Compositions and methods comprising n-acetylcysteine and nicotinamide riboside for the prevention and treatment of neurological diseases and conditions

Abstract

To provide novel compounds, compositions, and methods of prevention and / or treatment that address neurological diseases and / or conditions.SOLUTION: The present invention provides a composition comprising at least one N-acetylcysteine and at least one nicotinamide riboside or NAD + precursor for use in a method of preventing and / or treating a neurological disease and / or condition. In one embodiment of the invention, the composition of the invention maintains or improves brain function, in particular brain energy deficit. In another embodiment of the invention, the composition of the invention improves neurological recovery and regeneration after injury or surgery. In another embodiment of the invention, the composition of the invention can be used in a method for the prevention and / or treatment of neurological diseases and / or conditions and / or for recovery after injury or surgery.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention provides compounds and compositions containing cysteine ​​and nicotinamide riboside for use in methods for the prevention and / or treatment of neurological diseases and / or conditions. In one embodiment of the present invention, the compounds and compositions of the present invention maintain or improve brain function, particularly brain energy deficiency. In another embodiment of the present invention, the compounds and compositions of the present invention improve neurological recovery and regeneration after injury or surgery. In another embodiment of the present invention, the compounds and compositions of the present invention can be used in methods for the prevention and / or treatment of neurological diseases and / or conditions, and / or methods for recovery after injury or surgery. [Background technology]

[0002] Population aging is a significant demographic phenomenon. Due to longer lifespans, the growth of the middle-aged and elderly population is outpacing the growth of the overall population, resulting in a significant increase in the proportion of the middle-aged and elderly population relative to the rest of the population. For example, in the 1950s, one in twelve people was aged 60 or older; by the end of the 2000s, this figure had dropped to one in ten. By the end of the 2050s, it is projected that one in five people worldwide will be aged 60 or older.

[0003] Middle-aged and elderly individuals often experience some degree of cognitive impairment, including progressive age-related cognitive decline, and age-related changes in brain morphology and cerebrovascular function are commonly observed. Cognitive decline has consistently been reported in conjunction with aging in a wide range of cognitive domains, including processing speed, attention, episodic memory, spatial ability, and executive function. Brain imaging studies have shown that these normal age-related cognitive declines are associated with a decrease in both gray and white matter volume, with the fronto-striatal system being the most severely damaged with age. This loss of cortical volume may be due to many deleterious cellular processes associated with normal aging, such as the long-term accumulation of free radical damage leading to oxidative damage, chronic low-grade inflammation, homocysteine ​​accumulation (increased accumulation is a risk factor for cognitive impairment and dementia), and decreased mitochondrial function. In addition to direct cellular damage, the brain also suffers indirect damage from damage to the microvasculature. It is clear that the pathology of aging, and even dementia, involves a complex interplay between these interconnected factors. For example, mitochondrial dysfunction results in increased oxidative stress, which can trigger inflammation and vascular damage.

[0004] Furthermore, cognitive decline is an early predictor of Alzheimer's disease and begins before the onset of dementia. In this case, a comprehensive cognitive score provides a reliable means of assessing cognitive decline that occurs before dementia. A large body of evidence suggests that maintaining brain health and preventing age-related cognitive decline can prevent or slow the progression of dementia due to Alzheimer's disease and other age-related neuropathologies.

[0005] In biology and psychology, the term "stress" refers to the failure of humans or other animals to respond appropriately to physiological, emotional, or physical threats, whether real or imagined. Psychobiologically, stress can be characterized as a manifestation of oxidative stress, i.e., an imbalance between the production and expression of reactive oxygen species and the ability of the living system to rapidly detoxify reactive intermediates or repair the resulting damage. Disruption of the normal redox state of tissues can cause toxic effects through the production of peroxides and free radicals, which damage all components of the cell, including proteins, lipids, and DNA. Some reactive oxidative species can also act as messengers through a phenomenon called "redox signaling."

[0006] In humans, oxidative stress is involved in many diseases, including atherosclerosis, Parkinson's disease, heart failure, myocardial infarction, Alzheimer's disease, schizophrenia, bipolar disorder, fragile X syndrome, and chronic fatigue syndrome.

[0007] One source of ROS under normal conditions in humans is the leakage of ROS from mitochondria during oxidative phosphorylation. Other enzymes that can produce superoxide (O2-) include xanthine oxidase, NADPH oxidase, and cytochrome P450. Another potent oxidant, hydrogen peroxide, is produced by a variety of enzymes, including several oxidases. Reactive oxygen species play an important role in cellular signaling processes called redox signaling. Therefore, a balance between the production and consumption of ROS is required to maintain proper cellular homeostasis.

[0008] Oxidative stress contributes to tissue damage after ultraviolet irradiation and hyperoxia, and this damage is suspected to be important in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease.

[0009] Furthermore, the free radical theory of aging suggests that the biological process of aging is driven by increased oxidative stress in older adults. The ability of cells to resist potential damage caused by oxidative stress depends on the balance between the body's production of oxidant free radicals and the availability of numerous protective antioxidants. Multiple antioxidant defense systems exist, among which glutathione (GSH) is the most abundant intracellular component involved in comprehensive antioxidant defense. GSH is a tripeptide synthesized de novo from the precursor amino acids glutamate, cysteine, and glycine in two steps catalyzed by glutamate cysteine ​​ligase (GCL, also known as γ-glutamylcysteine ​​synthetase, EC 6.3.2.2) and γ-L-glutamyl-L-cysteine:glycine ligase (also known as glutathione synthetase, EC 6.3.2.3). GSH synthesis occurs de novo within cells.

[0010] NAD+ also plays an important role in neurological development, regeneration, aging, and disease. NAD+ mediates multiple biological processes in the brain, including neurotransmission and learning and memory. NAD+ may also mediate brain aging and tissue damage in various brain diseases. NADH can transport across the plasma membrane of astrocytes, and NAD+ administration can significantly reduce ischemic brain damage (Ying et al., "NAD(+) and NADH in brain functions, brain diseases, and brain aging," February 2007, Frontiers in Bioscience 12(5):1863-88). Low NAD+ levels can be detrimental to brain health, whereas high NAD+ levels are known to promote brain health. Therefore, addressing neurological diseases and / or conditions with novel compounds, compositions, and methods of prevention and / or treatment that affect the above pathways is an urgent problem that needs to be solved.

[0011] [Summary of the Invention] The present invention provides compositions comprising a combination of at least one N-acetylcysteine ​​or functional derivative thereof and at least one nicotinamide riboside or NAD+ precursor, the combination comprising the combination in an amount effective to prevent and / or treat a neurological disease or condition.

[0012] In one embodiment, the combination is administered orally or enterally via a nasogastric tube.

[0013] In one embodiment, the composition is selected from the group consisting of a food or beverage product, a dietary supplement, a functional food, an oral nutritional supplement (ONS), a medical food, a food for special medical purposes (FSMP), a nutraceutical, a dietary supplement, a ready-to-drink formula, a low-volume liquid supplement, a powder for reconstitution with liquid, a meal replacement beverage, and combinations thereof.

[0014] In another embodiment, the composition does not contain glycine or a functional derivative.

[0015] In further embodiments, the compositions can improve glucose uptake / utilization in the brain, providing one or more benefits to neurological and / or brain function.

[0016] In one embodiment of the present invention, a composition is provided for maintaining or improving brain function in a subject.

[0017] In yet another embodiment of the present invention, a composition is provided for enhancing neurological recovery after injury or surgery.

[0018] In another embodiment, the present disclosure provides a method for maintaining cognitive function in a healthy elderly person, the method comprising administering to the healthy elderly person an effective amount of a combination of an NAD+ precursor and at least one N-acetylcysteine ​​or functional derivative thereof. The healthy elderly person may be elderly.

[0019] In another embodiment of the invention, the composition is a nutritional composition containing at least one N-acetylcysteine ​​or functional derivative thereof and at least one nicotinamide riboside or NAD+ precursor, and the improvement in neurological function in the brain is measured, for example, by suitable neurological and cognitive tests, brain imaging, and clinical examinations.

[0020] In one embodiment, the at least one N-acetylcysteine ​​or functional derivative thereof and the at least one nicotinamide riboside or NAD+ precursor are administered in the same composition.

[0021] In one embodiment, the at least one N-acetylcysteine ​​or functional derivative thereof and one or more of the at least one nicotinamide riboside or NAD+ precursor are administered as different compositions. DETAILED DESCRIPTION OF THE INVENTION

[0022] definition All percentages stated herein are by weight of the total composition unless otherwise specified. As used herein, "about," "approximately," and "substantially" are understood to refer to numbers within a numerical range, for example, within -10% to +10% of the referenced number, preferably within -5% to +5% of the referenced number, more preferably within -1% to +1% of the referenced number, and most preferably within -0.1% to +0.1% of the referenced number.

[0023] All numerical ranges herein should be understood to include all integers or fractions within that range. Furthermore, these numerical ranges should be construed to support claims directed to any number or subset of numbers within that range. For example, a disclosure of 1 to 10 should be construed to support ranges of 1 to 8, 3 to 7, 1 to 9, 3.6 to 4.6, 3.5 to 9.9, etc.

[0024] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a component" or "the component" includes two or more components.

[0025] The terms "comprise," "comprises," and "comprising" should be interpreted as inclusive rather than exclusive. Similarly, the terms "include," "including," and "or" should all be interpreted as inclusive unless such interpretation is clearly prevented by the context. However, the compositions disclosed herein may not include elements not specifically disclosed herein. Thus, disclosure of an embodiment using the term "comprising" includes disclosure of embodiments "consisting essentially of," as well as embodiments "consisting of," the specified components. Any embodiment disclosed herein can be combined with any other embodiment disclosed herein.

[0026] As used herein, the terms "examples" and "such as," particularly when followed by a list of terms, are merely exemplary and illustrative and should not be considered exclusive or inclusive. As used herein, a condition "associated with" or "linked with" another condition means that the conditions occur simultaneously, preferably that the conditions are caused by the same underlying condition, and most preferably that one of the specified conditions is caused by the other specified condition.

[0027] The terms "food," "food product," and "food composition" refer to a product or composition intended for ingestion by an individual, such as a human, and which provides at least one nutrient to such an individual. A food product typically comprises at least one of protein, lipid, carbohydrate, and optionally one or more vitamins and minerals. The term "beverage" or "beverage product" refers to a liquid product or liquid composition intended for oral ingestion by an individual, such as a human, and which provides at least one nutrient to such an individual.

[0028] The compositions of the present disclosure, including the many embodiments described herein, can include, consist of, or essentially consist of the elements disclosed herein as well as any additional or optional ingredients, components, or elements that are useful in the diet, whether described herein or not.

[0029] As used herein, the term "isolated" means separated from one or more other compounds or components with which the compound may otherwise be found, e.g., as found in nature. Preferably, for example, "isolated" means that the specified compound is separated from at least a portion of the cellular material with which it is typically found in nature. In one embodiment, an isolated compound is free of any other compounds.

[0030] "Prevention" includes reducing the risk, incidence, and / or severity of a condition or disorder. The terms "treatment," "treat," and "to alleviate" include both prophylactic or preventive treatment (which prevent and / or delay the onset of the targeted condition or disorder) and curative, therapeutic, or disease-modifying treatment, including therapeutic measures that cure, delay, attenuate the symptoms, and / or halt the progression of a diagnosed condition or disease; and include treatment of patients who are ill or diagnosed as suffering from a disease or medical condition, as well as treatment of patients at risk of or suspected of having the disease. The term does not necessarily imply that a subject is treated to the point of cure. The terms "treatment" and "treating" also refer to maintaining and / or promoting the health of individuals who are not afflicted with the disease but who may be susceptible to an ill health condition. The terms "treatment / therapy," "treat / treating," and "alleviating" are also intended to include synergistic or otherwise potentiating action of one or more primary preventative or therapeutic measures. The terms "treatment / therapy," "treat / treating," and "alleviating" are further intended to include dietary management of a disease or condition, or dietary management for the prophylaxis or prevention of a disease or condition. Treatment may be patient-related or physician-related.

[0031] As used herein, the term "unit dosage form" refers to a physically discrete unit suitable as a dosage unit for human and animal subjects, each unit containing a predetermined amount of a composition disclosed herein, in an amount sufficient to produce a desired effect, together with a pharmaceutically acceptable diluent, carrier, or vehicle. The specifications for the unit dosage form depend on the particular compound used, the effect to be achieved, and the pharmacodynamics associated with each compound in the host.

[0032] As used herein, an "effective amount" is an amount that prevents a deficiency, treats a disease or medical condition in an individual, or more generally, alleviates symptoms, manages the progression of a disease, or provides a nutritional, physiological, or medical benefit to an individual. The relative terms "improve," "enhance," "boost," "promote," and the like refer to the effect of a composition disclosed herein, i.e., a composition comprising at least one N-acetylcysteine ​​or functional derivative thereof and at least one nicotinamide riboside or NAD+ precursor, compared to an identical composition that does not contain nicotinamide riboside. As used herein, "promoting" refers to enhancing or inducing compared to a value prior to administration of a composition disclosed herein.

[0033] A "subject" or "individual" is a mammal, preferably a human. The term "elderly," in reference to humans, means an age of at least 60 years, preferably greater than 63 years, more preferably greater than 65 years, and most preferably greater than 70 years. The term "older adult," in the human context, means a postnatal age of 45 years or older, preferably greater than 50 years, and more preferably greater than 55 years, and includes elderly individuals.

[0034] As used herein, "cognitive ability" refers to the degree to which a subject performs one or more cognitive functions well. As used herein, "cognitive function" refers to any mental process by which a person becomes aware of, perceives, or understands ideas. This function encompasses all aspects of perception, thinking, reasoning, and remembering, including, for example, perception, memory, attention, language comprehension, language expression, reading comprehension, mental recall, learning, and reasoning. Typically, cognitive function refers to at least memory.

[0035] Methods for measuring cognitive function are well known and can include, for example, individual tests or battery tests for any aspect of cognitive function. One such test is the Prudhoe Cognitive Assessment by Margallo-Lana et al. (2003) J. Intellect. Disability Res. 47:488-492. Another such test is the Mini Mental State Exam (MMSE), which is designed to assess orientation to time and place, memory, attention and calculation, recall, language use and comprehension, repetition, and complex commands. Folstein et al. (1975) J. Psych. Res. 12:189-198. Other tests useful for measuring cognitive function include the Alzheimer's Disease Assessment Scale-Cognitive Test (ADAS-Cog) (Rosen et al. (1984) Am. J. Psychinatry. 141(11): 1356-64), and the CANTAB (Cambridge Neuropsychological Test Automated Battery) (Robbins et al. (1994) Dementia. 5(5): 266-81), and the Montreal Cognitive Assessment (MoCA) (Ciesielska N. et al., 2016: DOI: 10.12740 / PP / 45368 and Carson N. et al., 2018: DOI: 10.1002 / gps.4756). Such tests can be used to objectively assess cognitive function, thereby enabling measurements and comparison of changes in cognitive function, for example, in response to treatment by the methods disclosed herein.

[0036] As used herein, "cognitive disorder" refers to any condition that impairs cognitive function. Non-limiting examples of cognitive disorders include delirium, dementia, learning disabilities, attention deficit disorder (ADD), and attention deficit hyperactivity disorder.

[0037] Neurological Diseases and Conditions As used herein, the term "neurological condition" refers to a disorder of the nervous system. A neurological condition can be the result of damage to the brain, spinal column, or nerves caused by disease or injury. Non-limiting examples of symptoms of a neurological condition include paralysis, muscle weakness, poor coordination, loss of sensation, seizures, confusion, pain, and an altered level of consciousness. Assessment of responses to touch, pressure, vibration, limb position, heat, cold, and pain, as well as reflexes, can be performed to determine whether a subject has a nervous system disorder.

[0038] Some neurological conditions are lifelong and their onset can be experienced at any time. Other neurological conditions, such as cerebral palsy, are present from birth. Some neurological conditions, such as Duchenne muscular dystrophy, generally manifest in early childhood, while others, such as Alzheimer's disease and Parkinson's disease, primarily affect older adults. Some neurological conditions develop suddenly due to injury or disease, such as a head injury or stroke, or cancer of the brain and spine.

[0039] In one embodiment, the neurological condition is the result of a traumatic brain injury. Additionally, or alternatively, the neurological condition is the result of an energy deficiency in the brain or muscles.

[0040] Examples of neurological conditions include migraine, memory impairment, age-related memory impairment, brain injury, neurorehabilitation, stroke and post-stroke, amyloid lateral sclerosis, multiple sclerosis, cognitive impairment, mild cognitive impairment (MCI), post-intensive care cognitive impairment, age-related cognitive impairment, Alzheimer's disease, Parkinson's disease, Huntington's disease, inborn errors of metabolism (such as glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase complex deficiency), bipolar disorder, schizophrenia, and / or epilepsy.

[0041] It will be appreciated that the compounds, compositions and methods of the present invention may be useful in the prevention and / or treatment of the above-mentioned neurological diseases or conditions, particularly in maintaining or improving brain or nervous system function.

[0042] Migraine A migraine is a severe headache accompanied by other symptoms such as nausea (feeling unwell), visual disturbances, and increased sensitivity to light or sound. A migraine may be preceded by an aura; the main symptom of the aura is visual disturbances such as blurred vision (difficulty focusing), scotoma, flashing lights, or zigzag patterns moving from the center to the edges of the field of vision.

[0043] It can be appreciated that the compounds, compositions and methods of the present invention may be useful in the prevention and / or treatment of migraine headaches or the neurological symptoms thereof.

[0044] stroke A stroke (also known as a cerebrovascular accident (CVA) and cerebrovascular injury (CVI)) occurs when insufficient blood flow to the brain results in cell death. There are two main types of stroke: ischemic (caused by insufficient blood flow) and hemorrhagic (caused by bleeding). A stroke causes part of the brain to stop functioning normally. Signs and symptoms of a stroke may include an inability to move one side of the body, loss of feeling on one side of the body, problems with understanding or speaking, a feeling that the world is spinning, or loss of vision on one side. Signs and symptoms often appear immediately after a stroke occurs.

[0045] It can be appreciated that the compounds, compositions and methods of the present invention may be beneficial in the prevention and / or treatment of stroke or in recovery from stroke.

[0046] Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) (also known as Lou Gehrig's disease, Charcot's disease, and motor neuron disease) involves the death of neurons responsible for controlling voluntary muscles. ALS is characterized by gradually worsening weakness caused by muscle stiffness, muscle twitching, and muscle wasting; this leads to difficulty speaking, swallowing, and eventually breathing.

[0047] It can be appreciated that the compounds, compositions, and methods of the present invention may be useful in the prevention and / or treatment of ALS or its neurological symptoms.

[0048] Multiple sclerosis Multiple sclerosis (MS) affects the nerves in the brain and spinal cord, causing a wide range of symptoms including problems with muscle movement, motor function and balance, numbness and tingling, blurred vision (typically a visual field loss in one eye), and fatigue.

[0049] It can be appreciated that the compounds, compositions and methods of the present invention may be useful in the prevention and / or treatment of MS or its neurological symptoms.

[0050] Parkinson's disease Parkinson's disease is a degenerative disease of the central nervous system that primarily affects the motor system. In the early stages of the disease, the most prominent symptoms are movement-related; these include resting tremor, rigidity, and difficulty walking and gait. Later, during the course of the disease, problems with thinking and behavior may occur, and dementia generally occurs in the advanced stages of the disease. Other symptoms include depression, sensory, sleep, and emotional problems.

[0051] It can be appreciated that the compounds, compositions and methods of the present invention may be useful in preventing and / or treating Parkinson's disease or its neurological symptoms.

[0052] Alzheimer's disease Alzheimer's disease (AD) is a progressive neurodegenerative disorder. It is the most common cause of dementia. Symptoms include memory loss and difficulty with thinking, problem-solving, or language. The Mini-Mental State Examination (MMSE) is an example of a test used to diagnose Alzheimer's disease.

[0053] It can be appreciated that the compounds, compositions, and methods of the present invention may be useful in the prevention and / or treatment of AD or its neurological symptoms.

[0054] Huntington's disease Huntington's disease is a genetic condition that damages certain nerve cells in the brain. Huntington's disease affects muscle coordination, leading to mental decline and behavioral symptoms. The earliest symptoms often involve minor problems related to mood or cognition. A general lack of coordination and an unsteady gait then occur. As the disease progresses, jerky, spasmodic physical movements become more pronounced, along with a decline in mental ability and behavioral symptoms. Physical ability gradually deteriorates until coordination becomes difficult. Mental ability commonly declines to the point of dementia.

[0055] It can be appreciated that the compounds, compositions and methods of the present invention may be useful in preventing and / or treating Huntington's disease or its neurological symptoms.

[0056] Inborn errors of metabolism that affect the brain and nervous system Inborn errors of metabolism are a variety of diseases caused by defective genes. Typically, the defective gene(s) result in a deficiency in an enzyme or transport protein, which blocks the pathway by which the body processes a compound, resulting in the toxic accumulation of that compound. Inborn errors of metabolism can affect any organ, usually two or more organs. Symptoms often tend to be nonspecific and are usually related to the dysfunction or failure of a major organ. The onset and severity of metabolic disorders can be exacerbated by environmental factors such as diet and coexisting illnesses.

[0057] GLUT1 deficiency syndrome Glucose transporter 1 (Glut1) deficiency syndrome is an inherited metabolic disorder involving the GLUT1 protein, which transports glucose across the blood-brain barrier, the boundary separating small blood vessels from brain tissue. The most common symptom is seizures (epilepsy), which usually begin within the first few months of life. Additional symptoms that may occur include varying degrees of cognitive impairment and movement disorders characterized by ataxia, dystonia, and chorea. Glut1 deficiency syndrome can be caused by mutations in the SLC2A1 gene, which produces the GLUT1 protein.

[0058] Pyruvate dehydrogenase complex deficiency Pyruvate dehydrogenase complex deficiency (pyruvate dehydrogenase deficiency or PDCD) is a neurodegenerative disorder associated with impaired mitochondrial metabolism and disrupted carbohydrate metabolism. PDCD is characterized by the accumulation of lactic acid in the body and various neurological disorders. Signs and symptoms of the condition usually first appear shortly after birth but can vary greatly among affected individuals. The most common feature is a potentially life-threatening buildup of lactic acid (lactic acidosis), which can cause nausea, vomiting, severe breathing difficulties, and an abnormal heartbeat. Other symptoms include neurological problems; delayed development of mental abilities and motor skills such as sitting and walking; intellectual disability; seizures; decreased muscle tone (hypotonia); poor coordination; and difficulty walking. Some affected individuals have abnormal brain structures, such as underdevelopment of the tissue connecting the left and right hemispheres of the brain (corpus callosum), weakness (atrophy) of the outer part of the brain known as the cerebral cortex, or multiple areas of damaged tissue (lesions) in one part of the brain.

[0059] It can be appreciated that the compounds, compositions and methods of the present invention may be beneficial in the prevention and / or treatment of inborn errors of metabolism or conditions that affect the brain and / or nervous system.

[0060] Psychogenic conditions and disorders Psychogenic conditions and illnesses are associated with emotional or mental stressors that can affect brain function. Psychogenic disorders are divided into (i) dissociation (involving memory, consciousness, and identity disorders) and (ii) disorders involving somatization, which are divided into somatoform (unconscious), factitious (voluntary exploration of the patient's role), and malingering (seeking material gain). Normal activity in specific brain regions of the motor or sensory cortex is blocked by other brain regions associated with emotional integration in the anterior cingulate and orbitofrontal cortices.

[0061] Bipolar disorder Bipolar disorder is a brain disorder that causes abnormal shifts in mood, energy, activity level, and ability to perform daily tasks. Bipolar disorder is characterized by periods of elevated mood and periods of depressed mood. Bipolar disorder can be diagnosed using guidelines from the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the World Health Organization's International Statistical Classification of Diseases and Related Health Problems.

[0062] Schizophrenia Schizophrenia is a chronic, serious disorder in which the patient's interpretation of reality is abnormal, resulting in brain damage. Schizophrenia can result in some combination of visual and auditory hallucinations, delusions, and highly disorganized thinking and behavior. Schizophrenia can be diagnosed using guidelines from the Diagnostic and Statistical Manual of Mental Disorders (DSM) or the World Health Organization's International Statistical Classification of Diseases and Related Health Problems.

[0063] epilepsy Epilepsy is a neurological disorder in which the activity of nerve cells in the brain is disrupted, resulting in seizures or abnormal behavior, sensations and sometimes periods of loss of consciousness.

[0064] stress In biology and psychology, the term "stress" refers to the failure of humans or other animals to respond appropriately to physiological, emotional, or physical threats, whether real or imagined. Psychobiologically, stress can be characterized as a manifestation of oxidative stress, i.e., an imbalance between the production and expression of reactive oxygen species and the ability of the living system to rapidly detoxify reactive intermediates or repair the resulting damage. Disruption of the normal redox state of tissues can cause toxic effects through the production of peroxides and free radicals, which damage all components of the cell, including proteins, lipids, and DNA. Some reactive oxidative species can also act as messengers through a phenomenon called "redox signaling."

[0065] Motivated performance or motivation / mental capacity "Motivated performance" is synonymous with the term "drive / mental capacity" and the related terms "will," "will-power," "time-on-task," "persistence," "self-control," "persistence," and "self-efficacy." These terms all relate to a person's drive to initiate and perform. Motivated performance is related to subjectively perceived self-efficacy and well-being.

[0066] Motivated performance represents a subjective perception of available mental resources, which in turn relates to cognitive function. For example, motivated performance is reduced in states of depression and anxiety. Measurement of "motivated performance" can be based on both motor and cognitive tasks. Typically, these motor and cognitive tasks are performed under rewarded conditions, meaning that individuals receive rewards based on their performance on the task.

[0067] It can be appreciated that the compounds, compositions, and methods of the present invention may be useful in the prevention and / or treatment of the above-mentioned psychogenic disease states and other conditions related to stress and motivational performance, particularly in maintaining or improving brain or nervous system function.

[0068] The terms "cognitive disorder" and "cognitive disorder" refer to disorders that impair cognition, particularly disorders that primarily affect learning, memory, perception and / or problem-solving.

[0069] Cognitive impairment can occur in subjects after intensive care. Cognitive impairment can occur as part of aging, for example, as mild cognitive impairment (MCI).

[0070] The term "cognition" refers to the full range of mental abilities and processes, including knowledge, attention, long-term and working memory, judgment and evaluation, reasoning and "calculation," problem-solving and decision-making, and language comprehension and creation. Cognitive level and improvement can be readily assessed by one of skill in the art using any suitable neurological and cognitive tests known in the art, including cognitive tests designed to assess information processing speed, executive function, and memory. Examples of suitable tests include the Mini-Mental State Examination (MMSE), CANTAB (Cambridge Neuropsychological Test Automated Battery), Alzheimer's Disease Assessment Scale Cognitive Test (ADAScog), Wisconsin Card Sorting Task, Verbal and Picture Fluency Test and Trail Making Test, Wechsler Memory Scale (WMS), Immediate and Delayed Visual Reproduction Test (Trahan et al., Neuropsychology, 1988 19(3) p.173-89), Rey Auditory Verbal Learning Test (RAVLT) (Ivnik, RJ. et al., Psychological Assessment: A Journal of Consulting and Clinical Psychology, 1990(2):p.304-312), electroencephalography (EEG), magnetoencephalography (MEG), positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), computed tomography, and long-term potentiation.

[0071] EEG, the measurement of electrical activity of the brain, is achieved by placing electrodes on the scalp at various landmarks and recording highly amplified brain signals. MEG is similar to EEG in that it measures magnetic fields related to electric fields. MEG is used to measure spontaneous brain activity, including synchronous waves in the nervous system.

[0072] PET provides an index of oxygen utilization and / or glucose metabolism. In this technique, radioactive positron-emitting tracers are administered, and their uptake by the brain correlates with brain activity. These tracers emit gamma rays, which are detected by sensors surrounding the head, providing a 3D map of brain activity. As soon as the tracers are taken up by the brain, radioactivity is detected in response to regional cerebral blood flow. During activation, increases in cerebral blood flow and neuronal glucose metabolism can be detected within seconds.

[0073] Suitable analyses may also be based on neuropsychological testing, clinical examinations, and individual complaints of cognitive decline (e.g., subjective memory loss). Further, suitable tests may be based on assessments of movement, memory and attention, seizure susceptibility, and social interaction and / or social cognition.

[0074] Memory impairment is the result of neural damage to brain structure, which causes memory storage, retention and recall to be impaired.Memory impairment can progress with age (for example, Alzheimer's disease), or can be directly caused by, for example, head injury.The level and improvement of memory impairment can be easily evaluated by those skilled in the art by using any suitable test known in the art, such as Alzheimer's Disease Assessment Scale Cognitive Test (ADAScog), Mini-Mental State Examination (MMSE), computed tomography (CT) scan, magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), positron emission tomography (PET) and electroencephalography (EEG).

[0075] Embodiment The present invention provides compositions containing at least one N-acetylcysteine ​​or functional derivative thereof and at least one nicotinamide riboside or NAD+ precursor. Each of the compounds can be administered simultaneously with the other compounds (i.e., as a single unit) or separated by time intervals (i.e., in separate units). The present disclosure further provides kits comprising at least one N-acetylcysteine ​​or functional derivative thereof and at least one nicotinamide riboside or NAD+ precursor, e.g., as two or more solutions or dry powders in separate containers, for mixing to form one or more of the compositions disclosed herein and / or for use in one or more of the methods disclosed herein. In some embodiments, one or more of these compounds may be isolated compounds.

[0076] As used herein, "nicotinamide riboside" includes L-valine and L-phenylalanine esters of nicotinamide riboside. Non-limiting examples of suitable NAD+ precursors include tryptophan, nicotinic acid, nicotinamide, reduced nicotinamide riboside (NRH), nicotinamide mononucleotide (NMN), trigonelline, nicotinic acid mononucleotide, nicotinic acid riboside, and mixtures thereof. The present disclosure is not limited to a particular embodiment of an NAD+ precursor, and an NAD+ precursor may be any compound that stimulates NAD+.

[0077] Nicotinamide riboside can be provided by any of the compositions disclosed in U.S. Pat. Nos. 8,383,086 and 8,197,807, each entitled "Nicotinamide Riboside Kinase Compositions and Methods of Use," and U.S. Pat. No. 8,106,184, entitled "Nicotinoyl Riboside Compositions and Methods of Use," each of which is incorporated herein by reference in its entirety.

[0078] Some embodiments relating to non-human mammals, such as rodents, include administering an amount of the composition to provide 1.0 mg to 1.0 g, preferably 10 mg to 500 mg, more preferably 25 mg to 400 mg, and most preferably 50 mg to 300 mg of nicotinamide riboside per kg of body weight of the non-human mammal.

[0079] Some embodiments for humans include administering an amount of the composition to provide 1.0 mg to 10.0 g, preferably 10 mg to 5.0 g, more preferably 50 mg to 2.0 g, and most preferably 100 mg to 1.0 g of nicotinamide riboside per kg of human body weight.

[0080] In some embodiments, nicotinamide riboside or NAD+ precursors can be administered in an amount of about 0.001 mg / day to about 2000 mg / day, preferably about 0.001 mg / day to about 1000 mg / day, more preferably about 0.001 mg / day to about 750 mg / day, even more preferably about 0.001 mg / day to about 500 mg / day, and most preferably about 0.001 mg / day to about 250 mg / day, e.g., about 0.001 mg / day to about 100 mg / day, about 0.001 mg / day to about 75 mg / day, about 0.001 mg / day to about 50 mg / day, about 0.001 mg / day to about 25 mg / day, about 0.001 mg / day to about 10 mg / day, or about 0.001 mg / day to about 1 mg / day. Of course, the daily dose can be administered in smaller amounts at various times throughout the day. In any case, however, the amount of compound administered will vary depending on factors such as the solubility of the active ingredient, the formulation used, the condition of the subject (e.g., body weight), and / or the route of administration. For example, the daily doses of nicotinamide riboside disclosed above are non-limiting and may vary in some embodiments; in particular, the compositions disclosed herein may be utilized as foods for acute special medical purposes (FSMP) and contain up to about 2.0 mg / day of nicotinamide riboside.

[0081] A "functional derivative" of N-acetylcysteine ​​is a functional derivative of N-acetylcysteine ​​that is effective, alone or in combination with glycine (or a functional derivative thereof), to increase intracellular GSH concentrations in an individual.

[0082] N-acetylcysteine ​​or a functional derivative thereof can be administered in an amount of about 0.1 to 100 milligrams (mg) of N-acetylcysteine ​​(NAC) or a functional derivative thereof per kilogram (kg) of the subject's body weight.

[0083] In a specific, non-limiting example, the daily dose for a 60 kg subject may be as follows: NAC or its derivatives: 6 to 6,000 mg / day Nicotinamide riboside: 0.001 to 1,000 mg / day

[0084] The nicotinamide riboside or NAD+ precursor and N-acetylcysteine ​​or functional derivative can be combined in specific ratios. In some embodiments, the combination may include these components in the following exemplary ratios: 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:12, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1:85, 1:90, 1:95, 1:100, 1:150, 1:200, 1:300, 1:400, 1:500, 1:600, 1:750, 1:1000, and 1:10,000. In certain embodiments, the formulation may include these ingredients in the following weight percentages (either the same weight percentage for both or a different weight percentage for each): for example, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% by weight.

[0085] As used herein, "a composition essentially containing at least one N-acetylcysteine ​​or functional derivative thereof and at least one nicotinamide riboside or NAD+ precursor is free of, or substantially free of, or completely free of, any additional compounds that affect NAD+ production other than nicotinamide riboside." In certain non-limiting embodiments, the composition comprises N-acetylcysteine ​​or a functional derivative thereof, nicotinamide riboside or an NAD+ precursor, and an additive or one or more additives.

[0086] As used herein, "substantially free" means that any other compound is present in the composition at no more than 1.0% by weight relative to the amount of nicotinamide riboside, preferably no more than 0.1% by weight relative to the amount of nicotinamide riboside, more preferably no more than 0.01% by weight relative to the amount of nicotinamide riboside, and most preferably no more than 0.001% by weight relative to the amount of nicotinamide riboside.

[0087] In some embodiments, the compositions are substantially free or completely free of glycine or functional derivatives, and in particular free of exogenous glycine.

[0088] In one embodiment, the at least one glycine or functional derivative thereof is selected from the group consisting of L-glycine, L-glycine ethyl ester, D-allylglycine, N-[bis(methylthio)methylene]glycine methyl ester, Boc-allyl-Gly-OH (dicyclohexylammonium) salt, Boc-D-Chg-OH, Boc-Chg-OH, (R)-N-Boc-(2'-chlorophenyl)glycine, Boc-L-cyclopropylglycine, Boc-L-cyclopropylglycine, (R)-N-Boc-4-fluorophenylglycine, Boc-D-propargylglycine, The alkyl group is selected from the group consisting of Boc-(S)-3-thienylglycine, Boc-(R)-3-thienylglycine, Da-cyclohexylglycine, La-cyclopropylglycine, N-(2-fluorophenyl)-N-(methylsulfonyl)glycine, N-(4-fluorophenyl)-N-(methylsulfonyl)glycine, Fmoc-N-(2,4-dimethoxybenzyl)-Gly-OH, N-(2-furoyl)glycine, La-neopentylglycine, D-propargylglycine, sarcosine, Za-phosphonoglycine trimethyl ester, and mixtures thereof.

[0089] In another aspect, the present disclosure provides a method for improving cognitive function. Increasing GSH can improve glucose uptake / utilization in the brain and provide one or more benefits to an individual, such as, for example, a human (e.g., a human undergoing medical treatment), a pet or horse (e.g., a pet or horse undergoing medical treatment), or a cow or poultry (e.g., a cow or poultry used in agriculture), with respect to the prevention or treatment of a neurological disease and / or condition.

[0090] The method includes administering to the individual an effective amount of a combination of at least one N-acetylcysteine ​​or functional derivative thereof and at least one nicotinamide riboside or NAD+ precursor. The cognitive function can be selected from the group consisting of perception, memory, attention, language comprehension, language expression, reading comprehension, imagery, learning, reasoning, and combinations thereof. In one embodiment, the individual does not have a cognitive impairment, or alternatively, the individual has a cognitive impairment. The individual may be elderly and / or may have age-related cognitive decline.

[0091] Another aspect of the present invention is a method for improving glucose uptake / utilization in the brain in a mammal in need thereof, comprising administering to the mammal a composition comprising at least one N-acetylcysteine ​​or functional derivative thereof and at least one nicotinamide riboside or NAD+ precursor in an amount effective to improve glucose uptake / utilization in the brain. The method involves increasing intracellular GSH and / or NAD in cells and tissues, e.g., neural cells and tissues, particularly the brain, to improve cell and tissue survival and overall cell and tissue health. + This can promote an increase in value.

[0092] Nicotinamide adenine dinucleotide (NAD+) is considered a coenzyme and an essential cofactor in redox reactions that generate cellular energy. NAD+ plays a key role in energy metabolism because the oxidation of NADH to NAD+ facilitates hydride transfer and, consequently, ATP production by mitochondrial oxidative phosphorylation. NAD+ also serves as a catabolic substrate for several enzymes (Canto, C., KJ Menzies, and J. Auwerx, 2015. NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus. Cell Metab. 22(1):31-53).

[0093] Mammalian organisms can synthesize NAD+ from four different raw materials. First, NAD+ can be obtained from tryptophan via a 10-step de novo pathway. Second, nicotinic acid (NA) can also be converted to NAD+ via the three-step Preiss-Handler pathway, which merges with the above de novo pathway. Third, the intracellular NAD+ salvage pathway from nicotinamide (NAM) constitutes the primary pathway by which cells build NAD+. It occurs via a two-step reaction in which NAM is first converted to NAM-mononucleotide (NMN) via the catalytic activity of NAM-phosphoribosyltransferase (NAMPT) and then converted to NAD+ via the enzyme NMN adenylyltransferase (NMNAT). Finally, nicotinamide riboside (NR) constitutes a fourth additional pathway to NAD+, characterized by the initial phosphorylation of NR to NMN by NR kinase (NRK).

[0094] In each of the compositions and methods disclosed herein, the composition is preferably a food or beverage product, including a food additive, a food ingredient, a functional food, a dietary supplement, a medical food, a nutraceutical, an oral nutritional supplement (ONS), or a dietary supplement. For example, the composition may be selected from the group consisting of a food product, a food for special medical purposes (FSMP), a dietary supplement, a ready-to-drink formula, a dairy-based beverage, a low-volume liquid nutritional supplement (i.e., about 50 mL or less, e.g., about 30 mL or less), a powder for reconstitution with liquid, a meal replacement beverage, and combinations thereof.

[0095] The composition may be administered at least one day per week, preferably at least two days per week, more preferably at least three or four days per week (e.g., every other day), and most preferably at least five days per week, six days per week, or seven days per week. The administration period can be at least one week, preferably at least one month, more preferably at least two months, and most preferably at least three months, e.g., at least four months. In some embodiments, administration is at least once daily; for example, the subject may receive one or more administrations per day, and in one embodiment, multiple administrations per day. In some embodiments, administration continues for the remainder of the individual's lifespan. In other embodiments, administration is administered until there are no detectable symptoms of the medical condition. In specific embodiments, administration is administered until there is a detectable improvement in at least one symptom, and in further cases, is continued to maintain remission.

[0096] The compositions disclosed herein may be administered to a subject enterally, for example orally, or parenterally. Non-limiting examples of parenteral administration include intravenous, intramuscular, intraperitoneal, subcutaneous, intra-articular, intrasynovial, intraocular, intrathecal, topical, and inhalation. Accordingly, non-limiting examples of the composition form include natural foods, processed foods, natural fruit juices, concentrates and extracts, injections, microcapsules, nanocapsules, liposomes, plasters, inhalation forms, nasal sprays, nasal drops, eye drops, sublingual tablets, and sustained-release formulations.

[0097] The compositions disclosed herein can be administered in any of a variety of formulations for therapeutic purposes. More specifically, the pharmaceutical compositions can contain suitable pharmaceutically acceptable carriers or diluents and can be formulated as solid, semi-solid, liquid, or gaseous preparations, such as tablets, capsules, powders, granules, ointments, liquids, suppositories, injections, inhalants, gels, microspheres, and aerosols. Thus, administration of the compositions can be achieved in a variety of ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, and intratracheal administration. The active agent may be systemic after administration, or may be localized by the use of topical administration, intramural administration, or the use of an implant that acts to retain an effective dose at the implantation site.

[0098] In pharmaceutical dosage forms, the compounds may be administered as pharmaceutically acceptable salts. They may also be used in appropriate association with other pharmaceutically active compounds. The following methods and additives are merely illustrative and in no way limiting.

[0099] In oral formulations, the compounds can be used alone or in combination with suitable additives for producing tablets, powders, granules or capsules, for example, in combination with conventional additives such as lactose, mannitol, corn starch or potato starch; in combination with binders such as crystalline cellulose, functional cellulose derivatives, gum arabic, corn starch or gelatin; in combination with disintegrating agents such as corn starch, potato starch or sodium carboxymethylcellulose; in combination with lubricants such as talc or magnesium stearate; and, if desired, in combination with diluents, buffers, wetting agents, preservatives and flavoring substances.

[0100] The compounds can be formulated as injectable preparations by dissolving, suspending or emulsifying them in aqueous or non-aqueous solvents such as, for example, vegetable oils or other similar oils, synthetic fatty acid glycerides, esters of higher aliphatic acids or propylene glycol, and, if desired, together with conventional additives such as solubilizers, isotonicity adjusting agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[0101] The compounds can be utilized in aerosol formulations to be administered via inhalation. For example, the compounds can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.

[0102] Furthermore, the compound can be prepared as a suppository by mixing with various bases, such as emulsifying bases or water-soluble bases.The compound can be administered rectally by suppository.Suppository can contain a vehicle such as cocoa butter, carbowax and polyethylene glycol, which melts at body temperature but solidifies at room temperature.

[0103] Unit dosage forms for oral or rectal administration, such as syrups, elixirs, and suspensions, may be provided, with each dosage unit, e.g., a teaspoon, tablespoon, tablet, or suppository, containing a predetermined amount of the composition. Similarly, unit dosage forms for injection or intravenous administration may contain the compound in a composition as a solution in sterile water, saline, or another pharmaceutically acceptable carrier, with each dosage unit, e.g., mL or L, containing a predetermined amount of a composition containing one or more of the compounds.

[0104] Compositions intended for non-human animals include food compositions, animal treats (e.g., biscuits), and / or dietary supplements that supplement the nutritional needs of animals. The compositions may be dry compositions (e.g., kibble), semi-moist compositions, wet compositions, or any mixture thereof. In one embodiment, the composition is a dietary supplement such as gravy, drinking water, beverage, yogurt, powder, granules, paste, suspension, chew, morsel, treat, snack, pellet, pill, capsule, tablet, or other suitable delivery form. The dietary supplement may contain high concentrations of UFAs and NORCs, as well as B vitamins and antioxidants. This allows such dietary supplements to be administered in small amounts to animals or can be diluted before administration to the animal. The dietary supplement may need to be or can be mixed with water or other diluents before administration to the animal. [Brief explanation of the drawings]

[0105] [Figure 1] FIG. 1 shows that NAC+NR increases ATP production in rat primary cortical neurons as measured by real-time ATP production rate on a Seahorse XFe96 analyzer. [Figure 2] FIG. 1 shows that NAC+NR does not increase ATP production in rat primary astrocytes as measured by real-time ATP production rates on a Seahorse XFe96 analyzer. [Figure 3] FIG. 1 shows that NAC+NR increases glucose uptake in rat primary astrocytes as measured by the Glucose Uptake-Glo™ assay. [Example]

[0106] Example 1: The following non-limiting hypothetical examples discuss experimental data that are being investigated and / or will be investigated to further support the compounds, compositions, and methods disclosed herein. Menadione-induced oxidative stress in primary rat astrocytes and / or neurons treated with or without BSO (GSH synthesis inhibitor), + / - NAC and / or + / - NR_Seahorse measurements (mitochondrial respiration rate) Synergistic reduction of oxidative stress and oxidative stress-related effects, as measured by + / -NAC+ / -NR_CellROX Primary rat astrocytes treated with or without BSO (GSH synthesis inhibitor), + / - NAC and / or + / - NRGSH production Treated primary rat astrocytes, + / - NAC and / or + / - NR_NAD+ / NADH redox state Treated primary rat astrocytes and neurons + / - NAC and / or + / - NR_glucose uptake measurements Treated primary rat neurons, baseline and post-stimulation + / - NAC and / or + / - NR_synaptic plasticity genes.

[0107] Example 2: NAC + NR increases ATP production in rat primary cortical neurons as measured by real-time ATP production rate on a Seahorse XFe96 analyzer. Primary rat cortical neurons were treated with aCSF (120 mM NaCl, 3.5 mM KCl, 1.3 mM CaCl, 0.4 mM KHPO, 1 mM MgCl, 5 mM HEPES) plus 10 mM glucose, 10 mM sodium pyruvate, pH 7.4, in Millipore water for 48 hours and analyzed. The results are shown in Figure 1.

[0108] Example 3: NAC + NR does not increase ATP production in rat primary astrocytes as measured by real-time ATP production rate on a Seahorse XFe96 analyzer. NAC+NR does not increase ATP production in rat primary astrocytes as measured by real-time ATP production rates on a Seahorse XFe96 analyzer. Primary rat astrocytes were treated with DMEM + 5 mM glucose, no phenol red, no glutamine, no pyruvate, and no FBS, pH 7.4, and analyzed. The results are shown in Figure 2.

[0109] Example 4: NAC + NR increases glucose uptake in rat primary astrocytes as measured by the Glucose Uptake-Glo™ assay. Real-time ATP production rates from glycolysis and mitochondrial oxidation were measured using a Seahorse XFe96 analyzer. Primary rat astrocytes were seeded at 13,000 cells / well in Seahorse plates, and primary rat cortical neurons were seeded at 20,000 cells / well. Calibration plates were hydrated overnight in a non-CO2 incubator. For ATP rate assay tests, 1.5 μM oligomycin and 1 μM + 0.5 μM rotenone / antimycin were used for subsequent port injections, and measurements were normalized to cell number. A wave report generator (Agilent) was used for analysis.

[0110] DAPI was used as a nuclear stain for cells and normalized by counting using MetaXpress® high content image acquisition and analysis software.

[0111] Glucose uptake was measured using the Glucose Uptake-Glo assay (Promega). Cells were incubated in glucose-deficient medium supplemented with 1 mmol / L 2-deoxy-D-glucose (2DG) for 10 min, and luminescence intensity (relative light units, RLU) was measured using a Varioskan LUX multimode microplate reader according to the manufacturer's instructions.

[0112] Protein quantification by the BCA method was used for normalization. 3.5 mL of cell lysate was collected after the addition of stop buffer but before the addition of luciferin. The results are shown in Figure 3.

[0113] Data from these experiments indicate that the pentose phosphate pathway (PPP) is an alternative route of glucose utilization that does not generate ATP but provides cells with ribose-5-phosphate and NADPH for detoxification of intracellular ROS, reductive biosynthesis, and ribose biosynthesis.

Claims

1. A composition comprising a combination of N-acetylcysteine ​​and tryptophan, wherein the combination is present in an amount effective for preventing and / or treating neurological diseases or disorders, A composition used to prevent and / or treat a brain energy deficiency disease or deficiency state.

2. The composition according to claim 1, wherein the composition is administered orally or enterally.

3. The composition according to claim 1 or 2, wherein the neurological disease or disorder is a brain energy deficiency disease and / or deficiency state, selected from the group consisting of migraine, memory impairment, age-related memory impairment, brain injury, neurorehabilitation, stroke and post-stroke, amyloid lateral sclerosis, multiple sclerosis, cognitive impairment, mild cognitive impairment (MCI), post-intensive care cognitive impairment, age-related cognitive impairment, Alzheimer's disease, Parkinson's disease, Huntington's disease, congenital metabolic disorders, bipolar disorder, schizophrenia, epilepsy, and stress.

4. The composition according to any one of claims 1 to 3, wherein the composition is a nutritional composition selected from food additives, food ingredients, functional foods, dietary supplements, medical foods, foods for special medical purposes (FSMPs), nutraceuticals, oral nutritional supplements (ONS), or food or beverage products containing nutritional supplements.

5. The composition according to any one of claims 1 to 4, used to prevent and / or treat a brain energy deficiency disease or deficiency state in a subject selected from the group consisting of humans, dogs, cattle, cattle, horses, pigs, and sheep.

6. The composition according to claim 5, wherein the subject is a human.

7. The composition according to any one of claims 1 to 6, wherein the N-acetylcysteine ​​and the tryptophan are administered as the same composition.

8. The composition according to any one of claims 1 to 6, wherein the N-acetylcysteine ​​and the tryptophan are administered as different compositions.

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