Composition for inhibiting increases in brain glutamate concentration

Abstract

To provide a new material capable of suppressing an increase in the intracerebral concentration of glutamic acid and a decrease in brain weight, and a composition containing the same.SOLUTION: A composition for suppressing an increase in the intracerebral concentration of glutamic acid and / or a decrease in brain weight contains as active ingredients a peptide having a WY amino acid sequence or its pharmaceutically acceptable salt or its solvated substance. The increase in the intracerebral concentration of glutamic acid and the decrease in brain weight occur, for example, in a hippocampus or are derived from aging.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a composition for inhibiting an increase in glutamate concentration in the brain. [Background technology]

[0002] It is known that age-related brain aging causes changes in the structure and function of the nervous system. A typical example of morphological changes in the brain due to aging is brain atrophy, which affects the brain's memory function. It is known that the hippocampus, which is the organ responsible for the brain, shrinks with age and its weight decreases (Non-Patent Document 1). Brain atrophy is not necessarily a pathological condition, but it can be an indicator of the degree of brain aging. It is known that the concentration of glutamate in the brain increases in the hippocampus and other areas as a result of Reference 2) Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. While glutamate is involved in higher brain functions such as cognition, memory, and learning, excess extracellular glutamate It is known that glutamate has a neuronal damaging effect called glutamate excitotoxicity. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Golomb J, Arch Neurol. 1993 Sep; 50(9):967-73 [Non-patent document 2] Brewer GJ, Exp Gerontol. 2000 Dec; 35(9-10):1165-83 Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention provides a novel compound capable of suppressing an increase in brain glutamate concentration and a decrease in brain weight. The present invention aims to provide novel materials and compositions containing the same. [Means for solving the problem]

[0005] The present inventors have now found that aged mice show a decrease in hippocampal weight and hippocampal motility compared to young mice. Increased glutamate levels in horses and aged mice fed WY peptides In this study, we found that the decrease in hippocampal weight and the increase in glutamate levels in the hippocampus were suppressed. The present invention is based on these findings.

[0006] That is, the present invention provides the following inventions. [1] A peptide having the amino acid sequence of WY, or a pharmaceutically acceptable salt or solvent thereof and a compound as an active ingredient, for increasing the concentration of glutamic acid in the brain and / or decreasing brain weight. for inhibiting a decrease in brain weight, and an agent for inhibiting an increase in brain glutamate concentration and an agent for inhibiting a decrease in brain weight - Patents.com . [2] Increased brain glutamate levels and decreased brain weight occur in the hippocampus. The composition and agent described in [1] above. [3] Increased brain glutamate levels and decreased brain weight are associated with aging. The composition and agent described in [1] or [2]. [4] A composition according to any one of [1] to [3] above for ingestion by middle-aged and elderly people. Relief agent. [5] The composition and method according to any one of [1] to [4] above for use in neuroprotection. Agent. [6] The above-mentioned [1] to [5] for use in suppressing neuronal loss and / or promoting neurogenesis. ] The composition and agent described in any one of the above. [7] The composition and agent according to any one of [1] to [6] above, which is in the form of a food product. [8] A peptide having the amino acid sequence of WY, or a pharmaceutically acceptable salt or solvent thereof A neuroprotective composition and a neuroprotective agent comprising a solvate of the compound as an active ingredient. [9] A peptide having the amino acid sequence of WY, or a pharmaceutically acceptable salt or solvent thereof A composition for suppressing neurological deficit and an agent for suppressing neurological deficit, each comprising a solvate of the compound as an active ingredient.

[10] A peptide having the amino acid sequence of WY or a pharmaceutically acceptable salt or solution thereof. A composition for promoting neurogenesis and a neurogenesis-promoting agent, each comprising a mediator as an active ingredient.

[0007] The compositions [1] and [8] to

[10] above are referred to as "the compositions of the present invention" in this specification. In this specification, the above-mentioned [1] and the above-mentioned [8] to

[10] are referred to as "the agent of the present invention." Each of them has something to say.

[0008] The dipeptide WY, which is the active ingredient of the composition and agent of the present invention, has the effect of reducing hippocampal weight and It can be used as a functional material that suppresses the increase in glutamate levels in the hippocampus. This has the advantage that it can be used as a functional material that is safe for mammals, including humans. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 shows the effect of WY peptide intake on hippocampal weight in aged mice. [Figure 2] FIG. 2 shows the effect of WY peptide intake on glutamate levels in the hippocampus of aged mice. Specific Description of the Invention

[0010] The compositions and agents of the present invention comprise a peptide having the amino acid sequence of WY (hereinafter referred to as "the present invention"). The present invention is characterized in that it contains the peptide of the present invention as an active ingredient. A "peptide having an amino acid sequence" refers to a peptide whose sequence is specified by the amino acid sequence. means.

[0011] The peptide of the present invention may be obtained by chemical synthesis, or may be derived from milk, soybeans, wheat, or other organic compounds. Chemically and non-chemically derived from proteins and polypeptides derived from eggs, meat, fish, seafood, etc. Alternatively, those obtained by enzymatic decomposition may be used. The sequence of tides is at least the same as that of milk whey, casein, bovine serum albumin (BSA), and soybeans. Glycinin in wheat, glutenin in wheat, ribovitellin in egg yolk, ovalbumin in egg white, These are contained in transferrin, lysozyme, and collagen from chicken protein. Food or food ingredients are treated with acid hydrolysis, enzyme treatment with protease, or microbial fermentation. The composition and the preparation of the present invention can be used to produce the above peptide. The food or food ingredient preparations may be used as such, or as concentrates or supplements. It may also be used as a dry powder by spray drying or freeze drying. The protein may be used after being purified to any degree, for example by removing substances, salts, enzymes, etc.

[0012] The amino acids constituting the peptide of the present invention may be composed of only L-amino acids. Alternatively, the peptide may be composed of only D-amino acids, or a mixture of both. It may also be composed of only naturally occurring amino acids. In addition, only modified amino acids with any functional group attached, such as phosphorylation or glycosylation, are included. or a peptide containing both. In addition, when a peptide contains two or more asymmetric carbon atoms, enantiomers and diastereomers are generated. The peptide may be either a peptide containing only one of these two or a peptide containing both of these two.

[0013] Furthermore, the peptide of the present invention may be in the form of a free base, or may be in the form of a pharmaceutically acceptable salt or The compounds may be in the form of a solvate, and the compositions and preparations of the present invention may be any of these compounds. The pharmaceutically acceptable salts include those obtained by adding an acid to the compound. Pharmaceutically acceptable salts include salts, metal salts, ammonium salts and organic amine addition salts. Examples of acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, and phosphates, acetates, maleates, and fluorides. Examples include organic acid salts such as malate, citrate, and methanesulfonate. Acceptable metal salts include alkali metal salts such as sodium salts and potassium salts, magnesium salts, etc. Examples of suitable salts include alkaline earth metal salts such as calcium salts, aluminum salts, and zinc salts. Pharmaceutically acceptable ammonium salts include ammonium, tetramethylammonium, Examples of pharmaceutically acceptable organic amine addition salts include morpholino and the like. Examples of suitable salts include addition salts of benzophenone, piperidine, etc.

[0014] The composition and agent of the present invention may contain the peptide of the present invention alone or in combination with the peptide of the present invention. The composition and preparation of the present invention can be provided as a material (e.g., a food ingredient) containing the composition. The present invention also relates to a method for producing a peptide of the present invention or a material containing the peptide of the present invention in a mixture with other ingredients (e.g., food). The composition of the present invention may be provided by mixing with other ingredients (food ingredients, food additives, pharmaceutical additives). The content of the peptide of the present invention in the pharmaceutical preparation may vary depending on its purpose, use, form, dosage form, symptoms, The amount can be arbitrarily determined depending on the body weight, etc., and the present invention is not limited thereto. The content should be 0.00001 to 50% by mass (solid content equivalent) of the total amount. More preferably, the content is 0.0001 to 10% by mass (solid content equivalent). In the present invention, the agent of the present invention is a compound comprising the peptide of the present invention. The composition of the present invention can comprise the peptide of the present invention and other ingredients. Cut.

[0015] The content of the peptide of the present invention was measured by liquid chromatography tandem mass spectrometry (LCMS). Those skilled in the art can easily set the conditions for this. It is possible to use standard peptides of the purity suitable for LC / MS / MS measurement during the measurement. It goes without saying that we use AQUA PEP manufactured by SIGMA ALDRICH. Chid can be used.

[0016] Food materials containing the peptide of the present invention include enzymatic hydrolysates of proteins, and are preferred. or an enzymatic hydrolyzate of whey protein (hereinafter sometimes referred to as "whey hydrolyzate"). Methods for producing whey hydrolysates containing the peptides of the present invention are known, and are described, for example, in the International Publication It can be produced according to the description in Japanese Patent Publication No. 2017 / 086303. Commercially available whey enzyme hydrolysates containing the peptides of the invention may also be used, for example, LE80G F-US (manufactured by DMV) and HW-3 (manufactured by Megmilk Snow Brand) were used as the peptides of the present invention. It's fine.

[0017] The peptide of the present invention is contained in the composition and preparation of the present invention as a whey protein hydrolysate. When the peptide of the present invention is added to the whey protein hydrolysate, the amount of the peptide is 0.001 to 10 mass %. % (solid content equivalent), more preferably 0.01 to 5% by mass In addition, the composition and the preparation of the present invention may contain the above-mentioned hydroxybenzoates in an amount of 0.01 to 0.01% by weight. The whey protein hydrolysate is contained in a proportion of 0.001 to 95% by mass (solid content equivalent). Preferably, the content is 0.01 to 50% by mass (solid content equivalent). It is possible.

[0018] As will be shown in the Examples below, the peptide of the present invention has an inhibitory effect on the decrease in hippocampal weight and Therefore, the peptide of the present invention has an inhibitory effect on the increase of glutamate in the brain. and efficacy of compositions and agents for inhibiting increases in glutamic acid concentration or decreases in brain weight. It can be used as an ingredient.

[0019] In the present invention, the reduction in brain weight preferably occurs in the hippocampus. The composition and the agent can be used to suppress the decrease in hippocampal weight. In the present invention, the increase in brain glutamate concentration and the decrease in brain weight are preferably caused by aging. The composition and the agent of the present invention are caused by the increase in glutamate concentration in the brain due to aging. and for use in the prevention of age-related brain weight loss. do.

[0020] It is known that hippocampal weight decreases with age and glutamate levels in the brain increase. (Non-Patent Documents 1 and 2). Therefore, the composition and agent of the present invention are preferably For consumption by middle-aged and elderly people (e.g., those aged 45 or over, those aged 55 or over, and those aged 65 or over) In addition, drinking and smoking can cause brain atrophy and reduce the weight of the hippocampus. It is also known that (Anya Topiwala, BMJ 2017;357:j2353 doi: 10.1136 / bmj.j2353 (Published 6 June 2017) and KUBOTA, Tohoku J Exp Med. 1987 Dec;153(4):303-11) Therefore, the compositions and preparations of the present invention are preferably designed to be taken by drinkers or smokers. It can be of the following type.

[0021] The compositions and agents of the present invention suppress an increase in the concentration of glutamate in the brain. Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, While it is involved in higher brain functions such as cognition, memory, and learning, it also contributes to the prevention of excess extracellular glutamate. It is known that glutamate excitotoxicity is a neurotoxic effect on neurons. Excessive excitation of nerve cells by glutamate causes excessive calcium influx into the cells. Excitotoxicity-induced neuronal cell death is a common symptom of cerebral ischemia, brain trauma, epilepsy, and hepatic Not only acute neurological diseases such as encephalopathy, but also Alzheimer's disease and amyotrophic lateral sclerosis (ALS) ) is a common mechanism of neuronal cell death in chronic neurological diseases such as Huntington's disease. It has been attracting attention (Tanaka, CLINICAL NEUROSCIENCE, 35: 1412-1416(2017)). In addition, an increase in glutamate concentration in the brain is thought to be a factor in mental disorders such as schizophrenia, depression, autism, and obsessive-compulsive disorder. It is thought to be related to neurological disorders (Tanaka, Japanese Journal of Pharmacology, 1421-6 (2013)).

[0022] Therefore, the peptide of the present invention, which suppresses an increase in the concentration of glutamate in the brain, is neuroprotective (especially The nerves to be protected are preferably cranial nerves. That is, according to the present invention, a neuroprotective composition comprising the peptide of the present invention and a compound comprising the peptide of the present invention are provided. A neuroprotective agent comprising the peptide of the present invention is also provided. The peptide of the present invention also has a neuroprotective effect on the brain and nerves. It can be used as an active ingredient in agents for treating, preventing, and improving degenerative diseases (e.g., epilepsy). That is, according to the present invention, a method for treating neurodegenerative diseases comprising administering to a patient the peptide of the present invention. A composition for treatment, prevention or amelioration of a neurodegenerative disease comprising the peptide of the present invention. Therapeutic, preventative or ameliorative agents are provided.

[0023] The compositions and agents of the present invention also inhibit a decrease in brain weight (particularly hippocampal weight). It is known that aging causes the loss of brain neurons, which is associated with a decrease in brain weight. The following factors are involved (Takekawa, Dokkyo Journal of Medical Sciences 35(3):203-208(2008) ) In the past, it was believed that cranial nerves could not be regenerated, but in recent years, Neural stem cells in the subventricular zone and dentate gyrus of the hippocampus are continuously regenerated, and they are actually regenerating neurons within the ventricles. It was revealed that the patient continued to live (Sawamoto, Clin Neurol 49:830-833(2009)). In other words, the decrease in brain weight due to aging can be attributed to the loss of cranial nerves and the suppression of neurogenesis. Therefore, the peptide of the present invention that suppresses the decrease in brain weight is expected to have neuroprotective properties (preferably neuroprotective properties). and more preferably hippocampal neuroprotection), particularly for the prevention of neuronal loss and In other words, according to the present invention, the present invention can be used to promote neurogenesis and / or neurogenesis. A neuroprotective composition comprising a peptide and a neuroprotective agent comprising the peptide of the present invention. The present invention also provides a composition for suppressing neurological deficits, comprising the peptide of the present invention. The present invention also provides a compound according to the present invention and a neurological deficit inhibitor comprising the peptide of the present invention. a composition for promoting neurogenesis comprising the peptide of the present invention; and a composition for promoting neurogenesis comprising the peptide of the present invention. A neurogenesis promoting agent is provided.

[0024] The compositions and agents of the present invention can be used in the form of pharmaceuticals (e.g., pharmaceutical compositions), quasi-drugs, and foods (e.g., For example, it can be provided in the form of a food composition, feed (including pet food), etc., and can be used in the following ways: It can be carried out as described.

[0025] The peptides of the present invention can be orally administered to humans and non-human animals. Granules, powders, tablets (including sugar-coated tablets), pills, capsules, syrups, emulsions, suspensions, etc. These preparations can be prepared by techniques commonly used in the art, such as pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers include excipients, Binders, diluents, additives, flavorings, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspensions Examples of the additives include turbidifying agents and preservatives.

[0026] When the peptide of the present invention is provided as a food product, it is provided as is. Alternatively, it can be provided by being contained in a food product. When the peptide is provided as a food product, it is preferable to use a whey hydrolyzate containing the peptide of the present invention. The enzyme decomposition products of the proteins can be provided as food as they are, or The food product thus provided can be provided by being contained in the food product. In the present specification, the peptide of the present invention is referred to as a "food containing an effective amount of the peptide." "had" means that when an individual food is ingested in an amount that is normally consumed, it falls within the category described below. The term "food" refers to a content of the peptide of the present invention that allows it to be ingested within a certain range. Functional foods, nutritional supplements, health functional foods (e.g., foods for specified health uses, foods with nutritional functions, Foods with functional labeling), foods for special dietary uses (e.g., foods for infants, foods for pregnant women, foods for the sick) and The term "peptide of the present invention" is used to include supplements and other supplements. When the food is ingested, it goes without saying that the food in the present invention is used as a feed.

[0027] The peptide of the present invention has the above-mentioned inhibitory effect on the increase of brain glutamate concentration and brain weight. It can be added to foods that are consumed daily, or That is, the compositions and preparations of the present invention can be provided as a food supplement. In this case, the composition and agent of the present invention can be provided in the form of a single serving. The amount of food per serving can be provided in a predetermined unit package. Examples of the form include packs, wrapping, cans, bottles, etc., in which a certain amount is specified. In order to make the composition and agent of the present invention exert various effects more effectively, The amount of intake per meal can be determined according to the amount of intake of the peptide per serving. Foods are either labeled with dosage instructions on the packaging or are sold with instructions. It may be provided together with the document.

[0028] The amount of intake per serving, as determined in the unit packaging, is the effective daily intake. Even if you take it in the amount you need, you should take the effective amount twice or more times a day (preferably 2 or Therefore, the composition and the preparation of the present invention may be packaged in a unit package. In some embodiments, the peptide of the present invention can be contained in the amount of daily intake per person described below. Alternatively, the peptide of the present invention can be administered in an amount of one-half to one-sixth of the daily intake amount for humans described below. The compositions and preparations of the present invention may contain the following per serving for convenience of intake. The intake amount must be provided in a "unit package per serving" that is the effective intake amount per day. is preferred.

[0029] The form of the "food" is not particularly limited. For example, even if it is in the form of a drink, it may be a semi-liquid It may be in the form of a liquid or gel, or in the form of a solid or powder. The "tablet" is prepared by adding an excipient, a binder, etc. to the peptide of the present invention, kneading the mixture, and then tableting the mixture. Examples of the formulation include tablets produced by the above method and capsules enclosed in capsules.

[0030] The food provided by the present invention is not particularly limited as long as it contains the peptide of the present invention. However, for example, soft drinks, carbonated drinks, fruit juice drinks, vegetable juice drinks, fruit juice and Vegetable juice drinks, milk and other animal milk, soy milk, dairy drinks, drink-type yogurt, drinks Jelly and stick-type drinks, coffee, cocoa, tea drinks, nutritional drinks, energy drinks - Beverages, sports drinks, mineral water, near water, non-alcoholic drinks Non-alcoholic beverages such as beer-flavored drinks; carbohydrate-rich foods such as rice, noodles, bread, and pasta Foods and drinks containing: cheeses, hard or soft yogurt, milk and other Dairy products such as cream and ice cream made from fats and oils; cookies, cakes, chocolate Western confectionery such as tofu, Japanese confectionery such as manju and yokan, tablet sweets (refreshing sweets) such as ramune, Various confectioneries such as candies, gums, frozen desserts such as jelly and pudding, ice cream, snacks, etc.; Whiskey, bourbon, spirits, liqueurs, wine, fruit wine, sake, Chinese sake, and shochu Liquor, beer, non-alcoholic beer with an alcohol content of 1% or less, low-malt beer, other miscellaneous alcoholic beverages, liquor Alcoholic drinks such as highballs; processed foods made with eggs, seafood, and meat (including liver and other offal) Processed foods (including delicacies), soups such as miso soup, miso, soy sauce, furikake, Other examples include seasonings such as condiments, and liquid foods such as concentrated liquid foods. Mineral water includes both sparkling and non-sparkling mineral water. The food provided by the present invention also includes any of the raw materials for food production and food additives. All of these are included.

[0031] Tea beverages include fermented tea, semi-fermented tea, and non-fermented tea. Tea, green tea, barley tea, brown rice tea, sencha, gyokuro tea, roasted green tea, oolong tea, turmeric tea, pu-erh tea , rooibos tea, rose tea, chrysanthemum tea, ginkgo leaf tea, herbal tea (e.g., mint tea, Jasmine tea).

[0032] Examples of fruits used in fruit juice drinks and fruit and vegetable juice drinks include apples. , mandarin oranges, grapes, bananas, pears, peaches, mangoes, acai, blueberries and plums In addition, vegetables used in vegetable juice drinks and fruit and vegetable juice drinks include: Examples include tomatoes, carrots, celery, pumpkins, cucumbers, and watermelons. do.

[0033] The amount of intake of the peptide of the present invention depends on the recipient's sex, age, and weight, symptoms, administration time, dosage form, etc. The amount of glutamate in the brain can be determined depending on the route of administration and the drugs to be combined. Daily intake of the peptide of the present invention for adults to suppress the increase in blood pressure and the decrease in brain weight (dry mass equivalent) is, for example, 0.001 to 10,000 mg (preferably 1 to 1,000 mg g) The above-mentioned intake amount of the peptide of the present invention and the following intake timing and intake period. The above is applicable to both non-therapeutic and therapeutic uses of the peptides of the present invention. In the case of therapeutic purposes, the term "intake" can be read as "administration." non-human mammals (e.g., mice, rats, rabbits, dogs, cats, cows, horses, It can also be administered to animals such as monkeys, dolphins, and sea lions, and the amount and timing of administration can be adjusted. The dosage and duration of intake can be determined by referring to the data for humans.

[0034] The intake period of the peptide of the present invention is at least 3 days (preferably 3 days) at the above daily dose. (1 or 2 weeks, more preferably 1 month, 3 months or 5 months) The interval for taking the peptide of the present invention is once every three days, once every two days, or at the above-mentioned daily dose. Or it can be once a day.

[0035] The composition, agent and food of the present invention have the effect of suppressing an increase in glutamate concentration in the brain and In this case, the consumer may be informed that the product has the effect of suppressing the decline in brain weight and / or brain mass. In order to make the labeling easier for the public to understand, the composition, agent and food of the present invention may contain some or all of the following: In the present invention, "inhibition of increase in brain glutamate concentration" may be indicated. It goes without saying that the terms "control" and "control of brain weight decline" are used in the sense that includes the following expressions: do not have. For those concerned about brain aging For brain anti-aging · For those concerned about brain atrophy

[0036] According to another aspect of the present invention, an effective amount of the peptide of the present invention or a pharmaceutically acceptable salt thereof is administered. or a solvate thereof or a composition containing the same is ingested by a subject in need thereof. and a method for suppressing an increase in brain glutamate concentration, comprising administering a The present invention also provides a method for inhibiting a decrease in the amount of a peptide of the present invention. The pharmaceutically acceptable salt or solvate thereof or a composition containing the same is provided to a person in need thereof. and administering the same to a subject suffering from a neurodegenerative disease. The present invention also provides a method for preventing or improving the symptoms of rheumatoid arthritis by administering an effective amount of the peptide or peptides of the present invention. or a pharmaceutically acceptable salt or solvate thereof, or a composition containing the same, and administering the compound to a subject. The present invention provides a method for inhibiting neuronal loss and a method for promoting neurogenesis. The method can be carried out according to the description of the substances and agents.

[0037] According to yet another aspect of the present invention, there is provided a method for producing an agent for suppressing an increase in brain glutamate concentration, comprising: As an inhibitor of an increase in brain glutamate concentration, or as an inhibitor of brain glutamate concentration of the present invention The peptide of the present invention, or a pharmaceutically acceptable salt or solvate thereof, in a method for inhibiting an increase The present invention also provides a method for the preparation of an agent for suppressing a decrease in brain weight. The present invention is directed to a method for suppressing a decrease in brain weight, or a method for suppressing a decrease in brain weight, The present invention provides the use of a peptide or a pharmaceutically acceptable salt or solvate thereof. and a method for producing a therapeutic, preventive or ameliorating agent for a neurodegenerative disease. As a therapeutic, preventive or ameliorating agent or in the therapeutic, preventive or ameliorating method of the present invention The use of the peptide of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is provided. The present invention also provides a method for the preparation of a neuroprotective agent, ... or a method for the preparation of a neuroprotective agent according to the present invention. The peptide of the present invention or a pharmaceutically acceptable salt or solution thereof in the method for neuroprotection of the present invention. The present invention also provides a method for the preparation of a medicament for suppressing neurological deficits. The peptide of the present invention as an inhibitor of neurological loss or in the method of inhibiting neurological loss of the present invention The present invention provides the use of methicillin-containing compounds, such as methicillin-containing compounds, in the treatment of rheumatoid arthritis, and in the treatment of rheumatoid arthritis. For example, for the production of a neurogenesis promoting agent, as a neurogenesis promoting agent, or The peptide of the present invention, or a pharmaceutically acceptable salt or solvent thereof, in a method for promoting neoplasia The use of the present invention is provided in accordance with the description of the composition and preparation of the present invention. This can be implemented.

[0038] According to yet another aspect of the present invention, there is provided a method for inhibiting an increase in intracerebral glutamate concentration, comprising administering to said patient a A peptide having an amino acid sequence of WY or a pharmaceutically acceptable salt or solvate thereof The present invention also provides a method for inhibiting a decrease in brain weight, comprising administering to a mammalian animal the amino acid sequence of WY. The present invention provides a peptide having the formula: According to the present invention, the amino acid sequence of WY can be used to treat, prevent, or improve neurodegenerative diseases. The present invention provides a peptide having the sequence, or a pharmaceutically acceptable salt or solvate thereof. The disclosure also provides a peptide having the amino acid sequence of WY or its derivatives for use in neuroprotection. The present invention also provides a pharmaceutically acceptable salt or solvate of the compound of formula (I). Peptide having the amino acid sequence of WY or a pharmaceutically acceptable salt thereof for use in inhibiting The present invention also provides a compound or solvate of WY for use in promoting neurogenesis. or a pharmaceutically acceptable salt or solvate thereof. The present invention also provides a method for producing a vector having the amino acid sequence of WY for use in the method of the present invention. The present invention provides a peptide or a pharmaceutically acceptable salt or solvate thereof. The peptides having the amino acid sequence and pharmaceutically acceptable salts and solvates thereof are included in the present invention. This can be carried out according to the description of the compositions and preparations.

[0039] The methods and uses of the present invention may be for use in mammals, including humans, Both therapeutic and non-therapeutic uses are contemplated. does not include the act of operating, treating, or diagnosing humans (i.e., medical procedures performed on humans) Specifically, it refers to the act of a doctor or a person under the direction of a doctor performing surgery or treatment on a human. or diagnostic methods. [Example]

[0040] The present invention will be described in more detail based on the following examples, but the present invention is not limited to these examples. It's not something like that.

[0041] Example 1: Effects of WY peptide on the central nervous system (1) Overview of the test The brain condition (hippocampal weight and intrahippocampal group) of the aged mice was compared between the test food intake group and the non-intake group. The rats were compared with a group of young mice that did not consume the test food. WY peptide was used as the test food.

[0042] (2) Mouse C57BL / 6J male mice (Charles River Biosciences Japan, hereinafter simply referred to as "the mice") According to the materials of Charles River Japan (http s: / / www.crj.co.jp / cms / cmsrs / img / usr / top / B6-Aged.pdf), this mouse is a Jackson Research This method was developed by the Institute of Neurology and is widely used in aging research. As a result, it was revealed that some individuals died at 100 weeks of age, and all individuals had died by 170 weeks of age. The Mouse Phenome Database (https: / / www.phenome.jax.org / ) is open to the public. The lifespan of this mouse corresponds to that of a human being, with a human age of 20-30 years being 3-6 months (adult age) for this mouse. 38-47 year old human mice are 10-14 months old (middle-aged individuals), and 56-69 year old human mice are 10-14 months old (middle-aged individuals). The ages correspond to the ages of the mice (aged 18 to 24 months). 62-week-old mice were used as the adult mice, and 7-week-old mice were used as the young mice. The mice were used after one month of acclimation. The old mice were fed the test food (WY peptide). The "old WY intake group" (9 animals) was given the test food, and the "old non-intake group" (12 animals) was given no test food. The young mice were divided into groups so that there would be no imbalance in their weight. This was called the "young non-fed group" (15 animals).

[0043] (3) Administration of test food (WY peptide) The aged WY intake group was allowed to freely consume a purified diet (AIN-93M, manufactured by Oriental Yeast Co., Ltd.) containing 0.05% (w / w) of WY peptide (manufactured by Bachem) in terms of dry mass (w / w). The aged non-intake group and the young non-intake group were allowed to freely consume AIN-93M without WY peptide. The intake period was 5 months.

[0044] (4) Measurement [[ID=I3]]After the end of the intake period, the hippocampus was excised and weighed. Also, the glutamate concentration in the hippocampus was quantified. The quantification of the glutamate concentration was carried out according to the method published by Eicom Co., Ltd. (https: / / www.eicomusa.com / hplc-ecd / applications / glutamate-gaba-12-minute-analysis / ). Specifically, methanol (manufactured by Wako Pure Chemical Industries, Ltd.) at 10 times the weight (W / V) of the hippocampus weight was added and homogenized, and then filtered through a 0.22 μm filter (manufactured by Millipore), which was used as the extraction sample. Next, the extraction sample was mixed with an OPA solution (0.5 mol / L carbonate buffer (manufactured by Wako Pure Chemical Industries, Ltd.) containing o-phthalaldehyde-2-mercaptoethanol (OPA-2ME, manufactured by Wako Pure Chemical Industries, Ltd.) at a concentration of 4 mM) at a ratio of 4:1 (v / v), and reacted at room temperature for 150 seconds for derivatization, which was used as the measurement sample. The measurement sample was introduced into HPLC to quantify the glutamate concentration. The concentration conversion was carried out according to the internal standard method using homotaurine (manufactured by Acros Organics). The HPLC conditions were as follows.

[0045] <HPLC Conditions> · Measuring device: ECD detector type high performance liquid chromatograph (HPLC-ECD, HTEC-510, manufactured by Eicom) Column: EICOMPAK FA-3ODS (φ3mm x 75mm, manufactured by EICOMPAK) Precolumn: CA-ODS precolumn (φ3 x 4 mm, manufactured by Eicom Co., Ltd.) ·solvent: Moving layer A: 100 mM phosphate buffer (pH 6.0) + 7% (v / v) methanol (Wako Pure Chemical Industries, Ltd.) Made by 13% acetonitrile (Wako Pure Chemical Industries, Ltd.) 100mM phosphate buffer (pH 6.0) Mobile phase B: 50% acetonitrile (Wako Pure Chemical Industries, Ltd.) Gradient conditions: Mobile phase A: 0-12 min (100%), Mobile phase B: 12-15 min (1 00%)

[0046] (5) Statistical processing The measured values for each group were expressed as the mean ± standard deviation. A significant difference was determined between the two groups when the significance level was P<0.05%.

[0047] (6) Results The results are shown in Figures 1 and 2. From the results in Figure 1, the hippocampus of the elderly non-intake group The weight of the young non-fed group was significantly reduced compared to that of the old WY-fed group. The hippocampal weight was significantly increased compared to the old non-intake group, but the difference with the young non-intake group was not significant. As shown in Figure 2, the glutamate concentration in the hippocampus of the elderly non-ingested group was higher than that of the young group. On the other hand, the elderly WY intake group had significantly higher levels of serotonin compared with the elderly non-intake group. The glutamate concentration was significantly lower in the young non-fed group, and the difference with the young non-fed group was not significant. These results suggest that WY peptide intake suppresses the age-related loss of hippocampal mass. It was also confirmed that it suppresses the increase in brain glutamate levels that occurs with aging. It was suggested that taking WY peptide could suppress neurodegenerative diseases associated with aging, etc.

Claims

1. A composition for use in improving symptoms of a psychiatric disorder caused by glutamate excitotoxicity due to an increase in brain glutamate concentration, comprising as an active ingredient a dipeptide consisting of the amino acid sequence of WY or a pharmaceutically acceptable salt or solvate thereof, wherein the psychiatric disorder is associated with an increase in brain glutamate concentration and / or a decrease in hippocampal weight.

2. 2. The composition according to claim 1, wherein the psychiatric disorder is one or more selected from the group consisting of schizophrenia, depression, autism, and obsessive-compulsive disorder.

3. 3. The composition according to claim 1, wherein the increase in brain glutamate concentration occurs in the hippocampus.

4. The composition according to any one of claims 1 to 3, wherein the increase in brain glutamate concentration is due to aging.

5. A composition for protecting brain neurons from glutamate excitotoxicity caused by increased glutamate concentration in the brain, comprising as an active ingredient a dipeptide consisting of the amino acid sequence WY or a pharmaceutically acceptable salt or solvate thereof.

6. The composition according to any one of claims 1 to 5, for ingestion by middle-aged and elderly people.

7. A composition according to any one of claims 1 to 6 for use in suppressing neuronal loss and / or promoting neurogenesis.

8. A food composition or a food composition for brain neuroprotection for use in improving symptoms of a mental disorder caused by glutamate excitotoxicity due to an increase in glutamate concentration in the brain, wherein the mental disorder is associated with an increase in glutamate concentration in the brain and / or a decrease in hippocampal weight, a composition described in any one of claims 1 to 7.

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