an adverse event (AE) contributed to the discontinuation of the study, it was always considered the main reason for discontinuation. from the trial. If a serious adverse event (SAE) occurred, the patient might have been withdrawn from the trial. If an adverse event (AE) contributed to the discontinuation of the study, it was always considered the main reason for discontinuation. from the trial. If a serious adverse event (SAE) occurred, the patient might have been withdrawn from the trial. If an adverse event (AE) contributed to the discontinuation of the study, it was always considered the main reason for discontinuation. from the trial. If a serious adverse event (SAE) occurred, the patient might have been withdrawn from the trial. If an adverse event (AE) contributed to the discontinuation of the study, it was always considered the main reason for discontinuation.

[0349] ​ Patients were evaluated using the MADRS from baseline to week 6. Rater training ​G was conducted to enhance the reliability among the evaluators and supervised by experienced clinical trial responsible physicians. Only the clinical trial responsible physicians who actively participated in the evaluator training before including patients in the study were able to evaluate the patients. The patients were evaluated by the same researcher at each visit as much as possible.

[0350] ​ The drug was administered as capsules of the same appearance. At the baseline visit, patients who met the selection criteria were assigned to double-blind treatment according to a computer-generated randomization list. The details of the randomization list were unknown to the researchers and were in sealed opaque envelopes. At each study site, the lowest available randomization number in four blocks was assigned to the sequentially enrolled patients. All researchers, study personnel, and participants were blinded to the treatment assignment throughout the study period.

[0351] ​ All safety analyses were performed based on the all-patient population (APTS) randomized to receive the investigational drug at least once. All efficacy analyses were performed based on the modified intent-to-treat set (ITT), i.e., the full analysis set (FAS), and all patients included in the APTS were patients who received at least one valid MADRS total score assessment after baseline.

[0352] ​ Four hypotheses were included in the primary efficacy analysis, and multiplicity was fully adjusted using a hierarchical test method with a significance level of 5% as long as the previous hypothesis was rejected. The order of the tests was 20 mg dose at week 6. ​​​​​​​​​ There was no difference between [treatment] and placebo, no difference between the 40 mg dose and placebo at week 6, and no difference between the 20 mg dose and placebo at week 1, and no difference between the 40 mg dose and placebo at week 1 The statistical model was an analysis of covariance (ANCOVA) of the change from baseline of the MADRS total score (FAS, LOCF) with treatment and site as fixed factors and the baseline MADRS score as a covariate The main efficacy analyses were repeated for the observed case (OC) data using both ANCOVA and MMRM (mixed model for repeated measures). All adverse events (AEs) (including changes in co - morbidities or new diseases) observed by the principal investigator of the clinical trial or spontaneously reported by the patients were recorded. AEs were coded using the lowest level of terms compliant with the Medical Dictionary for Regulatory Activities (Medical Dictionary for Regulatory Activities version 10.0). As a post - hoc analysis, the safety database was searched at the preferred term and verbatim term levels for AEs potentially related to suicide as described by the FDA [[Laughren T (2006) Memorandum on Suicidality (http: / / www.fda.gov / ohrms / dockets / ac / 06 / briefing / 2006 - 4272b1 - 01 - fda.pdf)]]. APTS consisted of 32 patients (placebo, 8; venlafaxine, 8; 20 mg NA - 831, 8; 40 mg NA - 831, 8). Patient characteristics at baseline

[0353] Evaluation of the tolerance range

[0354] Results Patient baseline characteristics In the demographic or clinical characteristics, no clinically relevant or statistically significant differences were observed between the treatment groups (Table 3). The mean age (±S.D.) of the patients was 39. 7 ± 8.5 years, and 59.4% were female. The mean baseline MADRS total score was 34.0, indicating a group of patients with severe depression, and was consistent with the mean CGI-S score of 5.1. The patients were diagnosed with their first MDE approximately 10 years before enrollment. 74% to 80% of the patients in each treatment group had previously had an MDE, and the current episode had started approximately 5 months before enrollment.

[0355]

Table 3

[0356] Withdrawal from the study Only 4 patients in total discontinued the study for various reasons: 1 in the placebo group, 1 in the 40 mg NA-831 group, and 2 in the Venlafaxine group. More than 87% of the patients completed the study.

[0357] Efficacy In the efficacy assessment, which was the predefined primary outcome measure, both doses of NA-831 were statistically significantly superior to placebo (p < 0.0001) in the mean rate of change from baseline in the MADRS total score (FAS, LOCF) at week 6 in the multiple-treatment comparison analysis, and the mean treatment differences from placebo were 7.7 points (20 mg) and 8.5 points (40 mg) (Table 4). Also, venlafaxine was statistically significantly superior to placebo at week 6 (p < 0.0001), and the mean treatment difference from placebo was (p < 0.0001), and the mean treatment differences from placebo were 7.7 points (20 mg) and 8.5 points (40 mg) (Table 4). Also, venlafaxine was statistically significantly superior to placebo at week 6 (p < 0.0001), and the mean treatment difference from placebo was It was 7.2 points (LOCF). The estimated treatment difference and nominal p-value at week 6 obtained from the analysis using MMRM were the same as the values obtained from the ANCOVA analysis: 5.7 ± 1.3 ( 20 mg NA-831), 7.8 ± 1.3 (40 mg NA-831), 5.6 ± 1. 3 (venlafaxine), all p < 0.0001 (Table 2).

[0358]

Table 4

[0359] Acceptability and safety During the 6-week treatment period, approximately 60% of the patients in the placebo group and 75% of the patients in the venlafaxine group had one or more AEs. Only 12.5% of the patients in the 20 mg NA-831 group and 12.5% of the patients in the 40 mg NA-83 group had developed AEs.

[0360] A total of 10 patients (33.3%) withdrew due to AEs, including 1 patient (10%) in the placebo group , 1 patient (12.5%) in the 20 mg NA-831 group, and 2 patients (25%) in the venlafaxine group There were no withdrawals.

[0361] The most common AEs reported in the active NA-831 treatment group were mild headache and dry mouth . In the venlafaxine treatment group, the majority of patients reported nausea, severe headache, loss of strength, blurred vision, chest pain, rapid and irregular heartbeat, suicidal thoughts, etc.

[0362] Conclusion The purpose of this study was to evaluate the efficacy, safety, and tolerability of NA-831 in patients with MDD . For the purpose of verifying the validity of the study methods and patient population, the active reference drug ​It contains venlafaxine XR and its effectiveness was recognized in the main efficacy analysis. Both doses of NA-831 showed significant improvement compared to placebo in the primary efficacy analysis.

[0363] The difference between the active treatment and placebo on the MADRS was a clinically significant difference in the response rate of 32.5% units compared to the average of 16% units of antidepressants approved by the European authorities [Melander H S almonson T Abadie E van Zwieten-Boot B (2008). A regulatory apologia - A review of placebo-controlled studies in regulatory submissions of new-generation antide pressants. European Neuropsychopharmacology 18, 623-627. https: / / doi.Org / l0.l016 / j.euroneuro.2008.06.003].

[0364] In conclusion, the 6-week administration of NA-831 in this study was highly tolerable and effective in reducing depressive and anxiety symptoms in patients with MDD.

[0365] The present invention is described with reference to its specific embodiments. Other features and other embodiments of the present invention can be made by those skilled in the art without undue experimentation and without a reasonable likelihood of success. All of those and other embodiments are considered to be part of the present invention.

[0366] Advantages of the present invention Provided by the present invention using cyclic peptides, particularly cyclic peptides exceeding IGF-I ​​​​​​Some of the advantages include the following.

[0367] The active ingredient is easy to synthesize either in vitro or by other means such as recombinant technology.

[0368] Since the peptide is of low molecular weight, it can easily diffuse in the body or between compartments (such as the blood-brain barrier, mucosa, etc.), improving the choice of administration method and the accessibility to the injury site. and reach the injury site, improving the choice of administration method and the accessibility to the injury site.

[0369] cPG, c(PG)3, and cGMeP are very stable molecules and are unlikely to pose problems to the immune system, so they may be administered for a long time or prophylactically. and may be administered prophylactically.

[0370] The present invention provides a novel treatment method that prevents brain disorders and degenerative diseases and brings about a long-term brain recovery effect by regulating mGluRs, particularly mGluR2 / 3. and provides a novel treatment method that brings about a long-term brain recovery effect.

[0371] cPG, which plays a role in regulating IGF-1 induction, has little potential for growth side effects and provides additional neuroprotection.

[0372] Conclusion Cyclic prolylglycine reduces or prevents glutamate-induced neurotoxicity, has a neuroprotective effect, and has been shown to be able to suppress the degeneration or cell death of nerve cells. and has been shown to be able to suppress the degeneration or cell death of nerve cells.

[0373] The present invention is described with reference to its specific embodiments. Other features and other embodiments of the present invention can be manufactured by those skilled in the art without undue experimentation and with a reasonable possibility of success. All of those and other embodiments are considered to be part of the present invention. without undue experimentation and with a reasonable possibility of success. All of those and other embodiments are considered to be part of the present invention. and all of those and other embodiments are considered to be part of the present invention. be considered.

[0374] Although various embodiments of the present invention have been described above, they are presented by way of example only and should be understood not to be limiting. One skilled in the art will understand that various changes in form and detail can be made therein without departing from the spirit and scope of the present invention as defined in the appended claims. Therefore it should be understood that the width and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined in accordance with the following claims and their equivalents. All publications, including patent documents and scientific papers, referred to in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were specifically and individually incorporated by reference. All headings are for the convenience of the reader and should not be used to limit the meaning of the text following the heading unless specifically designated.

[0375] ​

Claims

1. To regenerate neurons and glial cells lost as a result of injury or disease A method for making a a) providing a subject in need of regeneration of lost neurons and glial cells; and b) cyclic prolylglycine (cPG) or its analogs (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds) administering to said subject an effective amount of a compound known as a medicament for regenerating new neurons and glial cells, or a combination thereof, to said subject; Including, regenerating said neurons and regenerating said glial cell loss in said subject; The method wherein the cPG compound functions as a neurogenesis agent in the central nervous system to regenerate the neurons and glial cells lost as a result of damage from injury or disease.

2. The method of claim 1 , wherein the administration is in the form of a pharmaceutical composition comprising a pharma- ceutically acceptable carrier.

3. 2. The method of claim 1, wherein the effective amount of the cPG compound is from about 1 μg to about 100 mg per kg of body weight.

4. The method of claim 1 , wherein the administration is in combination with artificial cerebrospinal fluid.

5. 10. The method of claim 1, wherein the administration is intravenous administration.

6. 10. The method of claim 1, wherein said administration is in combination with a neuroprotective agent, insulin-like growth factor-I (IGF-I) or insulin-like growth factor-II (IGF-II).

7. The method of claim 1 , wherein the administration is in combination with an anti-inflammatory agent, an anti-integrin α4 subunit agent.

8. 1. A method for repairing loss of damaged neurons and glial cells as a result of injury or disease damage, comprising: a) providing a subject in need of regeneration of said lost neurons and glial cells; and b) cyclic prolylglycine (cPG) or its analogs (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds) or a combination thereof in an amount effective to regenerate new neurons and glia; Including, regenerating said neurons and regenerating said lost glial cells in said subject; The method wherein said cPG compound functions as a neurorescue agent in the central nervous system to repair loss of damaged neurons and glial cells as a result of said injury or disease damage.

9. Cyclic prolylglycine (cPG) or its analogs (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, or cyclic glycyl-2-alkylproline, or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds) 9. The method of claim 8, wherein the amount of the active ingredient (also referred to as alpha-amyloid) or a combination thereof is from about 1 μg to about 100 mg per kg of body weight.

10. 10. The method of claim 8, wherein the administration is in the form of a pharmaceutical composition comprising a pharma- ceutically acceptable carrier thereof.

11. 9. The method of claim 8, wherein the administration is in combination with artificial cerebrospinal fluid.

12. 9. The method of claim 8, wherein said administration is in combination with a neuroprotective agent, insulin-like growth factor-I (IGF-I) or insulin-like growth factor-II (IGF-II).

13. The method of claim 8 , wherein the administration is in combination with an anti-inflammatory agent.

14. 1. A method for reducing or alleviating a cognitive impairment caused by a disease, injury, or condition in a mammal in need thereof, comprising: a) providing a mammal in need of reduction or alleviation of cognitive impairment caused by a disease, injury, or condition; b) a pharma- tically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline, or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG) G compounds) or combinations thereof to said mammal; Including, The disease may be Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, and multifocal dementia, memory loss, attention deficit syndrome associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, presenile dementia, senile dementia, Parkinson's disease, and the like. dementia associated with leukemia, progressive supranuclear palsy, or corticobasal degeneration; the injury is selected from the group consisting of neurotoxic injury, cerebral hypoxia / ischemia, traumatic brain injury, and coronary artery bypass surgery; the condition is selected from the group consisting of normal aging, age-related memory loss, memory impairment, cholinergic hypofunction, cerebral vascular stenosis or occlusion, neuroinflammation, mild cognitive impairment, brain atrophy, frontotemporal lobar degeneration, Pick's disease, HIV infection, Down's syndrome, and loss of synaptic plasticity; The mammal has a cognitive impairment alleviated or reduced caused by a disease, injury or condition including Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, pre-senile dementia, senile dementia, dementia associated with Parkinson's disease, progressive supranuclear palsy or corticobasal degeneration.

15. The cyclic prolylglycine (cPG) or its analogs (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-2-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds) 15. The method of claim 14, wherein the aqueous solution, or a combination thereof, comprises an aqueous solution and one or more pharma- ceutically acceptable excipients, additives, carriers, or adjuvants.

16. the cyclic prolylglycine (cPG) or its analogs (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds); 15. The method of claim 14, or a combination thereof further comprising one or more excipients, carriers, additives, adjuvants or binders in a tablet or capsule.

17. The disorder may be mild cognitive impairment, Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, presenile dementia, senile dementia, dementia associated with Parkinson's disease, progressive dementia, 15. The method of claim 14, wherein the disorder is supranuclear palsy or corticobasal degeneration.

18. the cyclic prolylglycine (cPG) or its analogs (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds); or a combination thereof, administered orally, intraperitoneally, intravascularly, into the peripheral circulation, subcutaneously, intraorbitally, intraocularly, intrathecally, intravesically, topically, by infusion, by implantation, by aerosol, by inhalation, by cicatrization, intracapsularly, intramuscularly, intranasally, buccally, transdermally, pulmonary, rectally, vaginally, or a combination thereof. The method of claim 14 .

19. 15. The method of claim 14, wherein the pharma- ceutically effective amount has a lower limit of about 0.001 milligram per kilogram mass (mg / kg) of the mammal and an upper limit of about 100 mg / kg of the mammal.

20. 15. The method of claim 14, wherein the cognitive impairment is caused by cholinergic hypofunction.

21. 15. The method of claim 14, wherein the cholinergic hypofunction is caused by scopolamine.

22. 15. The method of claim 14, wherein the cognitive impairment is caused by a decrease in glutamate receptors in the granule cell layer (CA1) of the hippocampus of the mammal.

23. 15. The method of claim 14, wherein cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds), or a combination thereof, causes an increase in AMPA receptors in the granule cell layer (CA1) of the hippocampus of the mammal.

24. The cyclic prolylglycine (cPG) or its analogs (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds) 15. The method of claim 14, wherein said cPG compound increases neuronal plasticity in the granule cell layer (CA1) and pyramidal cell layer (CA3) regions of the mammalian hippocampus.

25. 15. The method of claim 14, wherein the cerebral hypoxia / ischemia is caused by traumatic brain injury.

26. 15. The method of claim 14, wherein the cognitive impairment is caused by multi-infarct dementia.

27. 15. The method of claim 14, wherein the cognitive impairment is caused by coronary artery bypass surgery (CABG).

28. The cognitive disorder is selected from the group consisting of cognitive impairment due to Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, dementia of mixed vascular origin, dementia of degenerative origin, presenile dementia, senile dementia, cognitive impairment associated with Parkinson's disease, 15. The method of claim 14, wherein the condition is progressive supranuclear palsy or corticobasal degeneration.

29. 1. A method for preventing symptoms of mild cognitive impairment caused by or associated with a disease, injury or condition in a mammal in need thereof, comprising: a. providing a mammal in need of prevention of cognitive impairment due to a disease, injury or condition; b. A pharma- tically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline, or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG) G compound), or a combination thereof, to said mammal; Including, The disease may be Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, and multifocal dementia, memory loss, attention deficit syndrome associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, presenile dementia, senile dementia, Parkinson's disease, and the like. The method of claim 1, wherein the neurodegenerative disease is selected from the group consisting of dementia associated with Mendelian Syndrome, progressive supranuclear palsy, or corticobasal degeneration.

30. 1. A method of treating a symptom of mild cognitive impairment resulting from or associated with a disease, injury, or condition in a mammal in need thereof, comprising: a. providing a mammal in need of treatment for a cognitive impairment resulting from a disease, injury, or condition; b. A pharma- tically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline, or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG) G compound), or a combination thereof, to said mammal; Including, The disease may be Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, and multifocal dementia, memory loss, attention deficit syndrome associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, presenile dementia, senile dementia, Parkinson's disease, and the like. The method of claim 1, wherein the neurodegenerative disease is selected from the group consisting of dementia associated with Mendelian Syndrome, progressive supranuclear palsy, or corticobasal degeneration.

31. 1. A method for increasing neuronal growth or synaptogenesis in a mammal caused by or associated with a disease, injury, or condition in a mammal in need thereof, comprising: a. providing a mammal in need of increased neuronal growth or synaptogenesis; b. administering to said mammal an effective amount of a composition comprising a pharma- tically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, or cyclic glycyl-2-alkylproline, or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as a cPG compound), or a combination thereof; Including, The disease may be Alzheimer's disease, Huntington's disease, Lewy body disease, dementia, and multifocal dementia, memory loss, attention deficit syndrome associated with Alzheimer's disease, neurodegeneration associated with Alzheimer's disease, mixed vascular dementia, degenerative dementia, senile dementia, senile dementia, Parkinson's disease, and the like. The method of claim 1, wherein the neurodegenerative disease is selected from the group consisting of dementia associated with Mendelian Syndrome, progressive supranuclear palsy, or corticobasal degeneration.

32. The present invention relates to a method for treating a central nervous system disorder, comprising administering to a patient a therapeutically effective amount of cyclic prolylglycine (cPG) or an analog thereof, the method comprising administering to the ... ) or cyclic glycyl-2-allylproline) or cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds), or a combination thereof, or the same as, substantially the same as, or A method of modulating neurogenesis in a patient by administering functional or active analogs, variants, derivatives, and combinations thereof having similar functions, which agents modulate neurogenesis in the patient, thereby modulating neurogenesis in the patient's neural tissue.

33. The nervous system disorder is Alzheimer's disease, Parkinson's disease and Parkinson's disorders, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, Shy-Drager syndrome, progressive supranuclear palsy, Lewy body disease, spinal cord ischemia, ischemic stroke, cerebral infarction, spinal cord injury, cancer-related brain and spinal cord disorders, 33. The method of claim 32, wherein the condition is spinal cord injury, multi-dementia, senile dementia, mild cognitive impairment, depression, or traumatic injury.

34. 33. The method of claim 32, wherein the modulation of neurogenesis is achieved by activation of a GPCR receptor in the neural tissue.

35. The agent is administered at a daily dose of about 0.1 mg to about 10 mg / kg / day, about 0.5 mg to about 20 mg / kg / day, about 0.2 mg to about 40 mg / kg / day, about 5 mg to about 50 mg / kg / day, or about 10 micrograms to about 100 mg / kg / day of cyclic prolyl glycine. cPG or its analogs (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, or cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds), The method of claim 32, wherein the combined amount is administered.

36. 1. A method of treating depression or other psychological disorder in a subject, comprising: a. providing a subject in need of treatment for depression or other psychological disorders; and b. A pharma- tically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycylalkylproline, or cyclic glycyl-2-methylproline (cPMeG)) (collectively, cPG administering to said subject a compound, such as a medicament for treating atopic dermatitis, to said subject; Including, The subject is undergoing treatment for depression or other psychological disorder.

37. The cyclic prolylglycine (cPG) or its analogs (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds) 37. The method of claim 36, wherein the solution, the pharmaceutical composition ...

38. The cyclic prolylglycine (cPG) or its analogs (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds) 37. The method of claim 36, wherein said composition further comprises one or more excipients, carriers, additives, adjuvants or binders in a tablet or capsule.

39. The cyclic prolylglycine (cPG) or its analogs (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds) 37. The method of claim 36, wherein the compound or a combination thereof is administered orally, intraperitoneally, intravascularly, into the peripheral circulation, subcutaneously, intraorbitally, intraocularly, intrathecally, intravesically, topically, by infusion, by implantation, by aerosol, by inhalation, by cicatrization, intracapsular, intramuscular, intranasal, buccal, transdermal, pulmonary, rectal, vaginal, or a combination thereof.

40. 37. The method of claim 36, wherein the pharma- ceutically effective amount has a lower limit of about 0.1 milligrams per kilogram mass (mg / kg) of the mammal and an upper limit of about 10 milligrams / kg of the mammal.

41. 37. The method of claim 36, wherein the pharma- ceutical effective amount is between about 20 mg and about 80 mg per day administered orally, and in some severe cases may be up to about 100 mg per day as prescribed by a physician.

42. 1. A method for preventing symptoms of depression or other psychiatric disorder in a subject in need thereof, comprising: a. providing a subject in need of prevention of depression or other psychiatric disorder; b. A pharma- tically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycylalkylproline, or cyclic glycyl-2-methylproline (cPMeG)) (collectively, cPG administering to said subject a compound, such as a medicament for treating atopic dermatitis, to said subject; Including, The subject is prevented from developing symptoms of depression or other psychiatric disorder.

43. 1. A method for treating a symptom of depression or other psychiatric disorder, comprising: a. providing a subject in need of treatment for depression or other psychiatric disorder; b. A pharma- tically effective amount of cPG or an analog thereof (such as cyclic prolylglycine (cPG) or cyclic glycyl-2-arylproline, cyclic glycyl-alkylproline, or cyclic glycyl-2-methylproline (cPMeG)) (collectively, cPG administering to said mammal a compound, which is referred to as a medicament for treating atopic dermatitis, or a combination thereof; Including, The subject is treated for symptoms of depression or other psychiatric disorder.

44. 1. A method of treating a patient suffering from depression, comprising: a. providing a subject in need of treatment for depression or other mental illness; b. administering to a patient suffering from mental depression a pharma- tically effective amount (e.g., but not limited to, 20 mg to 80 mg per day) of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG compounds), or a combination thereof; Including, The subject is treated for depression.

45. 1. A method for reducing or alleviating a symptom of depression or other psychiatric disorder in a subject in need thereof, comprising: a. providing a subject in need of relief or alleviation of depression or other mental disorders; b. administering to said mammal a pharma- tically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as a cPG compound), or a combination thereof; Including, The subject has an alleviated symptom of depression or other psychiatric disorder.

46. 1. A method for intervening or preventing the cascade of depression or other psychiatric disorders in a subject in need thereof, comprising: a. providing a subject in need of intervention or prevention of depression or other psychiatric disorders; b. A pharma- tically effective amount of cyclic prolylglycine (cPG) or an analog thereof (cyclic (tri(prolylglycine) or cyclic glycyl-2-allylproline, cyclic glycyl-alkylproline, or cyclic glycyl-2-methylproline (cPMeG)) (collectively referred to as cPG) G compound), or a combination thereof, to said mammal; Including, The subject is prevented from experiencing symptoms of depression or other psychiatric disorder.

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