Compositions and methods for dye-conjugated cyclized peptides for medical uses

Abstract

Methods for treating neurological disorders, central or peripheral nervous system injuries, and / or secondary pathologies thereof are provided. [Solution] The present disclosure also includes methods and compositions related to the use of compounds comprising specific peptides linked to dyes. In certain embodiments, the peptide DIRG is linked to a BODIPY dye. In specific embodiments, the compositions are used to treat neurological conditions and their associated secondary pathologies, such as spinal cord injury and Alzheimer's disease.

Description

[Technical Field]

[0001] This application claims priority to U.S. Patent Application Serial No. 63 / 395491, filed August 5, 2022, which is incorporated herein by reference in its entirety.

[0002] This invention was made with government support under R01EY029695 awarded by the National Institutes of Health. The government has certain rights in this invention.

[0003] The present disclosure relates to at least the fields of cell biology, neurology, molecular biology, small molecules, and medicine. [Background technology]

[0004] Neurotrauma and neurodegenerative diseases are devastating to both patients and economies, with spinal cord injury (SCI) and Alzheimer's disease (AD) serving as two examples.

[0005] More than 1.4 million people in the United States alone are living with paralysis due to spinal cord injury, with 17,000 new cases occurring each year. In addition to causing immense suffering to patients and their families, the cost of treating each SCI patient can reach up to $1 million in the year of injury and $5 million over the patient's lifetime. 1 SCI costs the US economy more than $40 billion annually 2 Neurons responsible for motor control extend their axons into the spinal cord, and after SCI, they degenerate along with local neurons in the spinal cord, causing paralysis. Spinal cord injury also causes cognitive impairment. 64% of people with spinal cord injury develop cognitive impairment, including declines in visual and working memory, which is 13 times higher than the general population. 3-7 Additionally, the ability to learn new tasks and form new memories is impaired, along with a decline in information processing speed and fluency. 8 To date, there are no FDA-approved treatments that can restore lost motor function or improve cognitive abilities after spinal cord injury.

[0006] Methylprednisolone, a corticosteroid, is the only FDA-approved treatment for SCI to alleviate secondary inflammatory pathology, such as swelling of the spinal cord. Methylprednisolone does not promote recovery of motor function. 9 May be harmful if administered more than 8 hours after injury 10 Even when administered within 8 hours, its effectiveness is controversial. 9 Spinal decompression is an approved surgical procedure performed on spinal cord injury patients immediately after injury to relieve swelling and pressure in the spinal cord and potentially alleviate secondary pathology. 11 While both strategies can improve overall neurological outcome, neither strategy is aimed at improving motor function. To date, there are no FDA-approved treatments aimed at restoring motor function or improving cognitive function after spinal cord injury.

[0007] Spinal cord injury not only affects motor and sensory functions within the central nervous system, but also disrupts peripheral neural circuits and signal transmission to major organs, leading to serious long-term complications outside the central nervous system. Spinal cord injury significantly impacts body composition and metabolism, leading to various risk factors, including obesity, atrophy of lower limb skeletal muscle, reduced daily energy expenditure, altered glucose-insulin homeostasis, and cardiovascular disease. Shortly after spinal cord injury, significant weight loss occurs due to a loss of lean body mass and adipose tissue. Ultrasound imaging has demonstrated abnormal liver function in approximately 80% of patients with chronic spinal cord injury. Magnetic resonance imaging (MRI) has demonstrated increased hepatic fat as a result of spinal cord injury, affecting metabolic profiles. Spinal cord injury also induces liver changes, including lipid infiltration and increased inflammation in the liver. Systemic inflammation and increased inflammatory cytokines in the liver after spinal cord injury are likely to cause liver dysfunction. Spinal cord injury disrupts cardiac innervation, causing autonomic dysfunction in the cardiovascular system, leading to blood pressure and heart rate disorders and cardiovascular disease. 12Additionally, people with spinal cord injuries have a 539% increase in infectious diseases, a 280% increase in respiratory diseases, and a 139% increase in gastrointestinal and kidney-related mortality rates per capita, compared to the average U.S. mortality rate. 13 Therefore, treatments that promote neurological recovery may also indirectly affect peripheral neural circuits and other organs, such as the liver, heart, kidneys, lungs, and gastrointestinal tract.

[0008] Alzheimer's disease (AD) is a progressive disorder characterized by the accumulation of amyloid-β plaques (Aβ) and neurofibrillary tangles (NFTs), synaptic loss, and cognitive decline. 14,15 Alzheimer's disease affects more than 6 million people in the United States. 16 , costing the US economy $305 billion annually 17 Despite recent significant advances in our functional understanding of Alzheimer's disease progression and economic incentives for the development of Alzheimer's disease treatments, with a market value of $9.5 billion and a projected compound annual growth rate (CAGR) of 17.5%, 18 There is still no cure. Current treatments, such as NMDA receptor antagonists and cholinesterase inhibitors, are FDA-approved to slow the progression of cognitive impairment, but they have limited or no effect and cause serious side effects. 19-21 , significantly reducing patients' quality of life. Many patients are not diagnosed early enough to receive effective treatment with FDA-approved drugs. 22,23 This is a major problem: even when diagnosed, only 35-45% of patients or their caregivers are informed of the diagnosis. 24 Therefore, there is a dire need for therapeutic agents that, in most cases, halt the progression of Alzheimer's disease and promote neurological recovery, rather than prevent its onset.

[0009] The tropomyosin receptor kinase (Trk) family has previously been targeted for functional restoration in several neurological disorders, including cognitive impairment, Alzheimer's disease, spinal cord injury, stroke, and Parkinson's disease. 25-30Brain-derived neurotrophic factor (BDNF) and neurotrophic factor (NT)-4 mediate distinct neuronal functions and bind to TrkB. 31 BDNF decreases with age. 32 , improves neuronal survival, neuritogenesis, and neuroplasticity 33,34 BDNF administration reduces inflammation and promotes recovery of motor function in a mouse model of spinal cord injury. 34-36 As we age, neurons become dependent on NT-4 for survival. 37 NT-4 enhances axonal regeneration after nerve injury. 38 Improves learning and memory 39 and reduce neuroinflammation 40 and promote recovery after stroke 41,42 Activation of TrkB has been shown to reduce neuropathic pain, improve plasticity and cognitive function, and promote functional recovery after spinal cord injury. 36,43-46 NT-3 binds to TrkC, but 47 , TrkC also decreases with age. 48 NT-3 is essential for the survival of neurons. 49,50 promotes myelination of regenerating axons in rodent spinal cord injury models 51 promotes regeneration of brain regions in a non-human primate spinal cord injury model 52 , improves cognitive function 53 , promote functional motor recovery 54,55 Therefore, activation of TrkB and TrkC is expected to promote both functional motor recovery and cognitive function in patients with motor and cognitive impairment. A translational challenge is that neurotrophic factors that activate TrkB / TrkC, such as BDNF and NT-3, are not suitable for therapeutic use due to their poor pharmacokinetic profiles, including short half-lives and lack of CNS penetration. 56,57 Synthetic TrkB / TrkC modulators may lack specificity and bioavailability, potentially hindering their clinical potential. Thus, there is a clear need for translatable, potent, and selective TrkB / TrkC modulators that can simultaneously act on multiple pathophysiological processes of therapeutic interest. Summary of the Invention

[0010] Embodiments of the present disclosure include methods and compositions for treating a medical condition, in which one or more dye-conjugated cyclized peptides and / or functional derivatives thereof are useful for treating at least one symptom of the medical condition. In certain embodiments, the medical condition affects the central or peripheral nervous system. In some embodiments, treatment with the dye-conjugated cyclized peptide and / or functional derivative thereof improves at least one symptom of the medical condition and, in certain embodiments, leads to improvement of secondary pathologies associated with the medical condition. In some embodiments, the dye-conjugated cyclized peptide and / or functional derivative thereof improves any type of neurological disorder in an individual, and in certain embodiments, also improves one or more secondary pathologies, such as liver fibrosis and / or cardiac atrophy, in the same individual. In certain embodiments, the dye-conjugated cyclized peptide induces improved neurological recovery and may also lead to improvement of other secondary pathologies, such as liver fibrosis and cardiac atrophy, either by directly promoting the recovery of the organ or indirectly by promoting overall health. In a specific case, the dye-conjugated cyclized peptide is, for example, 5c(i).

[0011] Embodiments of the present disclosure include methods of treating a subject with a therapeutic composition, the method comprising administering a therapeutic composition to the subject, wherein the therapeutic composition provides neuroprotection to the subject, modulates glial scar formation in the subject, treats neurotrauma in the subject, treats a neurodegenerative disease in the subject, or any combination thereof. In some embodiments, the therapeutic composition may comprise a peptide-based therapeutic composition. In certain embodiments, the peptide-based therapeutic composition may include any dye, including at least C-DIRG-C BODIPY® (a fluorescent dye). In some cases, the C-DIRG-C BODIPY® (a fluorescent dye) compound has the formula in FIG. 1. In certain embodiments, the neuroprotection provided by 5c(i) or another one or more dye-conjugated cyclized peptides and / or functional derivatives includes increased neurite regeneration, increased neurite sprouting, increased axonal regeneration, and / or increased axonal sprouting. In certain embodiments, the neuroprotection includes improved survival or viability of neurons and / or their neurites, axons, and / or dendrites, and / or neural cells involved in neuronal survival. In some embodiments, modulation of glial scar formation results in wound closure of spinal cord injury.

[0012] Embodiments of the present disclosure provide methods of treating a medical condition in an individual, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula I, or a functional derivative thereof, the medical condition being neuropathy, fibrosis, liver disease, kidney disease, colon disease, cardiac conditions, metabolic pathologies, muscle-related diseases, respiratory diseases, cancer, osteoporosis, bone loss, pain disorders (e.g., neuropathic pain), spleen disease, pancreatic disease, pathological hormonal changes, peripheral nerve damage, combinations thereof, and the like.

[0013] Because these compounds are bound by a dye (fluorescent or non-fluorescent, fluorescent in the case of 5c(i)), another use for these compounds may be as a tracking system for the compound itself (e.g., for mechanism of action, pharmacokinetics, and toxicity studies) and / or for the target to which the compound binds. For example, in certain embodiments, if the compound binds to a specific protein, the compound may be used in an immunohistochemical assay to visualize the protein or injected into a live animal to visualize the behavior of that protein therein. For example, if the protein target of the compound is cancer-related, the compound may be used to visualize, track, and / or quantify cancer markers, such as for diagnostic purposes and / or for monitoring disease targets (e.g., to monitor the effectiveness of one or more therapeutic agents in an individual).

[0014] Embodiments of the present disclosure include methods of treating neurological disorders, injuries to the central or peripheral nervous system, and / or secondary conditions thereof, comprising administering to an individual a therapeutically effective amount of a composition comprising a compound of Formula I, as described elsewhere herein. In some embodiments, the neurological disorder is a neurodegenerative disease. In some embodiments, the neurological disorder and / or secondary conditions thereof include Alzheimer's disease, multiple sclerosis, frontotemporal dementia, psychiatric disorders, amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumors, cerebral aneurysms, encephalitis, epilepsy, seizures of cerebral origin, Guillain-Barré syndrome, dementia, migraine, Friedreich's ataxia, Huntington's disease, Lewy body disease, spinal muscular atrophy, or Parkinson's disease. In certain embodiments, the injury to the central or peripheral nervous system includes neurotrauma, such as a concussion, traumatic brain injury, or neurotrauma including skull fracture, spinal fracture, and / or spinal cord injury. Any of the compounds encompassed herein may contain exactly or at least the amino acids DIRG. In certain embodiments, the compounds may contain the amino acids CDIRGC.

[0015] Any compound utilized herein may contain a Y group that is, for example, a rhodamine, fluorene, or BODIPY® dye, or it may be an organic fragment that provides a spacing between two sulfur atoms, such as a BODIPY® dye ±1 angstrom. Such a fragment may, in certain cases, include a chain with five atoms. In some embodiments, Y is not a dye. In certain embodiments, Y is:

[0016] [ka]

[0017] In certain cases, R5, R6, R7, and R8 are each independently H, halide, C1-C3 alkyl, or SO3H or a salt thereof; R5 and R6 can optionally be joined to form a ring; R7 and R8 can optionally be joined to form a ring; and / or R9 is H, halide, C1-C3 alkyl, or SO3H or a salt thereof, or aryl.

[0018] In certain embodiments, the individual has a secondary condition including fibrosis (e.g., liver fibrosis), liver disease, kidney disease, colon disease, cardiac conditions, metabolic pathologies, muscle-related diseases, respiratory diseases and / or cancer.

[0019] Embodiments of the present disclosure include methods of improving locomotor function, improving mobility, improving long-term memory, improving cognition, reducing fibrosis, and / or reducing inflammation in an individual, comprising administering to the individual a composition comprising a compound of Formula I as described elsewhere herein. In certain embodiments, the individual may have a neurological disorder, damage to the central or peripheral nervous system, and / or a secondary condition thereof. The neurological disorder may be a neurodegenerative disease. In certain embodiments, the neurological disorder and / or a secondary condition thereof includes Alzheimer's disease, multiple sclerosis, frontotemporal dementia, psychiatric disorders, amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumors, cerebral aneurysms, encephalitis, epilepsy, seizures of cerebral origin, Guillain-Barré syndrome, dementia, migraine, Friedreich's ataxia, Huntington's disease, Lewy body disease, spinal muscular atrophy, or Parkinson's disease. Injury to the central or peripheral nervous system can include neurotrauma such as concussion, traumatic brain injury, skull fracture, spinal fracture and / or spinal cord injury.

[0020] In certain embodiments of any of the compositions encompassed herein, the compound may comprise, consist of, or consist essentially of the amino acids DIRG. The compound may, in some instances, comprise the amino acids CDIRGC.

[0021] In certain embodiments, the Y group of formula I is a rhodamine, fluorene, or BODIPY® dye. In some cases, Y can be:

[0022] [ka]

[0023] R5, R6, R7, and R8 can each independently be H, a halide, a C1-C3 alkyl, or SO3H or a salt thereof; R5 and R6 can optionally be joined to form a ring; R7 and R8 can optionally be joined to form a ring; and R9 is H, a halide, a C1-C3 alkyl, or SO3H or a salt thereof, or aryl.

[0024] In some cases, the individual may have a secondary condition including fibrosis (including liver fibrosis), liver disease, kidney disease, colon disease, cardiac conditions, metabolic pathologies, muscle-related diseases, respiratory diseases and / or cancer.

[0025] Embodiments of the present disclosure include methods for monitoring the location of a compound in vivo or ex vivo, comprising directly or indirectly identifying a compound comprising Formula I and / or a molecule to which the compound binds in an individual. The compound may contain just the amino acid DIRG, or additional amino acids may be present. In some cases, the compound contains the amino acid CDIRGC. The Y group can be a rhodamine, fluorene, or BODIPY® dye. In some embodiments, Y is:

[0026] [ka]

[0027] wherein R5, R6, R7, and R8 are each independently H, halide, C1-C3 alkyl, or SO3H or a salt thereof; R5 and R6 can optionally be joined to form a ring; R7 and R8 can optionally be joined to form a ring; and / or R9 is H, halide, C1-C3 alkyl, or SO3H or a salt thereof, or aryl.

[0028] In some embodiments, the method provides information regarding the mechanism of action, pharmacokinetics, and / or toxicity of one or more compounds, for example, using immunohistochemical assays. In some embodiments, the method includes monitoring the location of the compound or the molecule to which it binds (which may or may not be a cancer antigen or marker) in a mammal. Any individual may be known to have cancer, suspected to have cancer, or at risk for having cancer. In some embodiments, the method provides diagnostic and / or prognostic information for individuals suspected of having cancer or at risk for having cancer. In certain embodiments, the method provides information regarding the effectiveness of treatment for individuals known to have cancer, suspected of having cancer, or at risk for having cancer.

[0029] Any method included herein can be performed on an individual once or multiple times on an individual.In certain cases, this method can monitor the effectiveness of treatment on an individual over time.In some cases, treatment is the compound itself, while in other cases, treatment is not the compound.

[0030] It is contemplated that any embodiment discussed herein can be implemented with respect to any method or composition of the present disclosure, and vice versa. Further, compositions of the present disclosure can be used to achieve the methods of the present disclosure.

[0031] Other objects, features, and advantages of the subject matter of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating particular embodiments of the present disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. [Brief explanation of the drawings]

[0032] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0033] [Figure 1] Chemical structure of 5c(i).

[0034] [Figure 2] 5c(i) binds to the TrkB and TrkC receptors. Trk-positive transfected cell lines (TrkB-HEK293 and TrkC-NIH / 3T3) and Trk-negative non-transfected cell lines (HEK293 and NIH / 3T3) were seeded at approximately 2,000 cells / well in 96-well plates and incubated for 24 hours. Cells were treated for 2.5 hours with serial dilutions of compound (0, 10, 25, 50, 100, 200, 500, and 1000 nM) in serum-free medium (SFM) with or without A) 0.6 nM BDNF (TrkB-HEK293 and HEK293) and B) 0.2 nM NT-3 (TrkC-NIH / 3T3 and NIH / 3T3). The cells were then washed once with PBS to remove unbound compound and lysed in 1% (w / v) aqueous sodium dodecyl sulfate. Cell-associated fluorescence was then determined by measuring the emission of the resulting solution at λex (540 / 25 nm) and λem (620 / 40 nm) using an Agilent BioTek Synergy H4 Hybrid Microplate Reader. Kd was calculated using GraphPad Prism 9 using binding saturation (single-site specific binding).

[0035] [Figure 3A]5c(i) enhances neurite formation and neuronal survival. Primary adult cortical neurons from 6-month-old female mice were treated with 5c(i) for 2 days. 5c(i) was added at the time of cell plating. Cells were fixed 2 days after cell plating. Graphs represent the mean ± SEM of the percent change in neurite outgrowth and number of surviving neurons per cell. [Figure 3B] Representative images of the vehicle-treated group. [Figure 3C] Representative images from the 5000 nM 5c(i) treatment group. Linear regression was performed to determine statistical significance. N=2-8. *(p<0.05), **(p<0.01), ***(p<0.001), ****(p<0.0001) vs. vehicle control group. Scale bar=50 μm.

[0036] [Figure 4A] 5c(i) induces synapsin I production and reduces C3 and GSK-3β expression from astrocytes, promoting neuronal survival and neurite outgrowth. Primary adult cortical astrocytes from 6-month-old male mice were incubated with 5 μM 5c(i) for 3 days. Graphs represent the mean ± SEM of the percent change in fluorescence intensity (synapsin I and C3) or chemiluminescence (GSK-3β) relative to vehicle (4A and 4D). [Figure 4B] Images represent vehicle-treated groups stained with synapsin I and DAPI. [Figure 4C] Images represent the 5 μM 5c(i) treated group stained with synapsin I and DAPI. [Figure 4D] Cortical astrocytes from 6-month-old male mice were seeded and incubated with 5c(i) or vehicle for 2 days. The cells were then washed, and cortical neurons from 6-month-old male mice were added on top of the astrocytes. Graphs represent the mean ± SEM of percent change relative to vehicle as measured using immunocytochemistry. *(p<0.05)**(p<0.01)***(p<0.001)****(p<0.0001). Scale bar = 50 μm.

[0037] [Figure 5A] 5c(i) reduces lesion size. Primary adult cortical astrocytes from 6-month-old female mice were scratched to form a lesion model and immediately incubated with 5c(i) for 48 hours (5A). Graphs show mean ± SEM. [Figure 5B] Images represent phalloidin stained vehicle-treated group. [Figure 5C] Images represent phalloidin-stained 5000 nM 5c(i)-treated group. Linear regression was performed to determine statistical significance. N=10. Scale bar=500 μm.

[0038] [Figure 6] 5c(i) penetrates the blood-brain and spinal cord barriers. Four-month-old, uninjured female mice were administered 60 mg / kg 5c(i) IP. One hour after 5c(i) administration, the mice were euthanized and perfused with PFA. Spinal cords were dissected, sectioned sagitally at 25 μm, and stained with NeuN and DAPI. Brains were dissected, sectioned sagitally at 50 μm, and stained with GFAP and DAPI. 5c(i) was identified by its intrinsic fluorescence. Scale bar = 100 μm.

[0039] [Figure 7] Illustration of the activity of 5c(i) on neurons and astrocytes.

[0040] [Figure 8]Timeline of preclinical in vivo animal studies used to support the claims. Mice underwent baseline cognitive testing and blood sampling immediately prior to SCI. Mice underwent SCI at 8 weeks of age. SCI model: thoracic vertebral vertebral contusion (50 kDyne impact) and compression (2-second dwell time), a severe contusion / compression model closely resembling clinically observed injury. To reflect clinically observed delays, 5c(i) (5 or 25 mg / kg / day) or vehicle was administered IP daily starting 4 hours after injury. Locomotor behavioral testing (BMS and rotarod) was performed weekly for 7 weeks. Seven weeks after injury, mice underwent cognitive behavioral testing (NOR and Y-maze), and blood was sampled again. Seven weeks after SCI, mice were euthanized for perfusion and tissue preparation for further analysis.

[0041] [Figure 9A] 5c(i) reversed paralysis and improved survival. Eight-week-old male mice with severe T8 contusion / compression SCI received daily IP injections of 5c(i) (5 and 25 mg / kg / day) for 7 weeks, during which behavioral testing was performed. BMS scores were recorded and graphed over time after injury. [Figure 9B] BMS subscores were recorded and graphed with respect to time after injury. [Figure 9C] Percentage of mice surviving 49 days post-injury. Sham mice undergo only a T7-T9 laminectomy and are treated with vehicle only. N=6-8. Graph shows mean and SEM. The following symbols #(p<0.1)*(p<0.05)**(p<0.01)***(p<0.001)****(p<0.0001) indicate significant differences between that cohort and vehicle (injury). Student's T-test.

[0042] [Figure 10A] 5c(i) improves memory function. Eight-week-old male mice with severe T8 contusion / compression SCI received daily IP injections of 5c(i) (5 and 25 mg / kg / day) for 7 weeks. Seven weeks after injury, NOR was performed. Total number of independent visits to the novel object. [Figure 10B] Latency to visit a novel object. [Figure 10C] Proportion of time spent with the object (ratio of novel / familiar object). Sham mice underwent T7-T9 laminectomy only and were treated with vehicle only. N=6-8. Graph shows mean and SEM. #(p<0.1)*(p<0.05)**(p<0.01)***(p<0.001)****(p<0.0001). Student's t-test.

[0043] [Figure 11A] Histological analysis of spinal cords after 5c(i) treatment. Eight-week-old male mice with severe T8 contusion / compression SCI received daily IP injections of 5c(i) (5 and 25 mg / kg / day) for 7 weeks. Seven weeks after injury, spinal cords were sectioned sagitally for histological analysis. Values for the change in 5-HT intensity versus distance from injury (- values represent rostral to injury, + values represent caudal to injury). [Figure 11B] Mean fluorescence intensity values of IBA1 versus distance from injury (- values represent rostral to injury, + values represent caudal to injury). [Figure 11C] Values of mean CD68 fluorescence intensity versus distance from injury (- values represent rostral to injury, + values represent caudal to injury). [Figure 11D] Values for number of CD68+ cells versus distance from injury (- values represent rostral to injury, + values represent caudal to injury). [Figure 11E] Values for the number of SOX9+ cells versus distance from injury (- values represent rostral to injury, + values represent caudal to injury). SHAM mice underwent only T7-T9 laminectomy and were treated with vehicle only. N=6-8. Graphs show mean and SEM. The following symbols, #(p<0.1)*(p<0.05)**(p<0.01)***(p<0.001)****(p<0.0001), represent significant differences between that cohort and vehicle (injury). Student's T-test.

[0044] [Figure 12A]5c(i) treatment reduced liver fibrosis. Eight-week-old male mice with severe T8 contusion / compression SCI received daily IP injections of 5c(i) (5 and 25 mg / kg / day) for 7 weeks. Seven weeks after injury, livers were sectioned and stained with Masson's trichrome to quantify collagen deposition. [Figure 12B] Seven weeks after injury, heparinized plasma was collected and alanine aminotransferase (ALT) levels were assessed. [Figure 12C] Seven weeks after injury, heparinized plasma was collected and alkaline phosphatase (ALP) levels were assessed. [Figure 12D] Seven weeks after injury, heparinized plasma was collected and aspartate aminotransferase (AST) levels were assessed. [Figure 12E] Seven weeks after injury, heparinized plasma was collected and blood urea nitrogen (BUN) levels were assessed. Sham mice underwent T7-T9 laminectomy only and were treated with vehicle only. N=6-8. Graphs show mean and SEM. #(p<0.1)*(p<0.05)**(p<0.01)***(p<0.001)****(p<0.0001). Student's t-test. DETAILED DESCRIPTION OF THE INVENTION

[0045] I. Example Definitions Following long-standing patent law practice, the words "a" and "an" herein, including in the claims, when used in conjunction with the word "comprising," refer to "one or more." Some embodiments of the present disclosure may consist of, or consist essentially of, one or more elements, method steps, and / or methods of the present disclosure. It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein, and that different embodiments may be combined.

[0046] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for any measuring or quantitating method.

[0047] When used with the term "comprising," the use of the words "a" or "an" may mean "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more."

[0048] The phrase "and / or" means "and" or "or." By way of example, A, B, and / or C includes A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination, and A, B and C in combination. In other words, "and / or" operates as an inclusive or.

[0049] The words "comprising" (and any form of comprising, such as "comprises", "comprises", "including"), "having" (and any form of having, such as "have", "has", "having"), "including" (and any form of including, such as "includes", "include", "containing") or "containing" (and any form of containing, such as "contains", "contain") are inclusive or open-ended and do not exclude additional, non-repeated elements or method steps.

[0050] Compositions and methods of use thereof may "comprise," "consist essentially of," or "consist of" any of the components or steps disclosed throughout this specification. Compositions and methods "consisting essentially of" any of the disclosed components or steps limit the scope of the claim to the specified materials or steps that do not materially affect the basic and novel characteristics of the claimed invention.

[0051] Throughout this specification, references to "one embodiment," "one embodiment," "particular embodiment," "related embodiment," "an embodiment," "additional embodiment," or "further embodiment," or combinations thereof, mean that the particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the appearances of such phrases in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0052] As used herein, "pharmaceutically acceptable carriers" include any and all aqueous solvents (e.g., water, alcoholic / aqueous solutions, saline, parenteral vehicles such as sodium chloride and Ringer's dextrose), non-aqueous solvents (e.g., propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters such as ethylolate), dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial or antifungal agents, antioxidants, chelating agents, and inert gases), isotonicity agents, absorption delaying agents, salts, drugs, drug stabilizers, gels, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, fluid and nutrient replenishers, such materials and combinations thereof will be known to those skilled in the art. The pH and exact concentration of the various components in a pharmaceutical composition are adjusted according to well-known parameters.

[0053] The term "subject" as used herein generally refers to an individual having a condition treatable with 5c(i) and / or a functional derivative, or an individual suspected of having a condition treatable with 5c(i) and / or a functional derivative. A subject can be any living organism or animal subject that is the subject of a method or material, including mammals, such as humans, experimental animals (e.g., primates, rats, mice, rabbits), livestock (e.g., cows, sheep, goats, pigs, turkeys, chickens), domestic pets (e.g., dogs, cats, rodents), horses, and transgenic non-human animals. A subject can be a patient, e.g., having or suspected of having a disease (sometimes referred to as a condition), such as a neurological disorder. A subject can be undergoing or have previously undergone treatment. A subject can be asymptomatic. A subject can be a healthy individual, or an individual wishing to prevent a neurological disorder. The terms "individual" and "individual" can be used interchangeably, at least in some cases. As used herein, a "subject" or "individual" may or may not be housed in a medical facility, or may be treated as an outpatient in a medical facility. An individual may receive one or more medical compositions via the internet. An individual may include humans or non-human animals of any age, and thus includes both adults and juveniles (i.e., children) and infants, including individuals in utero. The term does not imply the need for medical treatment; therefore, an individual may participate in an experiment, whether clinical or in support of basic scientific research, whether voluntary or involuntary.

[0054] As used herein, "treatment" or "treating" includes any beneficial or desired effect on the symptoms of a disease or pathological condition or pathological state, and may also include a minimal reduction in one or more measurable markers of the disease or condition being treated, e.g., cancer. Treatment can optionally include either a reduction or amelioration of one or more symptoms of the disease or condition, or a delay in the progression of the disease or condition. "Treatment" does not necessarily indicate a complete eradication or cure of the disease or condition or its associated symptoms. "Treatment" can also refer to the alleviation of at least one symptom of a disease or condition.

[0055] As used herein, the term "functional derivative" refers to a compound comprising a peptide linked to a dye having structural similarity to 5c(i) and retaining at least 10, 20, 30, 40, 50, 60, 70, 80, or 90% or more of the activity of 5c(i). Multiple activities for a functional derivative may be measured to determine functionality. In certain embodiments, the activity measured is modulation of TrkB and / or TrkC. In some embodiments, the activity measured is activating TrkB and / or TrkC. In certain embodiments, the activity measured is binding TrkB and / or TrkC. In some embodiments, the activity measured is modulation of pathways either upstream or downstream of TrkB and / or TrkC. In some embodiments, the activity measured may include interaction with GSK3beta, complement competent 3 (C3), and / or synapsin I, and in certain cases, such interaction results in alternative methods of action. In some embodiments, the activity measured relates to pathways associated with or linked by GSK3beta, C3 and / or synapsin I. In certain embodiments, the activities measured include the ability to improve wound healing; alter astrogenesis; increase the number of pro-regenerative astrocytes; improve neurite regeneration, sprouting, and / or sparing; improve axonal regeneration, sprouting, and / or sparing; improve cell survival and / or neuroprotection; improve synaptogenesis; reduce levels of CD68 (e.g., systemically and / or locally in any region, particularly the central and peripheral nervous system and / or vital organs (heart, spleen, liver, lungs, and / or GI tract)); reduce inflammation; and target stem cell differentiation and / or proliferation in one or more of the following locations: the peripheral nervous system (PNS), Schwann cells located in the PNS, glial cells (astrocytes, oligodendrocytes, microglia, Shawn cells, ependymal cells, or a combination thereof), hepatic stem / progenitor cells, and / or intestinal cells.

[0056] As used herein, terms such as "secondary pathology" refer to any pathology associated with or resulting from a primary pathology (disease / disorder) that is not the predominant phenotype. In certain embodiments, it includes one or more diseases resulting from changes in one organ or tissue as a result of disease in another organ or tissue. In certain embodiments, it refers to a disease or disorder or condition that is a direct or indirect result of neurological damage and / or damage to the central and / or peripheral nervous system.

[0057] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight-chain (i.e., unbranched) or branched carbon chain that may be fully saturated, monounsaturated, or polyunsaturated. Unsaturated alkyl groups are those having one or more double or triple bonds. Saturated alkyl groups include those having one or more carbon-carbon double bonds (alkenyl, also olefinic) and those having one or more carbon-carbon triple bonds (alkynyl). The groups -CH(Me), -CHCH(Et), -CHCHCH(n-Pr), -CH(CH)(iso-Pr), -CHCHCHCH(n-Bu), -CH(CH)CHCH(sec-butyl), -CHCH(CH)(iso-butyl), -C(CH)(tert-butyl), -CHC(CH)(neo-pentyl) are all non-limiting examples of alkyl groups. As used herein, alkyl groups can be substituted or unsubstituted.

[0058] The term "aryl" refers to a polyunsaturated aromatic hydrocarbon substituent. Aryl groups can be monocyclic or polycyclic (e.g., 2 to 3 rings fused together or covalently linked). The term "heteroaryl" refers to an aryl group containing 1 to 4 heteroatoms selected from N, O, and S. Heteroaryl groups can be attached to the remainder of the molecule through a carbon atom or a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, Examples of aryl and heteroaryl ring systems include 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. As used herein, alkyl groups can be substituted or unsubstituted.

[0059] The term "acyl" is defined as a carbonyl group attached to an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group, and includes, but is not limited to, groups such as acetyl and benzoyl.

[0060] As used herein, the term "heterocyclyl" refers to a saturated 3- to 8-membered ring containing 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Representative examples include indolyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl, and the like.

[0061] Various groups are described herein as substituted or unsubstituted (i.e., optionally substituted). Optionally substituted groups may contain one or more substituents independently selected from halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, oxo, carbamoyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and other substituents known in the art. In certain embodiments, the optional substituents may be further substituted with one or more substituents independently selected from halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, unsubstituted alkyl, unsubstituted heteroalkyl, alkoxy, alkylthio, alkylamino, (alkyl)amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. Exemplary optional substituents include -OH, oxo (=O), -Cl, -F, Br, C 1-3 Alkyl, phenyl, benzyl, -NH2, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, -NO2, -S(C 1-4 alkyl), -SO2(C 1-4 alkyl), -CO2(C 1-4 alkyl) and -O(C 1-4 alkyl), but are not limited to.

[0062] The term "pigment" refers to an organic compound that absorbs light in the visible spectrum (400-700 nm), contains at least one chromophore, and has a conjugated system of electrons, i.e., alternating double and single bonds. II. COMPOUND EMBODIMENTS

[0063] In certain embodiments, the compound is a modulator of TrkB, TrkC, or both, and in certain embodiments, the compound is an activator of TrkB, TrkC, or both, hi certain embodiments, the compound is capable of crossing the blood-brain barrier and / or the blood-spinal cord barrier.

[0064] In certain embodiments, compounds of the present disclosure for use in the present methods include compounds comprising a peptide linked to a dye. In certain embodiments, the compounds comprise one or more dye-linked cyclized peptides. The compounds may comprise peptides with specific amino acid compositions. In certain embodiments, the peptide is a hexamer. In certain embodiments, one or more amino acids for linking the hexamer to the dye are at the N-terminus and / or C-terminus of the hexamer. In some embodiments, the peptide is not a hexamer, but may instead be a trimer, tetramer, pentamer, heptamer, octamer, nonamer, etc.

[0065] In some embodiments, the peptide of the compound may comprise a tetrameric DIRG. In certain embodiments, the tetramer, pentamer, or hexamer is linked by its N- and C-termini to a dye, in some cases including a BODIPY® (fluorescent dye) dye. In some aspects, the tetramer, pentamer, or hexamer is linked to the dye through one amino acid or through two amino acids. For example, the peptide C-(DIRG)-C may be linked to the dye through the sulfur atoms on each terminal cysteine amino acid. In some cases, the peptide may be C-(AA 1-4)-C. In some cases, the peptide has the structure DIKG, DMSG, DLRG, INNS, VSKG, TQNS, TGNS, AGGS, DGKQ, DEKQ, DSKK, ENNK, or DAQG. In certain embodiments, the N- and C-termini of the tetramer, pentamer, or hexamer are linked to a C4-C6 alkyl. In some examples, the N- and C-termini of the tetramer, pentamer, or hexamer are linked to a spacer group such that the distance between the atom attached to the N-terminus and the C-terminus of the peptide moiety is the same as the distance between the BODIPY atom attached to the N-terminus and the C-terminus of the peptide moiety ±1 Å.

[0066] The composition of matter of 5c(i) (as an example) is described in International Publication No. WO2022256394A2, incorporated herein by reference. In certain cases, the DIRG peptide sequence is conjugated to a fluorescent dye, such as a BODIPY® (fluorescent dye) dye. In some cases, one or more amino acid changes in D, I, R, or G may be present. In some embodiments, the changes are conservative amino acid changes. In some examples, amino acid substitutions or replacements are selected so that the replacement amino acid has similar physicochemical properties, such as electronegativity, steric size, and lipophilicity, to the amino acid being replaced. Replacing one amino acid in a parent compound with a different amino acid with similar physicochemical properties can result in a compound that exhibits similar biological activity to the parent compound. For example, D can be changed to E; I can be changed to G, A, V, or L; R can be changed to H or K; and G can be changed to I, A, V, or L. If the peptide is a pentamer, hexamer or longer, the peptide may or may not contain the sequence DIRG, and is included as a contiguous sequence of DIRG.

[0067] In some embodiments, the dye is a divalent dye. The divalent dye may be represented by the following formula II: [ka] II (wherein R5, R6, R7, and R8 are each independently H, halide, C1-C3 alkyl, or SO3H or a salt thereof; R5 and R6 can optionally be joined to form an aryl ring; R7 and R8 can optionally be joined to form an aryl ring; and R9 is H, halide, C1-C3 alkyl, aryl, or SO3H or a salt thereof).

[0068] In some embodiments, the dye is rhodamine. When attached to a peptide as disclosed herein, the rhodamine dye can be represented by the following Formula III: [ka] III

[0069] In a further embodiment, the dye is a fluorene. When attached to a peptide as disclosed herein, the fluorene dye can be represented by the following Formula IV: [ka] IV

[0070] In some examples, the dye has a fluorescence emission greater than 490 nm. Fluorescence emission can be measured in water or in organic solvents such as acetone, pentane, hexane, ethyl acetate, tetrahydrofuran, methylene chloride, chloroform, isopropanol, dimethyl sulfoxide, diethyl ether, carbon tetrachloride, cyclohexane, butyl acetate, 1,4-dioxane, 1-butanol, and heptane. The dye can have a fluorescence emission at, below, above, between, or in any range of 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, or 700 nm. In certain embodiments, the dye is represented by the following formula: *represents the point of covalent attachment to the sulfur atom in the cysteine residue in the sequence below. [ka]

[0071] BODIPY® (fluorescent dye) dyes can be synthesized according to general procedures found in the literature (see Li, L.; Han, J.; Nguyen, B.; Burgess, K., J. Org. Chem. 2008, 73, 1963-1970). Any BODIPY® (fluorescent dye) dye or its derivatives can be used (see Loudet and Burgess, Chem. Rev. 2007, 107, 11, 4891-4932; or Poddar and Misra, Coordination Chemistry Reviews. Volume 421, 15 October 2020, 213462).

[0072] In some embodiments, the composition has one or more charged groups, while in some embodiments, there are no charged groups.

[0073] In certain embodiments, a therapeutic composition may include a DIRG peptide. In certain embodiments, a therapeutic composition may include a peptide containing one or more conservative substitutions in a DIRG peptide. In certain embodiments, a therapeutic composition may include a DIRG peptide linked to a dye. In certain embodiments, a therapeutic composition may include a peptide containing one or more conservative substitutions in a DIRG peptide, where the peptide is linked to a dye. Any peptide of the present disclosure may be linked to a dye through one, two, or more amino acids. Any peptide of the present disclosure may be linked to a dye at the N-terminus and C-terminus. Any peptide of the present disclosure may be linked to a dye through one or more amino acid side chains. Any peptide of the present disclosure may be linked to a dye at the N-terminus and C-terminus, where each linkage is the same amino acid. Any peptide of the present disclosure may be linked to a dye at the N-terminus and C-terminus, where each linkage is a different amino acid. In certain cases, any peptide of the present disclosure may be linked to a dye at the N-terminus and C-terminus, where each linkage may or may not be a cysteine. III. EMBODIMENTS OF USE OF THE COMPOUNDS

[0074] In certain embodiments, the present disclosure encompasses methods of use for compounds comprising one or more dye-conjugated cyclized peptides for one or more specific medical conditions, hi certain embodiments, the present disclosure encompasses methods of use for one or more dye-conjugated cyclized peptides and / or functional derivatives thereof for neurological symptoms and all other conditions associated with those neurological symptoms.

[0075] In certain embodiments, treatment of an individual in need with 5c(i) and / or a functional derivative thereof improves locomotor function, improves mobility, improves long-term memory, improves cognition, reduces fibrosis (including liver fibrosis), reduces inflammation, treats cancer, and the like.

[0076] In certain embodiments, there are methods of treating neuroinflammation, including, by way of example, neuroinflammation associated with various neurological disorders, neurodegenerative diseases, traumatic brain injury, bacterial, viral and fungal meningitis, and stroke. In certain embodiments, the individual in need thereof has or is at risk of having a neurological disorder, a neurodegenerative disease, a traumatic brain injury, bacterial meningitis, viral meningitis, fungal meningitis, or stroke.

[0077] Examples of neurological disorders (e.g., diseases of the brain, spine, and the nerves connecting them) include at least Alzheimer's disease, multiple sclerosis, frontotemporal dementia, psychiatric disorders (e.g., anxiety disorders, schizophrenia, behavioral and affective disorders, bipolar affective disorder, depression, dissociative and dissociative disorders, eating disorders, obsessive-compulsive disorder, paranoia), amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumors, cerebral aneurysms, encephalitis, epilepsy, seizures of cerebral origin, Guillain-Barré syndrome, dementia, migraines, or Parkinson's disease. Individuals with any neurological disorder may be subjected to the methods and compositions of the present disclosure. Individuals with symptoms such as headaches, seizures of cerebral origin, loss or tingling of sensation, muscle weakness or loss, blindness or double vision, memory loss, impaired mental ability, lack of coordination, and / or stroke may be subjected to the methods and compositions of the present disclosure. Individuals may be subjected to the methods and compositions for a disorder in which they are at risk for neuropathy, such as having an associated genetic mutation and / or a family history and / or personal history.

[0078] Examples of neurodegenerative diseases (e.g., when cells in the central nervous system stop functioning or die) include at least Alzheimer's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, or spinal muscular atrophy. In certain embodiments, individuals with neurodegenerative disorders deteriorate over time. Neurodegenerative diseases can be caused by a variety of reasons, such as related genetic mutations, tumors, strokes, alcoholism, exposure to toxins (mercury, aluminum, copper, lead, manganese, β-N-methylamino-L-alanine), exposure to chemicals (pesticides, metal-based nanoparticles), exposure to certain viruses (herpes simplex virus, varicella-zoster virus, some influenza virus strains, and viruses that cause encephalitis or meningitis), or are of unknown cause. An individual may have one or more of the following symptoms prior to initiation of treatment with the methods and compositions of the present disclosure: loss of inhibition, anxiety, agitation, blunted affect, difficulty moving, forgetfulness, memory loss, and mood changes. In certain embodiments, the methods and compositions prevent the onset of one or more symptoms, delay the onset of one or more symptoms, or reduce the severity of one or more symptoms.

[0079] For some medical conditions, the condition can be considered both a neurological disorder and a neurodegenerative disease.

[0080] An individual may have a traumatic brain injury (TBI), which includes brain dysfunction that can be caused by an external force such as a severe blow to the head. This can occur as a result of a severe sports injury, a car accident, or the like. In some embodiments, this is followed by immediate or delayed symptoms such as confusion, blurred vision, difficulty concentrating, headache, convulsions or seizures of cerebral origin, blurred or double vision, unequal pupil size or dilation, etc. The TBI can be penetrating or non-penetrating.

[0081] In certain embodiments, there are methods for improving locomotor function and / or long-term memory, such as for individuals with spinal cord injury, including after CNS trauma. In some embodiments, there are methods for treating one or more neurological disorders, including, by way of example, at least Parkinson's disease and Alzheimer's disease, stroke, dementia, neurotrauma, amyotrophic lateral sclerosis, and multiple sclerosis. In some embodiments, there are methods for treating neurological symptoms, such as those related to cognition and mobility, including age-related neurological conditions such as neurodegenerative diseases and neurotrauma.

[0082] In certain embodiments, there are methods for treating one or more secondary conditions associated with the primary condition (e.g., neurological symptoms). In certain embodiments, there are methods for reducing liver fibrosis, reducing inflammation, reducing markers of inflammation (e.g., C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and procalcitonin (PCT), serum amyloid A, cytokines, alpha-1 acid glycoprotein, plasma viscosity, ceruloplasmin, hepcidin and / or haptoglobin), cancer, etc. for individuals after spinal cord injury-induced paralysis.

[0083] In some embodiments, the methods are for treating a primary and / or secondary condition in an individual, although in certain embodiments, any medical condition referred to herein as a secondary condition is instead treated as a primary condition itself.

[0084] In certain embodiments, there are methods of treating any pathological condition resulting from the consequences of spinal cord injury or any other neurotraumatic injury, including at least the following: cardiac fibrosis, liver fibrosis, damage to any of the other organs (fibrosis, necrosis, dysfunction and inflammation to those organs), liver, kidney and colon disease, any cardiac and metabolic pathology (including diabetes, cardiometabolic syndrome, and cardiovascular disease), muscle-related diseases, respiratory diseases and cancer.

[0085] In some embodiments, the method includes treatment for any neurotrauma (head or spinal injury caused by sudden injury and / or peripheral neuropathy / neurotrauma and neuropathy).In certain embodiments, the neurotrauma includes at least concussion, TBI, skull fracture, spinal column fracture and spinal cord injury.In certain embodiments, the individual has head trauma, such as concussion, mild TBI, moderate TBI, severe TBI (e.g., accompanied by coma), penetrating brain injury (such as gunshot or stab wound), depressed skull fracture, craniofacial trauma, epidural hematoma, acute subdural hematoma, subacute subdural hematoma, chronic subdural hematoma, traumatic subarachnoid hemorrhage, traumatic intracerebral hemorrhage / cerebral contusion, traumatic cerebrospinal fluid leakage, traumatic pseudoaneurysm and blunt cerebrovascular injury. In certain embodiments, the individual has a spinal injury, such as a craniocervical spine injury, cervical spine injury, thoracic spine injury, lumbosacral spine injury, atlanto-occipital dissection, Jefferson (C1) fracture, Hangman (C2) fracture, odontoid (dental) fracture, traumatic central cord syndrome, perched / jumped facet, compression (anterior wedge) fracture, burst fracture, accidental fracture, fracture-dislocation, traumatic lumbar facet defect (lumbar spondylolysis), traumatic spondylolisthesis, traumatic disc herniation, complex sacral injury, hyperflexion injury, hyperextension injury, compression injury, traction injury, and spinal ligament injury.

[0086] In some embodiments, the disease to be treated is cancer, regardless of whether the individual has another medical condition, such as a neuropathy and / or damage to the central and / or peripheral nervous system.Cancers for which the present treatment method is useful include any malignant cell type, such as those found in solid tumors or blood tumors.Exemplary solid tumors may include, but are not limited to, tumors of organs selected from the group consisting of pancreas, colon, appendix, stomach, brain, head, neck, ovary, kidney, larynx, sarcoma, lung, bladder, melanoma, prostate, and breast.Exemplary blood tumors include tumors of the bone marrow, T- or B-cell malignancies, leukemia, lymphoma, blastoma, myeloma, etc. Further examples of cancers that can be treated using the methods provided herein include, but are not limited to, lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), cancer of the peritoneum, gastric or stomach cancer (including gastrointestinal cancer and gastrointestinal stromal cancer), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, various types of head and neck cancer, and melanoma.

[0087] Cancer may specifically be of the following histological types, but is not limited to: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant cell carcinoma and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; mixed hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyps; adenocarcinoma, familial polyposis coli; solid tumor; carcinoid tumor, malignant; bronchioloalveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; eosinophilic carcinoma ;Esiophilic adenoma;Basophilic carcinoma;Clear cell adenocarcinoma;Granular cell carcinoma;Follicle adenocarcinoma;Papillary and follicular adenocarcinoma;Non-encapsulated sclerosing carcinoma;Adrenal cortical carcinoma;Endometrial carcinoma;Cutaneous adenocarcinoma;Apocrine adenocarcinoma;Sebaceous gland carcinoma;Aural adenocarcinoma;Mucous epidermoid carcinoma;Cystadenocarcinoma;Papillary cystadenocarcinoma;Papillary serous cystadenocarcinoma;Mucinous cystadenocarcinoma;Mucinous adenocarcinoma;Signet ring cell carcinoma;Invasive ductal carcinoma;Medullary carcinoma;Lobular carcinoma;Inflammatory carcinoma;Paget's disease of the breast;Acinic cell carcinoma;Adenosquamous carcinoma;Adenocarcinoma with squamous metaplasia;Thymoma, malignant;Ovarian stromal tumor, malignant;Meningioma, malignant;Granulosa cell tumor, malignant;Androblastoma, malignant;Sertoli cell Carcinoma; Leydig cell tumor, malignant; Lipid cell tumor, malignant; Paraganglioma, malignant; Extramammary paraganglioma, malignant; Pheochromocytoma; Glomangiosarcoma; Malignant melanoma; Amelanotic melanoma; Superficial spreading melanoma; Lentiginous melanoma; Acral lentiginous melanoma; Nodular melanoma; Malignant melanoma in giant pigmented nevus; Epithelioid cell melanoma; Blue nevus, malignant; Sarcoma; Fibrosarcoma; Fibrous histiocytoma, malignant; Myxosarcoma; Liposarcoma; Leiomyosarcoma; Rhabdomyosarcoma; Embryonic rhabdomyosarcoma; Alveolar rhabdomyosarcoma; Stromal sarcoma; Mixed tumor, malignant; Müllerian mixed tumor; Nephroblastoma ;Hepatoblastoma;Carcinosarcoma;Mesenchymoma, malignant;Brenner tumor, malignant;Phyllodes tumor, malignant;Synovial sarcoma;Mesothelioma, malignant;Dysgerminoma;Embryonal carcinoma;Teratoma, malignant;Ovarian stroma, malignant;Choriocarcinoma;Mesonephroma, malignant;Angiosarcoma;Hemangioendothelioma, malignant;Kaposi's sarcoma;Hemangiopericytoma, malignant;Lymphangiosarcoma;Osteosarcoma;Paracortical osteosarcoma;Chondrosarcoma;Chondrosarcoma, malignant;Mesenchymal chondrosarcoma;Giant cell tumor of bone;Ewing's sarcoma;Odontogenic tumor, malignant;Ameloblastic odontoma;Ameloblastoma, malignant;Ameloblastic fibrosarcoma;Pinealoma, malignant;Chordoma;Glioma, malignant;Ependymoma;Astrocytoma;Protoplasmic astrocytoma;Fibrillary astrocytoma;Astroblastoma;Glioblastoma;Oligodendroglioma;Oligodendroglioma;Primitive neuroectodermal;Cerebellar sarcoma;Ganglioneuroblastoma;Neuroblastoma;Retinoblastoma;Olfactory neurogenic tumor;Meningioma, malignant;Neurofibrosarcoma;Neurilemoma, malignant;Granular cell tumor, malignant;Malignant lymphoma;Hodgkin's disease;Hodgkin's;Paragranuloma;Malignant lymphoma, small lymphocytic;Malignant lymphoma , large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-Hodgkin's lymphoma; B-cell lymphoma; low-grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate-grade / follicular NHL; intermediate-grade diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-cleaving cell NHL (high Grade small non-cleaved cell NHL); bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; Waldenstrom's macroglobulinemia; malignant histiocytic proliferation; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphocytic leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; hairy cell leukemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myeloid leukemia (AML); and chronic myeloblastic leukemia.

[0088] Embodiments of the present disclosure include methods of treating neurotrauma in an individual in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0089] Embodiments of the present disclosure include methods of treating a neurodegenerative disease in an individual in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0090] Embodiments of the present disclosure include methods of improving neuronal survival in an individual in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0091] Embodiments of the present disclosure include methods of improving neuritogenesis in an individual in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0092] Embodiments of the present disclosure include methods of improving neuroplasticity in an individual in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0093] Embodiments of the present disclosure include methods of regenerating neurites in an individual in need thereof, the method comprising administering one or more compounds of the present disclosure to the individual.Embodiments of the present disclosure include methods of promoting neuronal survival in an individual in need thereof, the method comprising administering one or more compounds of the present disclosure to the individual.Embodiments of the present disclosure include methods of reducing astroglial inflammation (in certain embodiments, as measured by the amount of synapsin I, C3, and / or GSK-3β) in an individual in need thereof, the method comprising administering one or more compounds of the present disclosure to the individual.Embodiments of the present disclosure include methods of promoting neuronal health (in certain embodiments, as reflected by the amount of neurite outgrowth and / or the number of surviving neurons) in an individual in need thereof, the method comprising administering one or more compounds of the present disclosure to the individual.

[0094] Embodiments of the present disclosure include a method for reducing lesion size in an individual in need thereof, the method comprising administering one or more compounds of the present disclosure to the individual. The lesion can be in any part of the individual, but in certain embodiments, the lesion is in the brain, kidney, lung, colon, eye, arm, leg, throat, stomach, breast, abdominal cavity, adrenal gland, aorta, bone, ear, eye, heart, kidney, large intestine, lung, nose, ovary, pancreas, pituitary gland, small intestine, spinal cord, spleen, stomach, testicle, thymus, thyroid, tooth, uterus, spinal column, etc. The lesion can be in any tissue in the body, including connective tissue, epithelial tissue, muscle tissue, nerve tissue, or a combination thereof.

[0095] Embodiments of the present disclosure include a method for halting paralysis in an individual in need thereof, the method comprising administering one or more compounds of the present disclosure to the individual.The paralysis to be halted can be of any type, including monoplegia, hemiplegia, paraplegia, or quadriplegia.The paralysis to be halted can be partial or complete.The paralysis may or may not be caused by stroke, spinal cord injury, neurological disorders (e.g., multiple sclerosis), Bell's palsy, etc.

[0096] Embodiments of the present disclosure include a method for enhancing memory in an individual in need thereof, the method comprising administering one or more compounds of the present disclosure to the individual.The type of memory can be any type, including episodic memory, semantic memory, procedural memory, short-term memory, working memory, sensory memory and long-term memory.In certain embodiments, the compound promotes long-term memory and / or short-term memory.

[0097]

[0010] Embodiments of the present disclosure include methods of causing or enhancing the regeneration of any cell type, including non-cancerous material, including regenerating healthy hepatocytes and neural cells (e.g., neurons, Schwann cells, astrocytes, and / or microglia and the stem cells from which these cells are derived) in an individual in need thereof, such that they are non-cancerous, non-inflammatory, and / or non-diseased, comprising administering to the individual one or more compounds of the present disclosure.

[0011] Embodiments of the present disclosure are methods of causing or enhancing the regeneration of axons and / or glial processes in an individual in need thereof, comprising administering to the individual one or more compounds of the present disclosure.

[0098]

[0010] Embodiments of the present disclosure include methods of reducing inflammation in an individual in need thereof, comprising administering to the individual one or more compounds of the present disclosure. In certain embodiments, the inflammation can be acute or chronic. In certain embodiments, reduced inflammation encompasses the reduction of disease-induced inflammatory pathways (e.g., pathways involving NF-κB, MAPK, JAK-STAT, IL-1, IL-6, TNF-α, lymphotoxin, IFN-γ, IL-17A, IL-10, IL-1b, any MMP (including MMP1, MMP2, MMP3, MMP7, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, MMP15, MMP16, MMP17, MMP18, MMP19, MMP20, MMP21, MMP23A, MMP23B, MMP24, MMP25, MMP26, MMP27, MMP28) and / or IL-13), either systemically or locally, either neurogenic or otherwise, through any mechanism.

[0099] Embodiments of the present disclosure include a method for alleviating fibrosis in an individual in need thereof, the method comprising administering one or more compounds of the present disclosure to the individual. In certain embodiments, the fibrosis can be of any type. In certain embodiments, the fibrosis can be in the lungs, liver, heart, lymph nodes, retroperitoneum, bone marrow, skin, connective tissue, or a combination thereof. In some embodiments, the fibrosis is not in the lungs, liver, gastrointestinal tract, peripheral nervous system, central nervous system, heart, lymph nodes, retroperitoneum, bone marrow, skin, connective tissue, or a combination thereof.

[0100] Embodiments of the present disclosure include methods of enhancing cognition in an individual in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0101] Embodiments of the present disclosure include methods of enhancing neurite outgrowth in an individual in need thereof, comprising administering to the individual one or more compounds of the present disclosure. In certain embodiments, neurites, which are processes from the cell body of a neuron, can be either axons or dendrites, or can occur as both.

[0102] Embodiments of the present disclosure include methods of providing neuroprotection against oxidation and ischemia in an individual in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0103] Embodiments of the present disclosure include methods of modulating astrocytes to increase synapsin I expression and / or decrease C3 and GSK-3β expression in an individual in need thereof, the method comprising administering one or more compounds of the present disclosure to the individual. In certain embodiments, the individual has a spinal cord injury, Alzheimer's disease, or any medical condition in which altered levels of synapsin I, one or more neurotrophic factors (e.g., BDNF, NT-3, and / or NT-4), C3, and / or GSK-3β are deleterious.

[0104] Embodiments of the present disclosure include methods of promoting astrocyte migration and / or proliferation in an individual in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0105] Embodiments of the present disclosure include methods of promoting astrocyte polarization in an individual in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0106] Embodiments of the present disclosure include methods of allowing one or more activators of TrkB / TrkC to penetrate the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) in an individual in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0107] Embodiments of the present disclosure include methods of improving functional locomotor recovery in an individual in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0108] Embodiments of the present disclosure include methods of improving post-SCI cognition in an individual in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0109] Embodiments of the present disclosure include a method of treating cognitive dysfunction in an individual in need thereof, the method comprising administering to the individual one or more compounds of the present disclosure.

[0110] Embodiments of the present disclosure include methods of improving memory function in an individual (such as having cognitive dysfunction) in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0111] Embodiments of the present disclosure include methods of improving memory in an individual in need thereof, such as those having a disease that impairs memory function (e.g., Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, HIV dementia, mild cognitive impairment, dementia associated with normal pressure hydrocephalus, vascular dementia, hyperthyroidism, stroke, head injury, spinal cord injury, alcoholism, sleep apnea, nutritional deficiencies, Parkinson's disease, depression, cancer, chemobrain, neurosyphilis, Creutzfeldt-Jakob disease, Huntington's disease, and / or infectious diseases), the method comprising administering to the individual one or more compounds of the present disclosure.

[0112] Embodiments of the present disclosure include methods of promoting axonal regeneration, axonal survival and / or axonal sprouting in an individual in need thereof, the methods comprising administering to the individual one or more compounds of the present disclosure.

[0113] Embodiments of the present disclosure include a method for alleviating one or more liver pathologies in an individual who needs to alleviate one or more liver pathologies, the method comprising administering one or more compounds of the present disclosure to the individual.In certain embodiments, the liver pathology is non-alcoholic fatty liver disease, and in some cases, the non-alcoholic fatty liver disease is in an individual with SCI.

[0114] Embodiments of the present disclosure include methods of alleviating any disease that directly or indirectly affects liver function in an individual in need thereof, the method comprising administering to the individual one or more compounds of the present disclosure.

[0115] The individual treated by the method of the present disclosure can be of any gender (including individuals with sex chromosome aneuploidy), any age, and any race.In some embodiments, the individual can be an individual who is not at risk of neurological disorders, while in other embodiments, the individual is an individual who is at risk of neurological disorders.In some embodiments, the individual at risk can be an individual with advanced age, genetic disorders, congenital abnormalities or disorders, infectious diseases, lifestyle or environmental health issues including malnutrition, and brain injury, spinal cord injury, or nerve injury.In specific cases, the elderly is an individual who is at least 60, 65, 70, 75, 80, 85, 90, 95, or 100 years old or older. In some cases, the individual is born, a newborn, an infant (under 1 year old), or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 7, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 years of age or older.

[0116] In some embodiments, any of the compounds encompassed herein (including one or more dyes) may be used to track the compound itself for any purpose. Examples include determining the mechanism of action of one or more compounds, determining the pharmacokinetic properties of one or more compounds, and / or determining the toxicity of one or more compounds. In some embodiments, one or more compounds are utilized as a tracking system to identify the location of the compound's target, such as the result of the compound's binding (indirectly or directly) to one or more targets. In certain embodiments, the molecule to which the compound binds is one or more of a protein, nucleic acid, carbohydrate, small molecule, biological material, metabolite, lipid, or combinations thereof. The compound and the molecule to which the compound binds may or may not be complexed with other components.

[0117] In certain embodiments, there are diagnostic and / or prognostic methods in which an effective amount of a compound is delivered to an individual in need of diagnosis and / or prognosis, the location (and in some cases, behavior) of the compound is visualized, and such tracking provides a diagnosis and / or prognosis for the individual. An individual may be known to have a medical condition, be suspected of having a medical condition, or be at risk for having a medical condition (e.g., a greater risk than the general population). Any individual at risk for having a medical condition may have a personal or family history of the disease, may have one or more behaviors and / or environments that predispose to the medical condition, may have one or more genetic markers that predispose to the medical condition, a combination thereof, etc.

[0118] In certain embodiments, the method includes monitoring the effectiveness of treatment for an individual. The individual may be provided with an effective amount of a compound prior to treatment, but not the compound itself, and at a certain time point after such initial administration, the individual is provided with the compound to determine whether the treatment is effective. The effectiveness of the treatment may be manifested as the location of the compound, the strength of the signal from the compound, or a combination thereof. The treatment may or may not be continued based on such a determination.

[0119] In some embodiments, the individual is provided with an effective amount of compound, wherein the compound itself is a therapeutic agent.At a later time point, the individual is visualized to identify the location of the compound, the intensity of the signal from the compound, or a combination thereof.Between the first administration of the compound and one or more subsequent time points, the individual can be periodically or continuously monitored for the location of the compound, the intensity of the signal from the compound, or a combination thereof. IV. Administration of Therapeutic Compositions

[0120] The treatment provided herein can include the administration of one or a combination of 5c(i) and / or its functional derivatives.Embodiments of the present disclosure relate to compositions and methods, including therapeutic compositions.When multiple treatments are provided, different treatments can be administered in one composition or in multiple compositions, for example, in two, three or four compositions.Various combinations of drugs can be used.

[0121] The therapeutic agents of the present disclosure may be administered by the same or different routes of administration. In some embodiments, the therapy is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implant, by inhalation, intrathecally, intraventricularly, or intranasally. In some embodiments, the antibiotic is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implant, by inhalation, intrathecally, intraventricularly, or intranasally. The appropriate dosage can be determined based on the type of disease to be treated, the severity and course of the disease, the individual's clinical condition, the individual's medical history and response to treatment, and the discretion of the attending physician.

[0122] Treatments may include various "unit doses." A unit dose is defined as containing a predetermined amount of a therapeutic composition. The amount to be administered, as well as the specific route and formulation, are within the skill of those skilled in the clinical arts to determine. A unit dose need not be administered as a single injection, but may include continuous infusion over a set period of time. In some embodiments, a unit dose comprises a single administrable dose.

[0123] In some embodiments, the therapeutic agent is administered at a dose of 1 mg / kg to 5000 mg / kg. In some embodiments, the therapeutic agent is administered at a dose of at least, at most, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 18 9, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 24 99, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258,259、260、261、262、263、264、265、266、267、268、269、270、271、272、273、274、275、276、277、278、279、280、281、282、283、284、285、286、287、288、289、290、291、292、293、294、295、296、297、298、299、300、301、302、303、304、305、306、307、308、309、310、311、312、313、314、315、316、317、318、319、320、321、322、323、324、325、326、327、328、329、330、331、332、333、334、335、336、337、338、339、340、341、342、343、344、345、346、347、348、349、350、351、352、353、354、355、356、357、358、359、360、361、362、363、364、365、366、367、368、369、370、371、372、373、374、375、376、377、378、379、380、381、382、383、384、385、386、387、388、389、390、391、392、393、394、395、396、397、398、399、400、401、402、403、404、405、406、407、408、409、410、411、412、413、414、415、416、417、418、419、420、421、422、423、424、425、426、427、428、429、430、431、432、433、434、435、436、437、438、439、440、441、442、443、444、445、446、447、448、449、450、451、452、453、454、455、456、457、458、459、460、461、462、463、464、465、466、467、468、469、470、471、472、473、474、475、476、477、478、479、480、481、482、483、484、485、486、487、488、489、490、491、492、493、494、495、496、497、498、499、500、501、502、503、504、505、506、507、508、509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539 , 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 57 and administered at a dose of 0, 571, 572, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, or 5000 mg / kg.

[0124] In some embodiments, a single dose of 5c(i) and / or functional derivative therapeutic agent is administered. In some embodiments, multiple doses of 5c(i) and / or functional derivative therapeutic agent are administered. In some embodiments, 5c(i) and / or functional derivative therapeutic agent is administered at a dose of 1 mg / kg to 100 mg / kg. In some embodiments, 5c(i) and / or functional derivative therapeutic agent is administered at a dose of at least, at most, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 10 and administered at a dose of 7, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 mg / kg.

[0125] The amount to be administered depends on the desired therapeutic effect, depending on both the number of treatments and the unit dose. It is understood that an effective dose refers to the amount required to achieve a specific effect. In certain embodiments, it is contemplated that a dose ranging from 10 mg / kg to 200 mg / kg can affect the protective capacity of these agents. Thus, doses are contemplated to include doses of about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, and 200, 300, 400, 500, 1000 μg / kg, mg / kg, μg / day, or mg / day, or any range derivable therein. Furthermore, such doses may be administered multiple times during the day and / or on multiple days, weeks, or months.

[0126] In certain embodiments, an effective dose of the pharmaceutical composition is one that can produce blood levels of about 1 μM to 150 μM. In other embodiments, an effective dose produces blood levels of about 4 μM to 100 μM; or about 1 μM to 100 μM; or about 1 μM to 50 μM; or about 1 μM to 40 μM; or about 1 μM to 30 μM; or about 1 μM to 20 μM; or about 1 μM to 10 μM; or about 10 μM to 150 μM; or about 10 μM to 100 μM; or about 10 μM to 50 μM; or about 25 μM to 150 μM; or about 25 μM to 100 μM; or about 25 μM to 50 μM; or about 50 μM to 150 μM; or about 50 μM to 100 μM (or any range derivable therein). In other embodiments, the dose may result in the following blood levels of the agent resulting from the therapeutic agent being administered to the subject: about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 μM, or any range derivable therein. In certain embodiments, a therapeutic agent administered to a subject is metabolized in the body to a metabolized therapeutic agent, in which case blood levels may refer to the amount of that agent. Alternatively, to the extent a therapeutic agent is not metabolized by the subject, blood levels discussed herein may refer to a non-metabolized therapeutic agent.

[0127] The precise amount of the therapeutic composition also depends on the judgment of the attending physician and is peculiar to each individual. Factors affecting dosage include the physical and clinical condition of the patient, the route of administration, the intended goal of treatment (palliation of symptoms versus cure), and the efficacy, stability, and toxicity of the particular therapeutic agent or other treatment the subject may be subjected to.

[0128] It will be understood and appreciated by those skilled in the art that dosage units of μg / kg body weight or mg / kg body weight can be converted and expressed in equivalent concentration units of μg / ml or mM (blood levels), such as 4 μM to 100 μM. It is also understood that uptake is species and organ / tissue dependent. Applicable conversion factors and physiological assumptions to be made regarding uptake and concentration measurements are well known, allowing one skilled in the art to convert one concentration measurement to another and make reasonable comparisons and conclusions regarding the doses, efficacy, and results described herein.

[0129] In certain instances, it may be desirable to have multiple administrations of the composition, for example, 2, 3, 4, 5, 6 or more administrations, which may be 1, 2, 3, 4, 5, 6, 7, 8, to 5, 6, 7, 8, 9, 10, 11, or 12 week intervals (including all ranges therebetween).

[0130] The phrases "pharmaceutically acceptable" or "pharmacologically acceptable" refer to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to animals or humans. As used herein, "pharmaceutically acceptable carriers" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in immunogenic and therapeutic compositions is contemplated. Other supplementary active ingredients, such as anti-infective agents and vaccines, may also be incorporated into the compositions.

[0131] Active compound can be formulated for parenteral administration, for example, can be formulated for injection via intravenous, intramuscular, subcutaneous or intraperitoneal route.Typically, such composition can be prepared as either liquid solution or suspension;Before injection, when adding liquid, solid form can also be prepared for use in preparing solution or suspension;Preparation can also be emulsified.

[0132] Pharmaceutical forms suitable for injection use include sterile aqueous solutions or dispersions; formulations containing, for example, aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.In all cases, the form must be sterile and fluid enough to be easily squirted.It must also be stable under the conditions of manufacture and storage, and must be protected from the contaminating action of microorganisms such as bacteria and fungi.

[0133] Proteinaceous compositions can be formulated in neutral or salt form. Pharmaceutically acceptable salts include acid addition salts (formed with the free amino groups of proteins), which are formed with inorganic acids, such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, mandelic acid, etc. Salts formed with free carboxyl groups can also be derived from inorganic bases, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, histidine, procaine, etc.

[0134] The compounds disclosed herein may contain one or more asymmetrically substituted carbon or nitrogen atoms and may be isolated in optically active or racemic forms. Therefore, all chiral, diastereomeric, racemic, epimeric, and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. The compounds may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. In some embodiments, single diastereomers are obtained. The chiral centers of the compounds of the present invention may have the S- or R-configuration as defined by the IUPAC 1974 Recommendations. The compounds may be, for example, in the D- or L-form. Methods for preparing and isolating such optically active forms are well known in the art. For example, mixtures of stereoisomers may be separated by standard techniques, including, but not limited to, racemic, normal-phase, reverse-phase, and chiral chromatographic resolution, preferential salt formation, recrystallization, and the like, or by chiral synthesis from chiral starting materials, or by intentional synthesis of the targeted chiral center.

[0135] The pharmaceutical compositions may contain a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Delayed absorption of injectable compositions can be achieved by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0136] Sterile injectable solution can be prepared by incorporating the active compound in the required amount in suitable solvent with various other components as listed above, and if necessary, then sterilize by filtration or equivalent procedures.Generally, dispersion can be prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains basic dispersion medium and other necessary components from those listed above.For the sterile powder that is used to prepare sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which can obtain the powder of active ingredient and any other desired components from its previously sterile-filtered solution.

[0137] Administration of the compositions may be via any suitable route, including, but not limited to, oral, intravenous, orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal, or intranasal administration. Such compositions are typically administered as pharmaceutically acceptable compositions containing physiologically acceptable carriers, buffers, or other excipients.

[0138] Upon formulation, solutions may be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically or prophylactically effective. The formulations are easily administered in a variety of dosage forms, such as the types of injectable solutions described above.

[0139] In certain embodiments, the compositions or agents for use in the methods, such as 5c(i) and / or its functional derivatives, are suitably contained in a pharmaceutically acceptable carrier. The carrier may be non-toxic and biocompatible and may be selected so as not to adversely affect the biological activity of the agent. The agents in some embodiments of the present disclosure may be formulated into preparations for local delivery (i.e., to a specific location in the body, such as a nerve or other tissue) or systemic delivery in solid, semi-solid, gel, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, depositories, inhalants, and injections, allowing for oral, parenteral, or surgical administration. Certain embodiments of the present disclosure also contemplate local administration of the compositions by coating medical devices and the like.

[0140] Suitable carriers for parenteral delivery via injection, infusion, or irrigation and local delivery include distilled water, physiological phosphate-buffered saline, normal or lactated Ringer's solution, dextrose solution, Hank's solution, or propanediol. In addition, sterile, non-volatile oils can be used as solvents or suspension media. For this purpose, any biocompatible oil, including synthetic monoglycerides or diglycerides, can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The carrier and drug can be formulated as a liquid, suspension, polymeric or non-polymeric gel, paste, or salve.

[0141] Carriers may also include delivery vehicles to sustain (i.e., extend, delay, or modulate) the delivery of an agent or to enhance the delivery, uptake, stability, or pharmacokinetics of a therapeutic agent. Such delivery vehicles may include, by way of non-limiting example, microparticles, microspheres, nanospheres, or nanoparticles composed of proteins, liposomes, carbohydrates, synthetic organic compounds, inorganic compounds, polymeric or copolymeric hydrogels, and polymeric micelles.

[0142] In certain embodiments, the actual dosage of a composition administered to a patient or subject may be determined by physical and physiological factors such as body weight, severity of the condition, the type of disease being treated, previous or concurrent therapeutic interventions, the patient's underlying disease, and the route of administration, etc. In any event, the physician responsible for administration will determine the concentration of active ingredient(s) in the composition and the appropriate dose for the individual subject.

[0143] The solution of the pharmaceutical composition can be prepared in water by suitably mixing with a surfactant such as hydroxypropyl cellulose.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, their mixtures, and oils.Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0144] In certain embodiments, the pharmaceutical composition is advantageously administered in the form of an injectable composition, either as a liquid solution or suspension; suitable solid forms or solutions or suspensions in liquid before injection can also be prepared. These preparations can also be emulsified. Typical compositions for such purposes include a pharmaceutically acceptable carrier. For example, the composition can contain up to 10 mg, 25 mg, 50 mg, or up to about 100 mg of human serum albumin per milliliter of phosphate-buffered saline. Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients (including salts, preservatives, buffers, etc.).

[0145] Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils, and injectable organic esters such as ethyl oleate.Aqueous carriers include water, alcoholic / aqueous solutions, physiological saline, parenteral vehicles such as sodium chloride, Ringer's dextrose, etc.Intravenous vehicles include fluid and nutritional replenishers.Preservatives include antibacterial agents, antifungal agents, antioxidants, chelating agents, and inert gases.The pH and precise concentration of various components of the pharmaceutical composition are adjusted according to well-known parameters.

[0146] Other formulations are suitable for oral administration. Oral formulations include typical excipients such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc. The compositions are in the form of solutions, suspensions, tablets, pills, capsules, sustained-release formulations or powders.

[0147] In further embodiments, the pharmaceutical compositions may comprise classical pharmaceutical formulations. Administration of pharmaceutical compositions according to certain embodiments may be via any common route, so long as the target tissue is accessible via that route. This may include oral, nasal, buccal, rectal, vaginal, or topical administration. Alternatively, administration may be via orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal, or intravenous injection. Such compositions are typically administered as pharmaceutically acceptable compositions containing physiologically acceptable carriers, buffers, or other excipients. Aerosol delivery may be used to treat pulmonary conditions. The volume of the aerosol may be, for example, about 0.01 ml to 0.5 ml.

[0148] The effective amount of the pharmaceutical composition is determined based on the intended goal.The term "unit dose" or "dosage" refers to a physically separate unit suitable for use in a subject, each unit containing a predetermined amount of pharmaceutical composition calculated to produce the desired response described above in relation to its administration, i.e., appropriate route and treatment regimen.The amount to be administered depends on the desired protection or effect, depending on both the number of treatments and unit dose.

[0149] The precise amount of the pharmaceutical composition also depends on the judgment of the attending physician and is peculiar to each individual. Factors affecting dosage include the physical and clinical condition of the patient, the route of administration, the intended goal of treatment (e.g., symptomatic relief versus cure), and the efficacy, stability, and toxicity of the particular therapeutic agent. [Example]

[0150] The following examples are included to demonstrate preferred embodiments of the invention. It should be understood by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventors to function well in the practice of the invention, and as such can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, understand that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention. Example 1 Examples of methods and materials

[0151] Embodiments of the present disclosure are encompassed in the following examples. In certain embodiments, the following methods were utilized, although one skilled in the art will recognize that modifications may be made to the methods in certain embodiments. Example of how to animal

[0152] All studies herein use wild-type C57Bl / 6 mice or other variations, including C57Bl / 6N, C57Bl / 6NJ, C57Bl / 6J, and B6NTac mice. All procedures were performed in accordance with protocols approved by the Institutional Review Board / Animal Ethics Committee of Texas A&M University. cell culture

[0153] For all cell culture experiments, primary neural cells were extracted from postnatal mouse cortex. The extraction, purification, and isolation of neurons and glia were performed as previously described in patent application WO2022266431, which is incorporated herein by reference in its entirety. 58 Briefly, after euthanasia of mice, brains were microdissected and placed into papain-filled GENTLEMACS™ (tissue dissector) C tubes. Cells were subsequently dissociated using a GENTLEMACS™ (tissue dissector) Octo Dissociator with a heating cuff using the GENTLEMACS™ (tissue dissector) Program 37C_ABDK_01 protocol. After completion of the protocol, the contents were strained through a 70 μm cell strainer to remove debris and red blood cells, and the remaining solution was labeled with glia-specific antibodies. The labeled glia were separated from the remaining neuron-enriched cell population using a MACS magnetic sorting system.

[0154] For neuronal culture, the neuron-enriched fraction was added to plastic-bottom (Greiner-Bio, 781091) plates and incubated at 37°C in a 5% CO2 incubator for 2 days. Drugs were added at the time of cell plating. For astrocyte culture, the glial fraction was added to plastic-bottom (Greiner-Bio, 781091) plates and incubated at 37°C in a 5% CO2 incubator for 5 days until 100% confluence was reached. Astrocytes were then scratched to create a scratch assay model, and drugs were added at the time of scratch generation. For both neuronal and glial cultures, 10,000 cells per well were plated in a 0.056 cm2 incubator. 2 The seeds were sown with a growth area of . immunocytochemistry

[0155] After completion of each in vitro experiment, cell cultures were fixed with 4% paraformaldehyde (PFA, 15 min). After fixation, immunocytochemistry was performed by first washing the cells three times with phosphate-buffered saline (PBS) and then incubating them in 5% normal horse serum for 60 min to block nonspecific binding (VWR® (Laboratory and Scientific Products), 102643-676). For neuronal cultures, neurons were then incubated in 1:500 TUBB3 (BIOLEGEND® (Scientific Reagents), 801202) for 24 h, followed by three washes with PBS and incubation in 1:500 Alexa Flour 488 (THERMO FISHER SCIENTIFIC® (Laboratory Reagents), A32723) and 1:10,000 DAPI (VWR, 95059-474) for 60 min, all at room temperature. This allowed for analysis of morphological features as previously performed. 58Astrocyte cultures for scratch assays were incubated in 1:500 DYLIGHT™ (Scientific Reagents) 554 and 1:10,000 DAPI (VWR® (Laboratory and Scientific Products), 95059-474) for 60 minutes at room temperature. This allows for analysis of scar size in culture. After immunocytochemistry was completed, cells were stored in FLUOROMOUNT-G® (Slide Mounting Medium) Mounting Medium (THERMO FISHER SCIENTIFIC® (Laboratory Reagents), 00-4958-02) until imaging. All experiments following incubation in secondary antibodies were performed in the absence of light. Protein dynamics

[0156] Trk-positive transfected cell lines (TrkA-HeLa, TrkB-HEK293, and TrkC-NIH / 3T3) and Trk-negative non-transfected cell lines (HeLa, HEK293, and NIH / 3T3) were plated in 96-well plates (0.32 cm 2 Cells were seeded at 2,000 cells / well on a 1000×1000 cell growth area (growth area) and incubated for 24 hours at 37°C in a 5% CO2 incubator. Cells were treated with different concentrations of drugs in serum-free medium for 150 minutes with or without 0.2 nM NGF (TrkA-HeLa and HeLa), 0.6 nM BDNF (TrkB-HEK293 and HEK293), and 0.2 nM NT-3 (TrkC-NIH / 3T3 and NIH / 3T3). Cells were then washed once with 1% sodium dodecyl sulfate in PBS to remove unbound compounds. λ was measured using an AGILENT® BioTek Synergy H4 Hybrid Microplate Reader. ex (540 / 25nm) and λ em Cell-associated fluorescence was determined by measuring the emission of the resulting solution at 620 / 40 nm. Binding saturation (unilateral specific binding) was used to calculate the dissociation constant (K d ) was calculated. Preclinical SCI Models

[0157] Eight-week-old male mice underwent surgery to undergo SCI. A laminectomy was performed at T7–T9 by splitting the sternospinalis muscle, exposing the spinal cord while keeping the dura intact. After immobilizing the mouse using two pairs of Adson forceps, a severe T8 contusion and compression was induced using an Infinite Horizon Impactor with a 2-second dwell time (compression) and a force of 50 kdyn (contusion). Autodegradable catgut sutures were used to close the sternospinalis muscle, followed by adhesion closure of the skin using 3M VETBOND™ (n-butyl cyanoacrylate adhesive veterinary tissue adhesive). To prevent infection, all procedures and instruments used in surgery were sterilized before surgery. After surgery, mice were allowed to recover in a heated cage and then transferred to a room-temperature cage with free access to food and water. All surgeries were performed in the morning (8:00 AM–12:00 PM) to limit potential circadian clock effects. For the same reasons, behavioral assays were performed for all cohorts at the same time in the morning. For drug administration, the vehicle was 100% dimethyl sulfoxide (DMSO) at 0.6 mL / kg. 5c(i) (5 and 25 mg / kg / day) diluted in vehicle or vehicle alone was administered once daily via intraperitoneal (IP) injection at a volume of 0.6 mL / kg / day. To minimize the risk of bladder rupture, bladders were manually expressed twice daily (morning and evening). Locomotor activity test

[0158] Open field Basso Mouse Scale (BMS): Mice were placed in an open field for 5 min, allowed to move freely, and the following parameters were visually assessed (by two people): ankle movement, stepping pattern, coordination, paw placement, trunk instability, and tail position. BMS scoring system 59 According to the BMS, the minimum score was 0 (no movement) to the maximum score of 9 (normal movement), followed by the BMS Subscore (assessment of stepping patterns, tail movements, trunk posture, foot position and coordination). 12、60Mice were scored using the following criteria: Rotating rod: Mice were placed on a rotating rod that rotated at increasing speeds of 5 to 45 revolutions per minute (rpm) at constant acceleration over 3-minute intervals to assess strength, endurance, and motor coordination. 12、60 First, mice were acclimatized to the rotorod during five habituation sessions per week before injury. Baseline testing was performed one day before injury. Cognitive testing

[0159] Before the start of the study, uninjured mice were placed in the room and all cognitive tests were performed for 1 hour. After that, mice were placed in the empty open-field white box for 5 minutes to acclimate to the box and recorded for baseline measurements and to identify abnormalities. Seven weeks after SCI, all post-injury cognitive tests were performed. Novel Object Recognition (NOR): Mice were placed in the empty open-field white box for 5 minutes and recorded. After 2 hours, each mouse was placed approximately 100 cm 3 Mice were placed in the same box containing two identical objects with a volume of 100 mm for 10 minutes. 24 hours after habituation to the two identical objects, mice were placed for 10 minutes with one object identical to that used in the previous day's test (familiar object) and another object of different color and shape but identical size (novel object). Behavioral patterns regarding the novel and familiar objects were recorded and analyzed. Y-maze: A forced alternation Y-maze test was performed by first habituating mice to the Y-maze by blocking the novel arm with a cardboard box for 8 minutes. After 3 hours, mice were placed inside the Y-maze with access to all arms, including the novel arm. Behavioral patterns regarding the arms visited by the mice were recorded and analyzed. Observers were blinded to the groups. All cognitive tests were performed under red light only. Histological analysis

[0160] Mice were sacrificed 7 weeks after injury with a lethal dose of Fatal plus (pentobarbital) and then transcardially perfused with PBS-heparin (10,000 units / L, 20 mL, 5 mL / min) followed by 4% paraformaldehyde fixative (30 mL / mouse, 5 mL / min). Immediately after perfusion, the tissue was immersed in 4% PFA for 24 hours, transferred to 15% sucrose for 24 hours, and then transferred to 30% sucrose for 24 hours before embedding. Subsequently, spinal cords (±1 mm from the injury site) were cut into 25 μm-thick cross sections using a freezing microtome (THERMO FISHER SCIENTIFIC® (Laboratory Reagents), Microm HM550). For immunohistochemistry (IHC), spinal cord tissue sections were placed in blocking solution (5% BSA, 0.4% Triton X-100, PBS) for 1 hour at room temperature. This was followed by overnight incubation with the primary antibody at room temperature, after which the tissue sections were washed three times with 0.4% Triton X-100-PBS and then incubated with the appropriate secondary antibody (1:500, INVITROGEN™ (Laboratory Reagents) ALEXA FLUOR® (Fluorescent Dye) Plus Series) for 1 hour at room temperature. Primary antibodies included biotinylated NeuN (EMD MILLIPORE® (Pharmaceuticals and Chemicals), MAB377B, 1:500), rat GFAP (FISHER SCIENTIFIC® (Laboratory Reagents), 130300, 1:500), rabbit Iba1 (FUJIFILM® (Camera Parts) Wako Chemicals, 019-19741, 1:500), rat CD68 (BIO-RAD® (Electrophoresis and Chromatography Materials) MCA1957, 1:500), goat SOX9 (R&D SYSTEMS® (Bioreagents), AF3075, 1:500), and rabbit anti-5-HT (ImmunoStar, 20080, 1:500). Sections were stained with DAPI (1:5000, Millipore Sigma) to visualize nuclei. Images were acquired using a VS120 Virtual Slide Microscope (Olympus) and Axio Observer7 (ZEISS® (Optical Products)) and analyzed with QuPath 0.4.3.Lesion and cavity size were traced and measured using the contour (polygon) tool of Zen 3.2 (Carl Zeiss AG, Jena, Germany) software. Lesion size was measured using DAPI. + Cavity size was measured by tracing the border of the GFAP-labeled glial scar surrounding the medial region. Cavity size was measured by measuring the area within the spinal cord without visible nuclei that was still surrounded by the GFAP-labeled glial scar. Three spinal cord sections per animal were imaged and analyzed. The three sections included the section containing the largest lesion size, along with 300 μm rostral and caudal sections. Images were quantified using QuPath software. Eight 200 μm-wide boxes were drawn both rostral and caudal to the epicenter of the lesion. A contour polygon was generated around the spinal cord in each of the 16 boxes. Fluorescence intensity and cell counting were performed using automated QuPath software. Histological analysis of liver tissue was performed by sectioning the left lobe of the liver into 8 μm-thick cross sections. To examine perivascular collagen accumulation in the liver, liver sections were stained with Masson's Trichrome Staining Kit (SIGMA-ALDRICH® (Chemical Supplies), HT15-1KT) according to the manufacturer's instructions. Collagen accumulation was quantified using automated QuPath software to determine the degree of fibrosis. Blood cytokine analysis

[0161] The MESO SCALE DISCOVERY® (Biological Assays) (MSD) U-PLEX® (Biological Assays) assay platform was utilized for cytokine analysis herein. First, whole blood was collected into heparinized tubes immediately before mice underwent SCI (baseline) and immediately before mice were perfused (final). The tubes were spun at 14,000 x g for 14 minutes, after which plasma from the tubes was collected. The plasma was then used to assess changes in blood cytokine levels. For cytokine measurements, individual U-PLEX® (Biological Assays) linker-conjugated antibodies and coating solutions were prepared and used to coat proprietary MSD 96-well plates, which were then incubated at 4°C for 24 hours and washed with PBS. Next, an 8-point calibration curve was generated using 4-fold serial dilutions; 50 μL of this was loaded onto the MSD plate along with 25 μL of diluent for wells reserved for mouse samples. 25 μL of each mouse sample was placed in a well, and two-fold dilutions of the mouse sample were made in the diluent. The MSD plate was incubated at room temperature for 2 hours, then washed with PBS. The detection antibody solution was prepared and loaded onto the plate, followed by incubation at room temperature for 1 hour and washing with PBS. Finally, Gold Read Buffer was loaded onto the plate, and the plate was read on a MESO QuickPlex SQ 120MM. statistics

[0162] All quantitative measurements were compared using one-way ANOVA with Tukey's post-hoc test or Kruskal-Wallis with Dunn's post-hoc test for immunohistochemistry (IHC) and Western blot (WB) analyses, and two-way repeated measures ANOVA with Bonferroni post-hoc test for analyzing longitudinal behavioral data. For consistency, any animals with a BMS score of 4 or higher 48 hours after SCI were considered to have not been successfully injured and were excluded from the study. Any subjects that did not survive the entire study were excluded from all analyses. The null hypothesis was rejected if p<0.05. All data were analyzed using GRAPHPAD PRISM® (graphing software) v9. Blinding procedures

[0163] We implemented an experimental design that maintained several levels of randomization and blinding procedures. First, experimenter #1 assigned mice to appropriate groups before assessing functional baselines. The experimenter ensured that mice in each experimental group were of similar age and weight. To minimize confounding variables, all mice weighed within 10% of the mean. Second, experimenters #2 and #3 performed the surgery blind to the cohorts they belonged to, while experimenter #4 prepared the syringes for injections and disguised the names of each cohort by labeling them with letters, e.g., A instead of the compound name. Finally, experimenter #5 performed the injections. Whenever possible, animals from all cohorts were mixed and housed together. All behavioral tests were performed by an observer blinded to the cohort organization and quantified by a different observer blinded to the groups. Unblinding occurred only after all data had been acquired and analyzed. Example 2 Compounds and methods for medical use

[0164] Embodiments of the present disclosure are encompassed in the examples.

[0165] Figure 1 shows the structure of exemplary compound 5c(i) (see also WO2022256394). Any of the compounds disclosed herein can be synthesized based on the general procedures provided in WO2022256394.

[0166] Using TrkB-HEK293 and TrkC-NIH / 3T3 cell lines, we demonstrated that 5c(i) is a highly specific TrkB and TrkC modulator with low nanomolar affinity that mimics BDNF and NT-3 activity (Figure 2). Specificity is suggested by the lack of binding and biological activity in cells lacking TrkB / TrkC receptors. Because neurotrophins such as BDNF are therapeutically inapplicable due to their poor pharmacokinetic profiles, TrkB / TrkC modulators are desperately needed. 56 Unlike other pan-Trk modulators, 61、62 5c(i) is not designed to bind to the notorious p75 "death receptor" that induces neuronal death. 63 , and in some embodiments are believed to provide enhanced neuroprotection over other Trk modulators.

[0167] Figure 3 demonstrates that promoting neuronal survival and neurite outgrowth is an effective strategy to promote functional recovery after injury. 64、65 Neurite regeneration is important for memory reconstitution; compounds that enhance neuritogenesis have been demonstrated to promote cognitive function in AD models. 66、67 As previously described 58 Two-day culture of adult neurons from 6-month-old mice with 5c(i) increased survival and neurite outgrowth by 94% and 42%, respectively. Therefore, 5c(i) is indicated for SCI, AD, and all other diseases, where neuroprotection and neurite regeneration may be of therapeutic value, such as stroke. 68 .

[0168] hippocampal LTP 69 Synapsin I, required for AD, is reduced in the dentate gyrus of human AD patients 70、71Astrocytes can release the synaptic protein synapsin I to provide neuroprotection against oxidation and ischemia and stimulate neurite outgrowth. 72、73 ,This is AD 69、74~77 It may help enhance neuronal survival and LTP in the brain. Reduction of complement component 3 (C3) levels effectively promoted functional recovery after SCI. 78、79 Reducing C3 levels effectively attenuates AD-induced synaptic loss and neurodegeneration in mice 80 Decreased astroglial glycogen synthase kinase-3β (GSK-3β) activity promotes axonal regeneration and functional recovery after SCI 81、82 GSK-3β impairs LTP, neurogenesis, and memory formation 83~85 Inhibition of GSK-3β expression attenuated Aβ, NFTs, neuronal death, and memory impairment in an AD model. 86~89 Taken together, modulation of astrocytes to increase synapsin I expression and decrease C3 and GSK-3β expression has many therapeutic benefits.

[0169] To determine whether 5c(i) can regulate astrocytes, adult astrocytes from 6-month-old male mice were treated with 5c(i) for 3 days and stained with synapsin I and C3 to measure changes in fluorescence intensity, or Western blots were performed on cell lysates to assess changes in GSK-3β expression (Figure 4). This resulted in a significant increase in synapsin I production and a decrease in C3 and GSK-3β expression. To determine whether 5c(i)-treated astrocytes could directly benefit neuronal recovery, astrocytes were cultured with 5c(i) for 2 days, after which 5c(i) was removed from the culture and adult neurons were placed on top of the astrocytes for 2 days, resulting in improved neuronal survival and neurite outgrowth. Therefore, it is hypothesized that 5c(i) may modulate astrocytes to increase synapsin I release to support synaptic plasticity, reduce the expression of neuroinflammatory substances C3 and GSK-3β to reduce neurotoxicity, and stimulate astrocytes to improve neuronal survival and neurite outgrowth, collectively promoting neurological recovery. 5c(i) is therefore indicated in SCI, AD, and all other diseases for the modulation of astrocytes, C3 expression, and GSK-3β expression to provide therapeutic value.

[0170] Figure 5 demonstrates that promoting astrocyte migration can reduce lesion size and promote functional recovery after SCI. 81 Astrocyte polarization, which is a normally beneficial extension of the process leading to seizures, is reduced in AD, leading to impaired clearance of Aβ plaques. 90、91 Therefore, a scratch assay using glial-astrocyte cultures was performed to determine whether this effect could be reproduced in adult astrocytes using 5c(i). Astrocytes from 6-month-old female mice were cultured until they reached full confluency. The plates were then scratched, mimicking the neuronal cell death and neurotoxic debris accumulation seen after SCI. 92、93Addition of 5c(i) for 48 hours immediately after scratching resulted in rapid artificial wound closure. Therefore, 5c(i) is indicated at least in SCI, AD, and all other diseases in which astrocyte migration and polarization are of therapeutic value.

[0171] Compound 5c(i), an endogenously fluorescent compound, was found to readily penetrate the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) through intraperitoneal (IP) administration to target neurons and other neural cells, even in uninjured animals without enhanced BBB or BSCB permeability (Figure 6). This is crucial because most drugs fail to penetrate the central nervous system (CNS), resulting in costly late-stage failure in CNS drug development. 94 Thus, in certain embodiments, 5c(i) may cross the BBB and target the brain, such as through IP administration, for indications related to brain function, such as AD and stroke. 5c(i) may be more likely to enter the CNS after SCI if its permeability is improved. 95-97 .

[0172] FIG. 7 provides a diagram of the activity of 5c(i) (as an example compound) on neurons and astrocytes.

[0173] In Figure 8, mice underwent baseline cognitive testing and blood sampling immediately before SCI, providing one embodiment of such a process. Mice then underwent SCI at 8 weeks of age. SCI model: thoracic vertebral contusion (50 kDyne impact) and compression (2-second dwell time), a severe contusion / compression model closely resembling clinically observed injury. To reflect the clinically observed delay, 5c(i) (5 or 25 mg / kg / day) or vehicle was administered IP daily starting 4 hours after injury. Locomotor behavioral testing (BMS) was performed weekly for 7 weeks. Seven weeks after injury, mice underwent cognitive behavioral testing (NOR), and blood was sampled again. Seven weeks after SCI, mice were euthanized for perfusion and tissue preparation for further analysis.

[0174] For locomotor behavior testing, the BMS test was performed (Figure 9). SCI induces paralysis, resulting in lower BMS scores. No significant differences were observed between injury cohorts for BMS and BMS Sub scores at 2 and 7 days post-injury (DPI), indicating that all treatment groups suffered similar damage. 5c(i) significantly improved BMS and BMS Sub scores after treatment. Therefore, 5c(i) is indicated for cases resulting in paralysis or decreased locomotor function.

[0175] Patients with neurodegenerative diseases and neurotrauma suffer from cognitive impairment. SCI can impair cognitive function. 5 , Novel Object Recognition (NOR) test (with a 24-hour probe / test interval) in SCI mice 7 weeks after injury. 98-100 Hippocampus-dependent learning and memory were assessed using 5c(i). Treatment with 5c(i) resulted in more frequent visits, shorter visit latency, and improved preference for the novel object, performing similarly to uninjured mice (Figure 10). This data indicates that, in certain embodiments, 5c(i) can improve long-term memory. Therefore, 5c(i) is useful for improving memory function in patients with cognitive impairment, etc., and therefore, 5c(i) is indicated in all diseases in which memory function is impaired.

[0176] Histological analysis of the spinal cord was performed 7 weeks after injury (Figure 11). 5c(i) enhanced serotonergic (5-HT) axon immunoreactivity caudal to the injury site, indicating that 5c(i) promoted axonal regeneration, survival, and / or sprouting. 101 5c(i) reduced IBA1 immunoreactivity, indicating reduced microglial activation. 102、103 Chronic microglial activation is associated with neurodegeneration and cognitive impairment. 104、105Therefore, as seen here, a reduction in the chronic phase is highly beneficial. 5c(i) shows CD68 immunoreactivity at the injury site and CD68 around the injury site. + (Mononuclear phagocytes 106 ) significantly reduced cell proliferation, indicating that 5c(i) has anti-inflammatory and anti-cancer properties. 106、107 , may prevent cognitive impairment 108、109 5c(i) shows the SOX9 activity around the injury site. + It reduced cell counts, which reduced the risk of cancer. 110-112 , and is expected to reduce chondroitin sulfate proteoglycan (CSPG) deposition and collagenous scarring at the lesion site. Therefore, 5c(i) is indicated in diseases related to the regeneration of tissues, cells, and other organic substances, inflammatory diseases, metabolic diseases, cancer, cognitive disorders, and diseases related to CSPGs and collagenous scarring.

[0177] Seven weeks after injury, livers were subjected to histological analysis and plasma was subjected to toxicity screening (Figure 12). 5c(i) attenuated collagen deposition, a marker for liver fibrosis that we found to be present in mice with SCI. 12 Thus, in certain embodiments, 5c(i) reduces liver pathologies, such as non-alcoholic fatty liver disease, seen in human SCI patients. 113、114 Thus, 5c(i) is indicated, in certain embodiments, in diseases affecting liver function. Plasma evaluation 7 weeks after injury showed that 5c(i) did not alter the liver function enzymes alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST). 115 and does not change blood urea nitrogen (BUN), a marker of kidney function. 116 It became clear that...

[0178] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the present invention have been described with reference to preferred embodiments, it will be apparent to those skilled in the art that variations can be applied to the methods described herein and in the steps of the methods or in the sequence of the steps of the methods without departing from the concept, spirit, and scope of the invention. More specifically, it will be apparent that certain chemically and physiologically related agents may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the invention as defined by the appended claims. References The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

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Claims

1. 1. A method for treating neurological disorders, damage to the central or peripheral nervous system and / or secondary conditions thereof, comprising administering to a patient of formula I: 【Chemistry 8】 I (In the formula, A １ and A ２ are each independently H, alkyl, acyl, heterocyclyl, or aryl; B １ , B ２ , B ３ and B ４ are each independently H or methyl; X １ and X ２ are each independently —S—, —O—, or —CH ２ - or -NH-, R １ teeth, 【Chemistry 9】 and R ２ teeth, 【Chemistry 10】 and R ３ teeth, 【Chemistry 11】 and R ４ teeth, 【Chemistry 12】 and M is H or alkyl; q is 0, 1, 2 or 3; Y is a dye or C ４ -C ６ is alkyl, Z is —OH, —O-alkyl or NA １ A ２ where A １ and A ２ is as defined above) administering to the individual a therapeutically effective amount of a composition comprising a compound of formula (I).

2. 10. The method of claim 1, wherein the neurological disorder is a neurodegenerative disease.

3. 3. The method of claim 1 or 2, wherein the neurological disorder and / or its secondary pathology comprises Alzheimer's disease, multiple sclerosis, frontotemporal dementia, psychiatric disorder, amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumor, cerebral aneurysm, encephalitis, epilepsy, seizures of cerebral origin, Guillain-Barré syndrome, dementia, migraine, Friedreich's ataxia, Huntington's disease, Lewy body disease, spinal muscular atrophy or Parkinson's disease.

4. 10. The method of claim 1, wherein the damage to the central or peripheral nervous system comprises neurotrauma.

5. 4. The method of claim 3, wherein the neurotrauma comprises a concussion, a traumatic brain injury, a skull fracture, a spinal fracture, or a spinal cord injury.

6. The method of any one of claims 1 to 4, wherein the compound comprises the amino acid DIRG.

7. The method of any one of claims 1 to 5, wherein the compound comprises the amino acids CDIRGC.

8. The method of any one of claims 1 to 6, wherein Y is a rhodamine, fluorene, or BODIPY® dye.

9. Y, 【Chemistry 13】 (In the formula, R ５ , R ６ , R ７ and R ８ are each independently H, a halide, or C １ -C ３ Alkyl or SO ３ H or a salt thereof, R ５ and R ６ may optionally be joined to form a ring, R ７ and R ８ may optionally be joined to form a ring, R ９ is H, halide, C １ -C ３ Alkyl or SO ３ H or a salt thereof, or aryl), The method according to any one of claims 1 to 6, wherein

10. 9. The method of any one of claims 1 to 8, wherein the secondary pathology comprises fibrosis, liver disease, kidney disease, colon disease, cardiac conditions, metabolic conditions, muscle-related diseases, respiratory diseases and / or cancer.

11. 10. The method of claim 9, wherein the fibrosis is liver fibrosis.

12. 1. A method for improving locomotor function, improving mobility, improving long-term memory, improving cognition, reducing fibrosis, and / or reducing inflammation in an individual, comprising administering to an individual a compound of Formula I: 【Chemistry 14】 I (In the formula, A １ and A ２ are each independently H, alkyl, acyl, heterocyclyl, or aryl; B １ , B ２ , B ３ and B ４ are each independently H or methyl; X １ and X ２ are each independently —S—, —O—, or —CH ２ - or -NH-, R １ teeth, 【Chemistry 15】 and R ２ teeth, 【Chemistry 16】 and R ３ teeth, 【Chemistry 17】 and R ４ teeth, 【Chemistry 18】 and M is H or alkyl; q is 0, 1, 2 or 3; Y is a dye or C ４ -C ６ is alkyl, Z is —OH, —O-alkyl or NA １ A ２ where A １ and A ２ is as defined above) administering to said individual a composition comprising a compound of formula (I).

13. 12. The method of claim 11, wherein the individual has a neurological disorder, damage to the central or peripheral nervous system, and / or a secondary pathology thereof.

14. 13. The method of claim 12, wherein the neurological disorder is a neurodegenerative disease.

15. 14. The method of claim 12 or 13, wherein the neurological disorder and / or its secondary pathology comprises Alzheimer's disease, multiple sclerosis, frontotemporal dementia, psychiatric disorder, amyotrophic lateral sclerosis (ALS), ataxia, Bell's palsy, brain tumor, cerebral aneurysm, encephalitis, epilepsy, seizures of cerebral origin, Guillain-Barré syndrome, dementia, migraine, Friedreich's ataxia, Huntington's disease, Lewy body disease, spinal muscular atrophy or Parkinson's disease.

16. 13. The method of claim 12, wherein the damage to the central or peripheral nervous system comprises neurotrauma.

17. 16. The method of claim 15, wherein the neurotrauma comprises a concussion, a traumatic brain injury, a skull fracture, a spinal fracture, or a spinal cord injury.

18. The method of any one of claims 11 to 16, wherein the compound comprises the amino acid DIRG.

19. The method of any one of claims 11 to 17, wherein the compound comprises the amino acids CDIRGC.

20. The method of any one of claims 11 to 18, wherein Y is a rhodamine, fluorene, or BODIPY® dye.

21. Y, 【Chemistry 19】 (In the formula, R ５ , R ６ , R ７ and R ８ are each independently H, a halide, or C １ -C ３ Alkyl or SO ３ H or a salt thereof, R ５ and R ６ may optionally be joined to form a ring, R ７ and R ８ may optionally be joined to form a ring, R ９ is H, halide, C １ -C ３ Alkyl or SO ３ H or a salt thereof, or aryl) The method according to any one of claims 11 to 18, wherein

22. 21. The method of any one of claims 11 to 20, wherein the secondary pathology comprises fibrosis, liver disease, kidney disease, colon disease, cardiac conditions, metabolic conditions, muscle-related diseases, respiratory diseases and / or cancer.

23. 22. The method of claim 21, wherein the fibrosis is liver fibrosis.

24. A method of monitoring the location of a compound in vivo or ex vivo, comprising directly or indirectly identifying in said individual a compound comprising Formula I and / or a molecule to which said compound binds: 【Chemistry 20】 I (In the formula, A １ and A ２ are each independently H, alkyl, acyl, heterocyclyl, or aryl; B １ , B ２ , B ３ and B ４ are each independently H or methyl; X １ and X ２ are each independently —S—, —O—, or —CH ２ - or -NH-, R １ teeth, 【Chemical 21】 and R ２ teeth, 【Chemical 22】 and R ３ teeth, 【Chemical 23】 and R ４ teeth, 【Chemistry 24】 and M is H or alkyl; q is 0, 1, 2 or 3; Y is a dye or C ４ -C ６ is alkyl, Z is —OH, —O-alkyl or NA １ A ２ where A １ and A ２ is as defined above).

25. 24. The method of claim 23, wherein the compound comprises the amino acid DIRG.

26. 25. The method of claim 23 or 24, wherein the compound comprises the amino acids CDIRGC.

27. 26. The method of any one of claims 23 to 25, wherein Y is a rhodamine, fluorene, or BODIPY® dye.

28. Y, 【Chemistry 25】 (In the formula, R ５ , R ６ , R ７ and R ８ are each independently H, a halide, or C １ -C ３ Alkyl or SO ３ H or a salt thereof, R ５ and R ６ may optionally be joined to form a ring, R ７ and R ８ may optionally be joined to form a ring, R ９ is H, halide, C １ -C ３ Alkyl or SO ３ H or a salt thereof, or aryl) The method according to any one of claims 23 to 26, wherein

29. The method of any one of claims 23 to 27, which provides information about the mechanism of action, pharmacokinetics and / or toxicity of said compound.

30. The method of any one of claims 23 to 28, comprising an immunohistochemical assay.

31. 29. The method of any one of claims 23 to 28, comprising monitoring the location of said compound or a molecule to which it binds in a mammal.

32. The method of any one of claims 23 to 30, wherein the molecule to which the compound binds is a cancer antigen or marker.

33. 32. The method of any one of claims 23-28 or 30-31, wherein the individual is known to have, suspected to have, or at risk of having cancer.

34. 33. The method of any one of claims 23-28 or 30-32, which provides diagnostic and / or prognostic information for an individual suspected of having or at risk of having cancer.

35. 34. The method of any one of claims 23-28 or 30-33, which provides information regarding the effectiveness of a treatment for an individual known to have, suspected of having, or at risk of having cancer.

36. 35. The method of any one of claims 23 to 28 or 30 to 34, which is administered once to an individual.

37. 35. The method of any one of claims 23 to 28 or 30 to 34, which is administered multiple times to an individual.

38. 35. The method of any one of claims 23 to 28 or 30 to 34, wherein the effectiveness of the treatment is monitored over time for the individual.

39. 37. The method of claim 36, wherein the treatment is the compound.

40. 37. The method of claim 36, wherein the treatment is not the compound.

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