WO2022186015A1 - Neuropsychological function improving agent - Google Patents

Neuropsychological function improving agent Download PDF

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Publication number
WO2022186015A1
WO2022186015A1 PCT/JP2022/007377 JP2022007377W WO2022186015A1 WO 2022186015 A1 WO2022186015 A1 WO 2022186015A1 JP 2022007377 W JP2022007377 W JP 2022007377W WO 2022186015 A1 WO2022186015 A1 WO 2022186015A1
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neuropsychological function
neuropsychological
improving
function
symptoms
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PCT/JP2022/007377
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French (fr)
Japanese (ja)
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康浩 鹿島
琢和 安田
泰治 松川
健二 長田
泰正 山田
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ユーハ味覚糖株式会社
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Priority to JP2023503742A priority Critical patent/JPWO2022186015A1/ja
Publication of WO2022186015A1 publication Critical patent/WO2022186015A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the present invention provides neuropsychological functions that have preventive and/or improving effects on symptoms and diseases caused by decreased neuropsychological functions, such as Alzheimer-type dementia (AD) and depression. Regarding improver. More specifically, the present invention relates to a neuropsychological function-improving agent that contains soybean peptide and ⁇ -aminobutyric acid that can be safely and easily ingested as active ingredients and that can prevent and/or improve neuropsychological function deterioration.
  • Non-Patent Document 1 Alzheimer's disease
  • Non-Patent Document 2 The brain inflammation hypothesis of AD, which has been advocated for some time, is attracting attention again. That is, in 1987, it was reported that activated microglia accumulated around senile plaques in the autopsy brains of AD patients (Non-Patent Document 3). The risk of developing AD in rheumatoid arthritis patients taking the drug was reduced to 1/6, and the importance of intracerebral inflammation in the development of AD has been pointed out (Non-Patent Document 4).
  • Non-Patent Document 5 Non-Patent Document 5
  • Non-Patent Document 7 It has been reported that neurons newly generated in the dentate gyrus of the hippocampus form a neural network and play important roles such as being involved in memory formation (Non-Patent Document 8). Recently, it has been reported that neurogenesis in the hippocampus rapidly declines as AD progresses, and the possibility of involvement in the onset of AD has been pointed out (Non-Patent Document 9).
  • GABA ⁇ -Aminobutyric acid
  • the present invention uses a pharmaceutical composition for improving psychological function and a food and drink composition for improving neuropsychological function containing the agent for improving neuropsychological function, and the agent for improving neuropsychological function.
  • the object is to provide a method for preventing and/or ameliorating symptoms and/or diseases caused by neuropsychological dysfunction.
  • the present inventors have made diligent efforts to find a material that contributes to the improvement of neuropsychological functions from the foodstuffs that are ingested on a daily basis. , has the effect of synergistically improving neuropsychological functions, leading to the completion of the present invention.
  • the gist of the present invention is [1] A neuropsychological function-improving agent for preventing and/or improving symptoms and/or diseases caused by neuropsychological function deterioration, comprising soybean peptide and ⁇ -aminobutyric acid (GABA) as active ingredients; [2] Symptoms and / or diseases caused by deterioration of neuropsychological function are Alzheimer's dementia, depression, memory impairment due to aging, autism spectrum disorder, bipolar disorder, schizophrenia or chronic fatigue syndrome The neuropsychological function improving agent according to [1] above, [3] The agent for improving neuropsychological function according to [1] or [2] above, wherein the soybean peptide is a thermolysin digest, [4] The agent for improving neuropsychological function according to any one of [1] to [3], wherein the soybean peptide comprises a peptide consisting of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1); [5] A pharmaceutical composition for improving neuropsychological function, comprising the agent for improving neuropsychological function according
  • soybean peptide and GABA which are active ingredients, are highly safe materials with a history of being used as food materials. Since the effect of improving psychological functions is exhibited, the neuropsychology of the present invention is applied to subjects who need prevention or improvement (treatment) of diseases or conditions (symptoms) caused by deterioration of neuropsychological functions Prevention or amelioration (treatment) of such diseases or conditions is expected without side effects when the therapeutic agents are administered.
  • FIG. 1 is a diagram showing core symptoms and behavioral/psychological symptoms (BPSD) of dementia.
  • 2 is a graph showing the results of the tail suspension test in Example 2.
  • FIG. 3 is a graph showing the results of the amount of brain-derived neurotrophic factor (mature BDNF) in the brain in Example 3.
  • FIG. 1 is a diagram showing core symptoms and behavioral/psychological symptoms (BPSD) of dementia.
  • 2 is a graph showing the results of the tail suspension test in Example 2.
  • FIG. 3 is a graph showing the results of the amount of brain-derived neurotrophic factor (mature BDNF) in the brain in Example 3.
  • the neuropsychological function-improving agent of the present invention contains soybean peptide and ⁇ -aminobutyric acid (GABA) as active ingredients, and can be used to improve neuropsychological functions.
  • GABA ⁇ -aminobutyric acid
  • the term "neuropsychological function” refers to general higher brain functions such as intelligence, memory function, language function, attention, frontal lobe function, and executive function as shown in Table 1 (hereinafter referred to as cognitive function It refers to a broad concept that includes psychological functions related to the degree of depression, anxiety, and depression.
  • the improvement and/or the degree of improvement in each of the above functions due to ingestion of the neuropsychological function-improving agent of the present invention can be examined by each test shown in Table 1 and the like.
  • Improving neuropsychological function includes improving cognitive function and depressive symptoms, inhibiting brain atrophy, inhibiting brain decline (strengthening functional connections with the hippocampus) associated with neuropsychological function, and It includes amelioration of nerve cell damage caused by inflammation.
  • symptoms and/or diseases caused by decreased neuropsychological function include Alzheimer's dementia, depression, autism spectrum disorder, bipolar disorder, schizophrenia, or those associated with aging. mentioned. Improving neuropsychological function therefore includes treatment of Alzheimer's disease, depression, age-related memory impairment, autism spectrum disorder, bipolar disorder, schizophrenia, and/or aging of the brain.
  • the symptoms of dementia include core symptoms and behavioral/psychological symptoms.
  • Core symptoms include memory impairment, disorientation, aphasia, apraxia, agnosia, and executive dysfunction.
  • BPSD has many symptoms, including wandering, agitation, violence, hallucinations, delusions, depression, and unclean behavior.
  • the core symptoms of cognitive dysfunction are related to the surrounding environment, personality, and psychological state. It is thought that it will appear as
  • soybean peptide used in the present invention is soybean protein decomposed by hydrolysis or the like to a specific degree of decomposition. Hydrolysis treatment can be performed on an aqueous dispersion containing soy protein. It is important to hydrolyze the soy protein in such a way as to obtain a peptide mixture that provides the neuropsychological function-improving effect of the present invention. That is, the hydrolysis of soybean protein is preferably enzymatic decomposition by a protease (also referred to as protease).
  • protease also referred to as protease
  • protease for example, an endo-type protease, which is an enzyme that hydrolyzes peptide bonds inside proteins or peptides in which amino acids are bound in a chain to form several peptides, is suitable. It is also possible to combine one or more exo-type proteases, which are enzymes that sequentially cleave amino acids, peptides, etc. from the amino-terminus and carboxy-terminus present at the ends of proteins and peptides. These endo-type proteases and exo-type proteases can be used as long as they are active in the solution environment of the soybean protein material. For example, proteases derived from microorganisms such as Bacillus can be preferably used.
  • proteases derived from the genus Bacillus include “Samoase (registered trademark) PC10F” (manufactured by Amano Enzyme Co., Ltd.), “Protin SD-AY10” (manufactured by Amano Enzyme Co., Ltd.), and “Protin SD-NY10” (manufactured by Amano Enzyme Co., Ltd.). ), “Protamex” (manufactured by Novozymes Japan Co., Ltd.), and the like.
  • thermolysin digest is preferable from the viewpoint of the potency of the neuropsychological function improving effect.
  • Thermolysin is a known protease derived from the heat-resistant bacterium Bacillus thermoproteolyticus (EC 3.4.24.4, EC 3.4.24.27). Thermolysin can be used as a food additive in Japan. Commercial products such as food additive grade thermolysin (for example, the above-mentioned "Samoase (registered trademark) PC10F" (manufactured by Amano Enzyme Co., Ltd.)) can be used.
  • thermolysin is not particularly limited as long as it contains soybean beta-conglycinin ( ⁇ -CG) protein.
  • soybeans themselves, pomace (also called meal or defatted soybeans) obtained by extracting soybean oil from soybeans, concentrated soybean protein obtained by removing sugars and ash from defatted soybeans, isolated soybean protein obtained by separating only protein from defatted soybeans ( Soy Protein Isolate: SPI), purified ⁇ -CG protein and the like.
  • the hydrolysis reaction with thermolysin is performed under conditions that yield a peptide of about 10 amino acid residues.
  • the reaction temperature can be appropriately selected from 30 to 70°C, 40 to 70°C, 50 to 65°C and the like.
  • the reaction time can be appropriately selected from about 30 minutes to 48 hours, about 1 to 10 hours, about 2 to 8 hours, and the like.
  • the pH for the reaction can be appropriately selected from about pH 6.5 to 8.5 and about pH 7 to 8. In one preferred embodiment, the reaction can be carried out for about 2 to 8 hours at a temperature of about 30 to 40° C. and a pH of 6.5 to 8.5 (especially about pH 7.5).
  • thermolysin may be deactivated by heating to a temperature at which thermolysin is deactivated (for example, heating at a temperature exceeding 80° C. for about 5 to 60 minutes).
  • the reaction product obtained by hydrolysis can be used as it is, and if necessary, the hydrolyzate obtained above is further subjected to molecular weight fractionation by means of gel filtration, membrane filtration, etc.
  • a fraction having a molecular weight of 300 to 1,500, preferably 500 to 1,300, more preferably 700 to 1,100 can be obtained by using a fractionation means utilizing adsorption properties such as an adsorption resin or an ion exchange resin.
  • the soybean peptide preferably contains a peptide consisting of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1) from the viewpoint of producing an agent having a high neuropsychological function-improving effect.
  • the soybean peptide whose amino acid sequence is known as described above may be a synthetic product obtained using a known chemical synthesis method, or may be a derivative as long as the desired effects of the soybean peptide can be obtained. good too.
  • GABA ⁇ -aminobutyric acid
  • the GABA used in the present invention is isolated from natural products or obtained by an industrial method such as fermentation.
  • Various can be used. Specific examples thereof include those derived from natural products such as brown rice, and those obtained through fermentation by microorganisms such as lactic acid bacteria.
  • Intermediates containing GABA can also be used.
  • the intermediates include edible crude products during the isolation and purification of GABA from natural products and fermented products, fermented products of microorganisms such as lactic acid bacteria, and the like.
  • the various GABA described above may be used alone or in combination of two or more.
  • the neuropsychological function-improving agent of the present invention exhibits a synergistic effect in improving neuropsychological functions by containing both the soybean peptide and GABA as active ingredients. It is.
  • the synergistic effect is a higher neuropsychological function-improving effect when used in combination than the sum of the neuropsychological function-improving effects when soybean peptide and GABA are used alone. is obtained.
  • a soybean peptide is a peptide consisting of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1).
  • the compounding ratio of soybean peptide and GABA is not limited as long as a synergistic effect in improving neuropsychological function is obtained, but is preferred. is 1-1000, more preferably 1-500, more preferably 1-200.
  • a mixture containing two components, soybean peptide and GABA is referred to as a "soybean-GABA mixture”.
  • the content of the soy-GABA blend may be 100% by weight, or may be 20% by weight or more when the additional ingredients described below are included. , 40% by weight or more is preferable, 60% by weight or more is more preferable, and 80% by weight or more is even more preferable.
  • the content of the soybean-GABA compound may be 2% by weight or more.
  • the neuropsychological function-improving agents of the present invention may further comprise polysaccharides as additional ingredients, and optionally, bulking agents, solubilizers, dispersing agents, suspending agents, emulsifying agents, antioxidants.
  • Ingredients such as agents, antibacterial agents, coloring agents, flavoring agents, flavoring agents and the like may also be included. Any of these additional ingredients are not particularly limited as long as they are used in foods, medicines, or medicinal products.
  • the total amount of these additional components is 80% by weight or less, preferably 60% by weight or less, more preferably 40% by weight or less, still more preferably 20% by weight, based on 100% by weight of the dry weight of the "neuropsychological function improving agent" % by weight or less.
  • the neuropsychological function-improving agent of the present invention can be blended as an active ingredient and used as a food and drink composition for preventing and/or improving symptoms and/or diseases caused by decreased neuropsychological function.
  • Symptoms and/or diseases caused by decreased neuropsychological function include Alzheimer's dementia, depression, memory impairment due to aging, autism spectrum disorder, bipolar disorder, and schizophrenia.
  • non-therapeutic is a concept that does not include medical treatment, that is, the treatment of the human body by therapy.
  • treatment refers to restoring a disease or symptom that has developed in an application subject to the pre-development state.
  • prevention means preventing or delaying the onset of a disease in a subject, or reducing the risk of developing a disease or condition in a subject.
  • amelioration refers to amelioration of a disease, symptom or condition; prevention or delay of worsening of a disease, symptom or condition or reversal, prevention or delay of progression of a disease or condition.
  • the food and drink composition containing the neuropsychological function-improving agent of the present invention as an active ingredient is ingested by animals including humans to prevent the development of diseases or symptoms associated with deterioration of neuropsychological functions. Also, it can be used in a method for improving or treating a disease or symptom.
  • Cerebral inflammation refers to a state in which inflammatory cytokines are excessively released in the brain beyond the physiological range and duration. It has been pointed out that intracerebral inflammation is involved in the onset process of Alzheimer's disease, depression, schizophrenia, chronic fatigue syndrome, and the like. Microglia, which are glial cells that support nerve cells, are thought to play a central role in brain inflammation because they produce and release inflammatory cytokines in response to infection, tissue damage, neurodegeneration, and the like. Normal microglia function is essential for maintaining brain homeostasis, but hyperactivated microglia release large amounts of pro-inflammatory cytokines, leading to intracerebral inflammation.
  • Microglia are also activated by the accumulation of A ⁇ and tau proteins, which are important in the pathology of Alzheimer's disease.
  • the hippocampus a memory center, is one of the brain regions with the highest number of microglia in the brain and is strongly affected through intracerebral inflammation.
  • the neuropsychological function-improving agent of the present invention when containing soybean peptide as an active ingredient, suppresses brain inflammation, thereby improving diseases and / or symptoms associated with deterioration of neuropsychological function. considered to contribute.
  • BDNF Brain-Derived Neurotrophic Factor
  • the neuropsychological function improving agent of the present invention by using soybean peptide and GABA in combination, the expression of BDNF in the brain can be enhanced, and the disease and / or symptoms associated with the deterioration of neuropsychological function It is thought that this will contribute to improvement.
  • Examples of the food and drink compositions include foods with functional claims, foods for sick people, foods for specified health uses, etc., based on the concept of prevention, improvement or treatment of various symptoms or diseases caused by deterioration of neuropsychological functions. mentioned.
  • the food and drink composition may be liquid, paste, solid, powder, or the like, and may be tablet confectionery, liquid food, feed (including pet food), or, for example, wheat flour products, instant foods, processed agricultural products, etc. , processed marine products, processed livestock products, milk and dairy products, oils and fats, basic seasonings, compound seasonings/foods, frozen foods, confectionery, beverages, and other commercially available foods.
  • the flour products include bread, macaroni, spaghetti, noodles, cake mixes, fried chicken powder, and bread crumbs.
  • the instant foods include instant noodles, cup noodles, retort/cooked foods, cooked canned foods, microwave oven foods, instant soups/stews, instant miso soups/soups, canned soups, freeze-dried foods, and other instant foods.
  • processed agricultural products include canned agricultural products, canned fruits, jams and marmalades, pickles, boiled beans, dried agricultural products, and cereals (processed grain products).
  • Examples of the processed marine products include canned marine products, fish hams and sausages, fish paste products, marine delicacies, and tsukudani.
  • the processed livestock products include canned livestock products, pastes, livestock hams, sausages, and the like.
  • the milk/dairy products include processed milk, milk drinks, yogurts, lactic acid beverages, cheese, ice creams, prepared milk powders, cream, and other dairy products.
  • the fats and oils include butter, margarines, and vegetable oils.
  • Examples of basic seasonings include soy sauce, miso, sauces, processed tomato seasonings, mirin, and vinegar.
  • the complex seasonings/foods include cooking mixes, curry bases, sauces, dressings, noodle soups, spices, and other complex seasonings.
  • the frozen food include material frozen food, semi-cooked frozen food, and cooked frozen food.
  • the confectionery includes gummy, jelly, caramel, candy, chewing gum, chocolate, cookie, biscuit, cake, pie, snack, cracker, Japanese confectionery, rice confectionery, bean confectionery, dessert confectionery, and other confectionery.
  • the beverages include carbonated drinks, natural fruit juices, fruit juice drinks, soft drinks containing fruit juice, pulp drinks, fruit drinks containing fruit, vegetable drinks, soy milk, soy milk drinks, coffee drinks, tea drinks, powdered drinks, concentrated drinks, and sports drinks.
  • Examples of commercial foods other than the above include baby food, furikake (furikake), and tea-soaked seaweed.
  • the neuropsychological function-improving agent of the present invention is for human use for prevention, improvement and / or treatment of diseases, diseases and symptoms involving deterioration of neuropsychological functions as described above.
  • it can be used as an active ingredient of pharmaceutical compositions such as veterinary medicines and quasi-drugs by blending it with other pharmaceutical ingredients.
  • the pharmaceutical composition containing the neuropsychological function-improving agent of the present invention as an active ingredient may be administered orally or parenterally, but is preferably administered orally.
  • Dosage forms for oral administration include tablets, capsules, troches, syrups, granules, powders, ointments and the like.
  • ingredients such as excipients, pH adjusters, colorants, and corrigents that are commonly used for formulation can be used.
  • functional ingredients that are known or will be found in the future to promote muscle synthesis.
  • the administration frequency and dosage of the agent for improving neuropsychological function of the present invention may be appropriately adjusted according to the subject, age, sex, condition, etc., and the amount of soybean peptide and GABA that can exhibit the desired effect is administered. It suffices if it can be administered to a subject.
  • the total content of soybean peptide and GABA in the pharmaceutical composition is preferably at least 0.001% by mass or more relative to the final product.
  • the intake or dosage of soybean peptide and GABA varies depending on the species, age, symptoms, etc. of the administration target, but is usually 0.001 to 8000 mg/kg body weight/day, preferably 0.01 to 6000 mg/kg body weight/day.
  • the intake or dosage for humans is 0.001-1500 mg/kg body weight/day, preferably 0.01-1000 mg/kg body weight/day, most preferably 0.01-500 mg/kg body weight/day.
  • HED Human Equivalent Dose
  • Reference 1 Guidance for Industry, Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, V.E. STEP 2: HUMAN EQUIVALENT DOSE CALCULATION, July 2005, Pharmacology and Toxicology, p. 6-7 / U.S.A. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER)
  • soybean peptide was prepared as follows. That is, 0.5 kg of isolated soybean protein (SPI, Spro 661, DuPont) was suspended and dissolved in 4.5 kg of water. The resulting mixture was heated to 60° C. with stirring, and 10 M sodium hydroxide solution was added to adjust the pH to 7.0 ( ⁇ 0.1). ) was added, and the reaction was allowed to proceed for 5 hours while stirring at 60°C. During the reaction, the pH was measured every 30 minutes, and 10M sodium hydroxide solution was added to adjust the pH to 7.0 ( ⁇ 0.1). After completion of the reaction, the temperature of the reaction solution was raised to 90° C. and maintained for 1 hour to deactivate the enzyme, followed by drying with a spray dryer to obtain soybean peptide powder (Soylax).
  • SPI isolated soybean protein
  • Spro 661 DuPont
  • decapeptide LSSTQAQQSY SEQ ID NO: 1; Soy-deprestatin contained in soybean peptide powder (Soylax) was measured under the following measurement conditions.
  • Capcell PAK C18 UG80 (2.0 ⁇ 150 mm, 5 ⁇ m) (manufactured by Osaka Soda Co., Ltd.) was used as the column.
  • the flow rate was 0.2 mL/min.
  • the MRM method multiple reaction monitoring
  • the detection method is used as the detection method
  • the ionization method is performed in ESI (positive mode)
  • precursor ions: 1112.7 (m/z) and product ions: 101.1 (m/z) are detected.
  • ⁇ Reagents> A standard of the decapeptide LSSTQAQQSY (SEQ ID NO: 1) was synthesized by the Fmoc method and purified by reverse-phase HPLC. It was dissolved in peptone water (0.1% aqueous solution of Bacto peptone) to create a calibration curve.
  • the prepared soybean peptide was dissolved in peptone water to a concentration of 10 mg/ml, and 10 ⁇ L was injected for analysis.
  • the concentration of decapeptide LSSTQAQQSY in the produced soybean peptide powder was 0.97 mg/g.
  • the ratio (%) of motionless time to the total measured time was calculated by the formula: motionless time (seconds)/360 (seconds) x 100.
  • administration of substances with antidepressant effects reduces this immobility time. Therefore, when a decrease in immobility time is observed, it can be evaluated as having an antidepressant-like effect.
  • a state of immobility is considered to be a state of despair, and a decrease in the period of immobility is an index of improvement of the state of despair, that is, improvement of motivation.
  • the results are shown in FIG.
  • the rate of immobility time was about 13.7% in the control group, while that of Soylax alone was about 14.1%, which was almost the same, and Soylax had no antidepressant effect.
  • the immobility time with GABA alone was 8.2% at 0.025 mg/kg BW, indicating that GABA has an antidepressant effect.
  • the non-work time was 3.2%, indicating that the antidepressant effect of GABA was enhanced by Soylax.
  • soybean peptide which has no antidepressant effect by itself, exerts a synergistic effect when used in combination with GABA, is unknown in detail.
  • interleukin-6 interleukin-6
  • soybean peptide has an anti-inflammatory effect in the brain.
  • neuroinflammation including intracerebral inflammation, is deeply involved in the onset and progression of central nervous system diseases such as Alzheimer's disease (e.g., BMC Neuroscience 20, 13 (2019 ) "Amyloid- ⁇ plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer's disease").
  • microglia which are responsible for immunity, mainly cause inflammatory reactions, and cytokines such as IFN ⁇ , IL1 ⁇ , IL-6, and TNF- ⁇ produced by active microglia independently induce neurogenesis. It is known to suppress (for example, Folia Pharmacol. Jpn. 140, pp. 216-220 (2012), Psychiatry and Neurology (2012) Vol. 114, No. 2, pp. 124-133).
  • the neuropsychological function improving agent of the present invention by containing soybean peptide, neuroinflammation such as intracerebral inflammation is suppressed, so that the antidepressant effect of GABA may have been exhibited more remarkably. It is thought that there is in addition, since soybean peptide has the effect of suppressing inflammation in the brain as described above, the neuropsychological function improving agent of the present invention is useful for functional psychiatric disorders such as depression and schizophrenia. It is also believed to be effective in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
  • Example 3 Effect of administration of Soylax and GABA on the amount of brain-derived neurotrophic factor (mature BDNF) in the brain After mixing Soylax at 5 mg/kg BW and GABA at 0.025 mg/kg BW, mice were administered a gastric tube. A control group was given water via a gastric tube. Forty-five minutes after dosing, brains were harvested and stored frozen at -80°C. The cryopreserved brain was thawed, homogenized in 1.5 ml of RIPA buffer (containing protease inhibitor cocktail), and centrifuged (25,000 ⁇ g, 10 min, 4° C.). Measured using the Mouse BDNF DuoSet ELISA (R&D Systems).
  • the value of mature BDNF was calculated as the concentration per amount of protein. The results obtained are shown in FIG. As a result, the mature BDNF value of the control group was 537 pg/mg protein, the mature BDNF value of the Soylax single administration group was 605 pg/mg protein, the mature BDNF value of the GABA single administration group was 565 pg/mg protein, and the Soylax single administration group , an increase in the mature BDNF value was observed compared to the control group, and no increase was observed in the GABA single administration group. In contrast, when Soylax and GABA were mixed and administered, the mature BDNF value was 631 pg/mg protein, which was significantly higher than that of the control group.
  • the Soylax dose is halved, but the mixture administration with GABA It can be seen that the amount of mature BDNF is increased in the group and that there is a synergistic effect.
  • the additive effect on BDNF expression promotion exhibited by the neuropsychological function-improving agent of the present invention was first shown by the present inventors, and the long-term increase in the brain of mature BDNF shown in the above results is considered to have a great effect in the prevention and treatment of various neurodegenerative diseases even in a very small amount.
  • BDNF neurotrophic factor family
  • BDNF a member of the neurotrophic factor family
  • BDNF is an important factor that plays a fundamental role in the expression of higher brain functions represented by memory and learning. Decreased levels of BDNF expression are found in disease.
  • central nervous system diseases such as Alzheimer's dementia (for example, BMC Neuroscience 20, 13 (2019) "Amyloid- ⁇ plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer's disease"); Cytokines such as IFN ⁇ , IL1 ⁇ , IL-6, and TNF- ⁇ produced are known to suppress neurogenesis alone (for example, Japanese Pharmacological Journal 140, pp.
  • NG2 glia central nervous progenitor cells
  • hippocampal neurogenesis is reduced in Alzheimer's patients (Nature medicine, 25, 554-560 (2019)), inflammation is detrimental to hippocampal neurogenesis (PNAS, 100 (23) , 13632-13637 (2003)) have been reported.
  • PNAS 100 (23) , 13632-13637 (2003)
  • the mainstream idea was that neurons are generated during the embryonic and juvenile stages and not during the adult stage.
  • Neural stem/progenitor cells are present even in the maturation stage, and it has been clarified that neural cells are generated by their proliferation and differentiation (Ming GL et al., Annu Rev Neurosci 28: 223-250 (2005)).
  • the neuropsychological function improving agent of the present invention by using a mixture of a trace amount of GABA and soybean peptide, further adds the mature BDNF raising effect of Soylax, so positive Since it is effective, it is considered that it acts effectively for prevention and improvement of neurodegenerative diseases such as depression and Alzheimer's dementia.

Abstract

The present invention relates to a neuropsychological function improving agent for preventing and/or ameliorating symptoms and/or diseases caused by the deterioration of neuropsychological function, said agent containing soybean peptide and γ aminobutyric acid (GABA) as active ingredients. The symptoms and/or diseases caused by the deterioration of the neuropsychological function include Alzheimer-type dementia, depression, memory disorder due to aging, autism spectrum disorder, bipolar disorder, schizophrenia, or chronic fatigue syndrome.

Description

神経心理学的機能改善剤Neuropsychological function improving agent
　本発明は、アルツハイマー型認知症（Ａｌｚｈｅｉｍｅｒ－ｔｙｐｅ　Ｄｅｍｅｎｔｉａ：ＡＤ）やうつ病等、神経心理学的機能の低下によってもたらされる症状や疾患に対し、予防及び／又は改善効果を有する神経心理学的機能改善剤に関する。より詳細には、安全で簡便に摂取できる大豆ペプチド及びγアミノ酪酸を有効成分とし、神経心理学的機能の低下を予防及び／又は改善を図ることができる神経心理学的機能改善剤に関する。 The present invention provides neuropsychological functions that have preventive and/or improving effects on symptoms and diseases caused by decreased neuropsychological functions, such as Alzheimer-type dementia (AD) and depression. Regarding improver. More specifically, the present invention relates to a neuropsychological function-improving agent that contains soybean peptide and γ-aminobutyric acid that can be safely and easily ingested as active ingredients and that can prevent and/or improve neuropsychological function deterioration.
　近年、世界的な高齢化に伴う認知症高齢者の急増により社会保障負担の増加が大きな問題となっている。また、健康なシニア層であっても、加齢に伴う脳機能の衰えの改善が望まれている。そのため脳機能、特に認知機能を低下させない予防法が社会的にも求められている。特に、日本では、６５歳以上の４人に１人が認知症になると予測されており、その６割以上がアルツハイマー型認知症（ＡＤ）と推定されている（非特許文献１）。 In recent years, the increasing social security burden has become a major problem due to the rapid increase in the number of elderly with dementia accompanying the global aging of the population. In addition, even in healthy seniors, it is desired to improve aging-related decline in brain function. Therefore, there is a social demand for a preventive method that does not reduce brain function, particularly cognitive function. In particular, in Japan, one in four people aged 65 or older is predicted to develop dementia, and more than 60% of them are estimated to have Alzheimer's disease (AD) (Non-Patent Document 1).
　ＡＤの初期には、脳における老人斑の主成分であるアミロイドβ（Ａｍｙｌｏｉｄ－β：Ａβ）の沈着が起こることが明らかになっている。Ａβの蓄積の後、タウタンパク（Ｔａｕ　ｐｒｏｔｅｉｎ）の異常リン酸化が起こり、神経原線維変化（Ｎｅｕｒｏｆｉｂｒｉｌｌａｒｙ　Ｔａｎｇｌｅ：ＮＦＴ）が生じる。その一連の流れはアミロイドカスケード仮説（非特許文献２）と呼ばれている。そして、以前から提唱されていたＡＤの脳内炎症仮説が再び注目されている。すなわち、１９８７年、ＡＤ患者の剖検脳において、活性化ミクログリアが老人斑の周囲に集積することが報告され（非特許文献３）、さらに、１９９０年、非ステロイド性抗炎症薬（ＮＳＡＩＤｓ）を長期服用しているリウマチ患者ではＡＤの発症リスクが６分の１に低下しており、ＡＤ発症における脳内炎症の重要性が指摘されていた（非特許文献４）。 It has been clarified that in the early stages of AD, deposition of amyloid-β (Amyloid-β: Aβ), which is the main component of senile plaques in the brain, occurs. After Aβ accumulation, abnormal phosphorylation of Tau protein occurs, resulting in neurofibrillary tangles (NFTs). This series of events is called the amyloid cascade hypothesis (Non-Patent Document 2). The brain inflammation hypothesis of AD, which has been advocated for some time, is attracting attention again. That is, in 1987, it was reported that activated microglia accumulated around senile plaques in the autopsy brains of AD patients (Non-Patent Document 3). The risk of developing AD in rheumatoid arthritis patients taking the drug was reduced to 1/6, and the importance of intracerebral inflammation in the development of AD has been pointed out (Non-Patent Document 4).
　ＡＤは、進行性の記憶障害を中心とした認知機能障害の他に、経過中に様々な行動・心理症状（認知症精神行動症状、ｂｅｈａｖｉｏｒａｌ　ｐｓｙｃｈｏｌｏｇｉｃａｌ　ｓｙｍｐｔｏｍｓ　ｏｆ　ｄｅｍｅｎｔｉａ：ＢＰＳＤ）が認められ、このＢＰＳＤの主要な症状の一つが、うつ症状である（非特許文献５）。 In AD, in addition to cognitive dysfunction centered on progressive memory impairment, various behavioral and psychological symptoms (behavioral psycho-behavioral symptoms of dementia: BPSD) are observed during the course of AD, and this BPSD One of the major symptoms is depressive symptoms (Non-Patent Document 5).
　うつ病患者では、海馬体積が減少していることや海馬機能が低下していることが報告されている（非特許文献６）。海馬は記憶・学習といった認知機能に関与する脳部位として知られているが、うつ病患者では気分の障害だけでなく記憶を含む認知機能も障害される。さらに、海馬は視床下部－下垂体－副腎皮質系（ｈｙｐｏｔｈａｌａｍｕｓ－ｐｉｔｕｉｔａｒｙ－ａｄｒｅｎａｌ　ａｘｉｓ：ＨＰＡ系）の機能を負に調節しているが、うつ病患者ではＨＰＡ系が過活動になっており、その要因としても海馬機能の低下が考えられている。 It has been reported that depression patients have decreased hippocampal volume and decreased hippocampal function (Non-Patent Document 6). The hippocampus is known to be a part of the brain involved in cognitive functions such as memory and learning, but in depressed patients, not only mood disorders but also cognitive functions, including memory, are impaired. Furthermore, the hippocampus negatively regulates the function of the hypothalamus-pituitary-adrenal axis (HPA system), and the HPA system is overactive in depressed patients. A decrease in hippocampal function is also considered as a factor.
　従来、神経細胞は胎生期、幼若期に新生され、成熟期では新生されないという考え方が主流であったが、近年では側脳室下帯や海馬歯状回といった特定の脳領域においては、成熟期においても神経幹・前駆細胞が存在し、それらが増殖、分化することにより神経細胞が新生されることが明らかにされている（非特許文献７）。そして、海馬歯状回で新生された神経細胞は、神経ネットワークを形成し、記憶形成に関わる等重要な役割を果たしていることが報告されている（非特許文献８）。最近、ＡＤが進行するにつれ、海馬における神経細胞の新生が急激に低下していることが報告され、ＡＤ発症に関わっている可能性が指摘されている（非特許文献９）。 In the past, the mainstream idea was that neurons are generated during the embryonic and juvenile stages and not during the adult stage. Neural stem/progenitor cells are present even in the stage, and it has been clarified that neural cells are generated by their proliferation and differentiation (Non-Patent Document 7). It has been reported that neurons newly generated in the dentate gyrus of the hippocampus form a neural network and play important roles such as being involved in memory formation (Non-Patent Document 8). Recently, it has been reported that neurogenesis in the hippocampus rapidly declines as AD progresses, and the possibility of involvement in the onset of AD has been pointed out (Non-Patent Document 9).
　近年、脳機能の解明が進むにつれ、記憶力等の神経心理学的機能の向上に作用し、神経心理学的機能の低下に伴う症状や疾患を予防、改善する物質を探索する試みが盛んに行われている。その一例として、日常的に摂取し得る食品由来の天然物に認知機能を向上、改善する物質が含まれていないか、その探索が盛んに行われている。そして、アルギニン、シトルリン、グリシン、プロリン及びチロシンからなる５種のアミノ酸の配合物を摂取することで、認知機能（ストループテストによる評価）が高まること（特許文献１）、小麦共生細菌パントエア・アグロメランス（Ｐａｎｔｏｅａ　ａｇｇｌｏｍｅｒａｎｓ）由来リポ多糖を経口摂取することにより脳内のＡβペプチド蓄積量が有意に減少し学習機能が改善すること（特許文献２）、コーヒー豆、ジャガイモ、米糠等に見出されるポリフェノール類であるクロロゲン酸類を摂取することにより、認知柔軟性、実行機能、注意制御機能等の高次脳機能が改善すること（特許文献３）等が開示されている。 In recent years, as the elucidation of brain functions progresses, many attempts have been made to search for substances that act to improve neuropsychological functions such as memory and prevent or improve symptoms and diseases associated with decreased neuropsychological functions. It is As an example, there is a lot of research being done to find out whether natural substances derived from foods that can be ingested on a daily basis contain substances that enhance and improve cognitive functions. Then, by ingesting a combination of five amino acids consisting of arginine, citrulline, glycine, proline and tyrosine, cognitive function (evaluation by Stroop test) is enhanced (Patent Document 1), wheat symbiotic bacteria Pantoea agglomerans ( Oral intake of Pantoea agglomerans-derived lipopolysaccharide significantly reduces the accumulation of Aβ peptide in the brain and improves learning function (Patent Document 2). It is disclosed that higher brain functions such as cognitive flexibility, executive function, and attention control function are improved by ingesting chlorogenic acids (Patent Document 3).
　また、γアミノ酪酸（ＧＡＢＡ）は、哺乳動物の中枢神経系において、最も広範かつ豊富な伝達物質の１つであり、脳刺激性の調整において主要な役割を果たしていることが知られている（特許文献４）。また、臨床試験でＧＡＢＡの経口摂取によって抗うつ効果や睡眠改善等の効果があることが報告されているが、ＧＡＢＡは血液脳関門を通過できないことから、その作用のメカニズムについては不明であった。 γ-Aminobutyric acid (GABA) is also one of the most widespread and abundant transmitters in the mammalian central nervous system and is known to play a major role in regulating brain stimulation ( Patent Document 4). In clinical trials, oral intake of GABA was reported to have effects such as antidepressant effect and sleep improvement. .
特開２０１９－１１２３６１号公報JP 2019-112361 A 特開２０１８－１９９６４３号公報JP 2018-199643 A 特開２０１８－３９７９７号公報JP 2018-39797 A 特開平２－３２０２９号公報JP-A-2-32029
　本発明は、アルツハイマー型認知症やうつ病等、神経心理学的機能の低下によってもたらされる症状や疾患に対し、予防及び／又は改善効果を有する神経心理学的機能改善剤を提供することを目的とする。 An object of the present invention is to provide a neuropsychological function-improving agent that has a preventive and/or improving effect on symptoms and diseases caused by a decrease in neuropsychological function, such as Alzheimer's dementia and depression. and
　また、本発明は、前記神経心理学的機能改善剤を含有する心理学的機能改善用医薬組成物及び神経心理学的機能改善用飲食品組成物、並びに前記神経心理学的機能改善剤を用いる神経心理学的機能低下に起因する症状及び／又は疾患を予防及び／又は改善する方法を提供することを目的とする。 In addition, the present invention uses a pharmaceutical composition for improving psychological function and a food and drink composition for improving neuropsychological function containing the agent for improving neuropsychological function, and the agent for improving neuropsychological function. The object is to provide a method for preventing and/or ameliorating symptoms and/or diseases caused by neuropsychological dysfunction.
　本発明者らは、日常的に摂取されている食材の中から、神経心理機能の改善に寄与する素材を見出すべく、鋭意努力した結果、驚くべきことに、大豆ペプチド及びＧＡＢＡを併用した場合に、神経心理学的機能を相乗的に改善させる効果があることを見出し、本発明を完成させるに至った。 The present inventors have made diligent efforts to find a material that contributes to the improvement of neuropsychological functions from the foodstuffs that are ingested on a daily basis. , has the effect of synergistically improving neuropsychological functions, leading to the completion of the present invention.
　本発明の要旨は、
　〔１〕大豆ペプチド及びγアミノ酪酸（ＧＡＢＡ）を有効成分として含む、神経心理学的機能低下に起因する症状及び／又は疾患の予防及び／又は改善のための、神経心理学的機能改善剤、
　〔２〕神経心理学的機能の低下に起因する症状及び／又は疾患が、アルツハイマー型認知症、うつ病、老化による記憶障害、自閉症スペクトラム障害、双極性障害、統合失調症又は慢性疲労症候群である、前記〔１〕に記載の神経心理学的機能改善剤、
　〔３〕大豆ペプチドが、サーモリシン消化物である、前記〔１〕又は〔２〕に記載の神経心理学的機能改善剤、
　〔４〕大豆ペプチドが、アミノ酸配列ＬＳＳＴＱＡＱＱＳＹ（配列番号１）から成るペプチドを含む、前記〔１〕～〔３〕のいずれかに記載の神経心理学的機能改善剤、
　〔５〕前記〔１〕～〔４〕のいずれかに記載の神経心理学的機能改善剤を含む、神経心理学的機能改善用医薬組成物、
　〔６〕前記〔１〕～〔４〕のいずれかに記載の神経心理学的機能改善剤を含む、神経心理学的機能改善用飲食品組成物、
　〔７〕前記〔１〕～〔４〕のいずれかに記載の神経心理学的機能改善剤を必要とする患者又は予備軍に、当該神経心理学的機能改善剤を投与する工程を含む、神経心理学的機能低下に起因する症状及び／又は疾患を予防及び／又は改善する方法
に関する。 The gist of the present invention is
[1] A neuropsychological function-improving agent for preventing and/or improving symptoms and/or diseases caused by neuropsychological function deterioration, comprising soybean peptide and γ-aminobutyric acid (GABA) as active ingredients;
[2] Symptoms and / or diseases caused by deterioration of neuropsychological function are Alzheimer's dementia, depression, memory impairment due to aging, autism spectrum disorder, bipolar disorder, schizophrenia or chronic fatigue syndrome The neuropsychological function improving agent according to [1] above,
[3] The agent for improving neuropsychological function according to [1] or [2] above, wherein the soybean peptide is a thermolysin digest,
[4] The agent for improving neuropsychological function according to any one of [1] to [3], wherein the soybean peptide comprises a peptide consisting of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1);
[5] A pharmaceutical composition for improving neuropsychological function, comprising the agent for improving neuropsychological function according to any one of [1] to [4] above;
[6] A food and drink composition for improving neuropsychological function, comprising the agent for improving neuropsychological function according to any one of [1] to [4] above;
[7] a neuropsychological function-improving agent comprising the step of administering the neuropsychological function-improving agent to a patient or potential patient in need of the neuropsychological function-improving agent according to any one of [1] to [4] above; It relates to a method for preventing and/or ameliorating symptoms and/or diseases caused by psychological impairment.
　本発明の神経心理学的機能改善剤によれば、有効成分である大豆ペプチド及びＧＡＢＡは、食品素材として用いられてきた食歴のある安全性の高い素材であり、これらを組み合わせることで高い神経心理学的機能を改善させる効果が奏されるため、神経心理学的機能の低下に起因する疾患若しくは状態（症状）の予防又は改善（治療）を必要とする対象者に本発明の神経心理学的機能改善剤を投与した場合、副作用を伴うことなく、かかる疾患若しくは状態の予防又は改善（治療）が期待される。 According to the neuropsychological function improving agent of the present invention, soybean peptide and GABA, which are active ingredients, are highly safe materials with a history of being used as food materials. Since the effect of improving psychological functions is exhibited, the neuropsychology of the present invention is applied to subjects who need prevention or improvement (treatment) of diseases or conditions (symptoms) caused by deterioration of neuropsychological functions Prevention or amelioration (treatment) of such diseases or conditions is expected without side effects when the therapeutic agents are administered.
図１は、認知症の中核症状と行動・心理症状（ＢＰＳＤ）を示した図である。FIG. 1 is a diagram showing core symptoms and behavioral/psychological symptoms (BPSD) of dementia. 図２は、実施例２における尾懸垂試験の結果を示したグラフである。2 is a graph showing the results of the tail suspension test in Example 2. FIG. 図３は、実施例３における脳内脳由来神経栄養因子（ｍａｔｕｒｅ　ＢＤＮＦ）量の結果を示したグラフである。3 is a graph showing the results of the amount of brain-derived neurotrophic factor (mature BDNF) in the brain in Example 3. FIG.
　以下、本発明の具体的な実施形態について詳細に説明するが、本発明は以下の実施形態に何ら限定されるものではなく、本発明の目的の範囲内において、適宜変更を加えて実施することができる。なお、説明が重複する箇所については、適宜説明を省略する場合があるが、本発明を限定するものではない。 Hereinafter, specific embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments at all, and can be implemented with appropriate modifications within the scope of the purpose of the present invention. can be done. In addition, although description may be suitably omitted about the part which description overlaps, this does not limit this invention.
　本発明の神経心理学的機能改善剤は、大豆ペプチド及びγアミノ酪酸（ＧＡＢＡ）を有効成分として含むものであり、神経心理学的機能の改善のために用いることができる。本発明において「神経心理学的機能」とは、表１に示したような知能、記憶機能、言語機能、注意力、前頭葉機能、遂行機能等の一般的な高次脳機能（以下、認知機能ともいう）の他、気持ちの落ち込み・不安・うつの度合いに関わる心理的機能を含んだ広い概念を指す。本発明の神経心理学的機能改善剤を摂取したことによる前記各機能の向上及び／又は改善の度合いは、表１に示した各検査等によって調べることができる。 The neuropsychological function-improving agent of the present invention contains soybean peptide and γ-aminobutyric acid (GABA) as active ingredients, and can be used to improve neuropsychological functions. In the present invention, the term "neuropsychological function" refers to general higher brain functions such as intelligence, memory function, language function, attention, frontal lobe function, and executive function as shown in Table 1 (hereinafter referred to as cognitive function It refers to a broad concept that includes psychological functions related to the degree of depression, anxiety, and depression. The improvement and/or the degree of improvement in each of the above functions due to ingestion of the neuropsychological function-improving agent of the present invention can be examined by each test shown in Table 1 and the like.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　神経心理学的機能の改善には、認知機能及びうつ症状の改善、神経心理学的機能に関連した、脳の萎縮の抑制、脳の機能低下の抑制（海馬との機能連結の強化）、及び炎症による神経細胞の損傷の改善が含まれる。
　また、神経心理学的機能の低下に起因する症状及び／又は疾患としては、アルツハイマー型認知症、うつ病、自閉症スペクトラム障害、双極性障害、統合失調症、又は加齢に関連したものが挙げられる。従って、神経心理学的機能の改善には、アルツハイマー型認知症、うつ病、老化による記憶障害、自閉症スペクトラム障害、双極性障害、統合失調症、及び／又は脳の機能老化の処置が含まれる。 Improving neuropsychological function includes improving cognitive function and depressive symptoms, inhibiting brain atrophy, inhibiting brain decline (strengthening functional connections with the hippocampus) associated with neuropsychological function, and It includes amelioration of nerve cell damage caused by inflammation.
In addition, symptoms and/or diseases caused by decreased neuropsychological function include Alzheimer's dementia, depression, autism spectrum disorder, bipolar disorder, schizophrenia, or those associated with aging. mentioned. Improving neuropsychological function therefore includes treatment of Alzheimer's disease, depression, age-related memory impairment, autism spectrum disorder, bipolar disorder, schizophrenia, and/or aging of the brain. be
　図１に示したように、アルツハイマー型認知症を含む認知症の症状には中核症状と行動・心理症状がある。中核症状としては記憶障害、見当識障害、失語、失行、失認、実行機能障害等がある。ＢＰＳＤには多くの症状があり、徘徊、興奮、暴力、幻覚、妄想、うつ状態、不潔行為等があるが、中核症状である認知機能障害に、周りの環境や、性格、心理状態等が関係して現れると考えられる。 As shown in Figure 1, the symptoms of dementia, including Alzheimer's disease, include core symptoms and behavioral/psychological symptoms. Core symptoms include memory impairment, disorientation, aphasia, apraxia, agnosia, and executive dysfunction. BPSD has many symptoms, including wandering, agitation, violence, hallucinations, delusions, depression, and unclean behavior. The core symptoms of cognitive dysfunction are related to the surrounding environment, personality, and psychological state. It is thought that it will appear as
〔１〕大豆ペプチド
　本発明において用いられる大豆ペプチドは、特定の分解度の範囲まで大豆タンパク質が加水分解等で分解されていることが重要である。加水分解処理は大豆タンパク質を含む水分散液に対して行うことができる。大豆タンパク質の加水分解は、本発明における神経心理学的機能改善効果が得られるペプチド混合物となるような方法により行うこが重要である。すなわち、大豆タンパク質の加水分解は、タンパク質分解酵素（プロテアーゼともいう）による酵素分解が好ましい。 [1] Soybean peptide It is important that the soybean peptide used in the present invention is soybean protein decomposed by hydrolysis or the like to a specific degree of decomposition. Hydrolysis treatment can be performed on an aqueous dispersion containing soy protein. It is important to hydrolyze the soy protein in such a way as to obtain a peptide mixture that provides the neuropsychological function-improving effect of the present invention. That is, the hydrolysis of soybean protein is preferably enzymatic decomposition by a protease (also referred to as protease).
　プロテアーゼとしては、例えば、アミノ酸が鎖状に結合するタンパク質やペプチド内部のペプチド結合を加水分解し、いくつかのペプチドとする酵素であるエンド型プロテアーゼが好適である。また、タンパク質やペプチドの端に存在するアミノ末端及びカルボキシ末端からアミノ酸やペプチド等を順に切断する酵素であるエキソ型プロテアーゼを１種類以上組み合わせることも可能である。これらエンド型プロテアーゼ及びエキソ型プロテアーゼの種類は、大豆タンパク質素材の溶液環境で活性を持つものであれば使用でき、例えば、Ｂａｃｉｌｌｕｓ属等の微生物に由来のプロテアーゼが好ましく使用できる。Ｂａｃｉｌｌｕｓ属に由来するプロテアーゼとして、「サモアーゼ（登録商標）ＰＣ１０Ｆ」（天野エンザイム株式会社製）、「プロチンＳＤ－ＡＹ１０」（天野エンザイム株式会社製）、「プロチンＳＤ－ＮＹ１０」（天野エンザイム株式会社製）、「プロタメックス」（ノボザイムズジャパン株式会社製）等を挙げることができる。 As a protease, for example, an endo-type protease, which is an enzyme that hydrolyzes peptide bonds inside proteins or peptides in which amino acids are bound in a chain to form several peptides, is suitable. It is also possible to combine one or more exo-type proteases, which are enzymes that sequentially cleave amino acids, peptides, etc. from the amino-terminus and carboxy-terminus present at the ends of proteins and peptides. These endo-type proteases and exo-type proteases can be used as long as they are active in the solution environment of the soybean protein material. For example, proteases derived from microorganisms such as Bacillus can be preferably used. Examples of proteases derived from the genus Bacillus include "Samoase (registered trademark) PC10F" (manufactured by Amano Enzyme Co., Ltd.), "Protin SD-AY10" (manufactured by Amano Enzyme Co., Ltd.), and "Protin SD-NY10" (manufactured by Amano Enzyme Co., Ltd.). ), “Protamex” (manufactured by Novozymes Japan Co., Ltd.), and the like.
　中でも、サーモリシン消化物であることが神経心理学的機能改善効果の力価の観点から好ましい。サーモリシンは、耐熱性菌Ｂａｃｉｌｌｕｓ　ｔｈｅｒｍｏｐｒｏｔｅｏｌｙｔｉｃｕｓ由来の、公知のプロテアーゼである（ＥＣ３．４．２４．４、ＥＣ３．４．２４．２７）。サーモリシンは、我が国において食品添加物として使用することができる。サーモリシンは、食品添加物グレード等の市販品（例えば、前記「サモアーゼ（登録商標）ＰＣ１０Ｆ」（天野エンザイム株式会社製））を使用することができる。 Among them, the thermolysin digest is preferable from the viewpoint of the potency of the neuropsychological function improving effect. Thermolysin is a known protease derived from the heat-resistant bacterium Bacillus thermoproteolyticus (EC 3.4.24.4, EC 3.4.24.27). Thermolysin can be used as a food additive in Japan. Commercial products such as food additive grade thermolysin (for example, the above-mentioned "Samoase (registered trademark) PC10F" (manufactured by Amano Enzyme Co., Ltd.)) can be used.
　サーモリシンにより加水分解をする基質は、大豆ベータコングリシニン（β－ＣＧ）タンパク質を含むものであれば特に限定されない。例えば、大豆それ自体、大豆から大豆油を抽出した搾りかす（ミール、脱脂大豆ともいう）、脱脂大豆から糖類と灰分を除去した濃縮大豆蛋白質、脱脂大豆から蛋白質だけを分離した分離大豆たん白質（Ｓｏｙ　Ｐｒｏｔｅｉｎ　Ｉｓｏｌａｔｅ：ＳＰＩ）、精製したβ－ＣＧタンパク質等が挙げられる。サーモリシンによる加水分解反応は、１０アミノ酸残基程度のペプチドが得られる条件で行う。反応温度は３０～７０℃、４０～７０℃、５０～６５℃等から適宜選択することができる。反応時間は、３０分～４８時間程度、１～１０時間程度、２～８時間程度等から適宜選択することができる。反応を行うｐＨは、ｐＨ６．５～８．５程度、ｐＨ７～８程度から適宜選択することができる。一つの好適な態様においては、３０～４０℃程度の温度、ｐＨ６．５～８．５（特に、ｐＨ７．５程度）の条件下で、２～８時間程度反応させることができる。また、必要に応じて、サーモリシンが失活する温度に加熱（例えば、８０℃を超える温度で５～６０分程度での加熱）することで、サーモリシンを失活させてもよい。加水分解で得られる反応生成物は、そのまま使用することができるし、必要に応じて、上記により得られた加水分解物を、さらにゲルろ過、膜ろ過等の手段により分子量で分画する手段、あるいは吸着樹脂やイオン交換樹脂等の吸着特性を利用した分画手段を使用し、分子量３００～１５００、好ましくは５００～１３００、より好ましくは７００～１１００の分画物として得ることもできる。 The substrate hydrolyzed by thermolysin is not particularly limited as long as it contains soybean beta-conglycinin (β-CG) protein. For example, soybeans themselves, pomace (also called meal or defatted soybeans) obtained by extracting soybean oil from soybeans, concentrated soybean protein obtained by removing sugars and ash from defatted soybeans, isolated soybean protein obtained by separating only protein from defatted soybeans ( Soy Protein Isolate: SPI), purified β-CG protein and the like. The hydrolysis reaction with thermolysin is performed under conditions that yield a peptide of about 10 amino acid residues. The reaction temperature can be appropriately selected from 30 to 70°C, 40 to 70°C, 50 to 65°C and the like. The reaction time can be appropriately selected from about 30 minutes to 48 hours, about 1 to 10 hours, about 2 to 8 hours, and the like. The pH for the reaction can be appropriately selected from about pH 6.5 to 8.5 and about pH 7 to 8. In one preferred embodiment, the reaction can be carried out for about 2 to 8 hours at a temperature of about 30 to 40° C. and a pH of 6.5 to 8.5 (especially about pH 7.5). Further, if necessary, thermolysin may be deactivated by heating to a temperature at which thermolysin is deactivated (for example, heating at a temperature exceeding 80° C. for about 5 to 60 minutes). The reaction product obtained by hydrolysis can be used as it is, and if necessary, the hydrolyzate obtained above is further subjected to molecular weight fractionation by means of gel filtration, membrane filtration, etc. Alternatively, a fraction having a molecular weight of 300 to 1,500, preferably 500 to 1,300, more preferably 700 to 1,100 can be obtained by using a fractionation means utilizing adsorption properties such as an adsorption resin or an ion exchange resin.
　中でも、高い神経心理学的機能改善効果を有する剤を製造する観点から、前記大豆ペプチドとしては、アミノ酸配列ＬＳＳＴＱＡＱＱＳＹ（配列番号１）から成るペプチドを含むことが好ましい。
　前記のようなアミノ酸配列が明らかな大豆ペプチドは、公知の化学合成法を用いて得られた合成品であってもよいし、さらに大豆ペプチドとして所望の効果が得られるのであれば誘導体であってもよい。 Among them, the soybean peptide preferably contains a peptide consisting of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1) from the viewpoint of producing an agent having a high neuropsychological function-improving effect.
The soybean peptide whose amino acid sequence is known as described above may be a synthetic product obtained using a known chemical synthesis method, or may be a derivative as long as the desired effects of the soybean peptide can be obtained. good too.
〔２〕γアミノ酪酸（ＧＡＢＡ）
　本発明で用いるＧＡＢＡは、天然物中から単離されたり、また発酵等の工業的な方法により得られたりするが、その由来に関わらず一定の性状を持つため、その由来に制限されず、種々のものを使用できる。その具体例としては、例えば、玄米等の天然物由来のもの、乳酸菌等の微生物による発酵を経たもの等が挙げられる。また、ＧＡＢＡを含む中間物を使用することもできる。該中間物とは、食用に供しても安全な、天然物や発酵物からＧＡＢＡが単離精製される途中の粗精製物、乳酸菌等の微生物の発酵物等である。前記された各種のＧＡＢＡは、単独で使用してもよいし、２種以上を混合して使用してもよい。 [2] γ-aminobutyric acid (GABA)
The GABA used in the present invention is isolated from natural products or obtained by an industrial method such as fermentation. Various can be used. Specific examples thereof include those derived from natural products such as brown rice, and those obtained through fermentation by microorganisms such as lactic acid bacteria. Intermediates containing GABA can also be used. The intermediates include edible crude products during the isolation and purification of GABA from natural products and fermented products, fermented products of microorganisms such as lactic acid bacteria, and the like. The various GABA described above may be used alone or in combination of two or more.
〔３〕神経心理学的機能改善剤
　本発明の神経心理学的機能改善剤は、前記大豆ペプチドとＧＡＢＡの両方を有効成分として含有することで、神経心理学的機能改善において相乗効果を発揮するものである。ここで、相乗効果とは、大豆ペプチドとＧＡＢＡとをそれぞれ単独で用いたときの神経心理学的機能改善効果の和よりも、両者を組み合わせて使用する方がより高い神経心理学的機能改善効果が得られることをいう。
　中でも、本発明の神経心理学的機能改善剤において、前記相乗効果を発揮し易いペプチドの種類としては、大豆ペプチドが、アミノ酸配列ＬＳＳＴＱＡＱＱＳＹ（配列番号１）から成るペプチドであることが挙げられる。 [3] Neuropsychological function-improving agent The neuropsychological function-improving agent of the present invention exhibits a synergistic effect in improving neuropsychological functions by containing both the soybean peptide and GABA as active ingredients. It is. Here, the synergistic effect is a higher neuropsychological function-improving effect when used in combination than the sum of the neuropsychological function-improving effects when soybean peptide and GABA are used alone. is obtained.
Among them, in the neuropsychological function-improving agent of the present invention, as a type of peptide that is likely to exhibit the synergistic effect, a soybean peptide is a peptide consisting of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1).
　本発明の神経心理学的機能改善剤において、大豆ペプチドとＧＡＢＡとの配合比（大豆ペプチド／ＧＡＢＡ、重量比）は、神経心理学的機能改善における相乗効果が得られる限り限定はないが、好ましくは１～１０００、より好ましくは１～５００、さらに好ましくは１～２００である。以下、大豆ペプチドとＧＡＢＡの２成分を配合した混合物を「大豆－ＧＡＢＡ配合物」という。 In the agent for improving neuropsychological function of the present invention, the compounding ratio of soybean peptide and GABA (soybean peptide/GABA, weight ratio) is not limited as long as a synergistic effect in improving neuropsychological function is obtained, but is preferred. is 1-1000, more preferably 1-500, more preferably 1-200. Hereinafter, a mixture containing two components, soybean peptide and GABA, is referred to as a "soybean-GABA mixture".
　例えば、固体状の神経心理学的機能改善剤の場合、大豆－ＧＡＢＡ配合物の含有量は１００重量％でもよいし、後述の追加成分を含有する場合には、２０重量％以上であればよく、４０重量％以上が好ましく、６０重量％以上がより好ましく、８０重量％以上がさらに好ましい。また、大豆－ＧＡＢＡ配合物を水等の媒体に分散・溶解させた溶液状の神経心理学的機能改善剤の場合、大豆－ＧＡＢＡ配合物の含有量は、２重量％以上であればよい。 For example, in the case of a solid neuropsychological function improving agent, the content of the soy-GABA blend may be 100% by weight, or may be 20% by weight or more when the additional ingredients described below are included. , 40% by weight or more is preferable, 60% by weight or more is more preferable, and 80% by weight or more is even more preferable. Further, in the case of a solution-like neuropsychological function-improving agent obtained by dispersing/dissolving a soybean-GABA compound in a medium such as water, the content of the soybean-GABA compound may be 2% by weight or more.
　本発明の神経心理学的機能改善剤は、さらに、追加成分として、多糖類を含んでもよいし、さらに必要に応じて、増量剤、可溶化剤、分散剤、懸濁剤、乳化剤、抗酸化剤、細菌抑制剤、着色剤、矯味剤、矯臭剤等の成分を含んでもよい。これらの追加成分は、いずれも、食品、医薬品又は医薬部材品において使用されているものであれば特に限定はない。これらの追加成分の合計量は「神経心理学的機能改善剤」の乾燥重量１００重量％に対して８０重量％以下、好ましくは６０重量％以下、より好ましくは４０重量％以下、さらに好ましくは２０重量％以下である。 The neuropsychological function-improving agents of the present invention may further comprise polysaccharides as additional ingredients, and optionally, bulking agents, solubilizers, dispersing agents, suspending agents, emulsifying agents, antioxidants. Ingredients such as agents, antibacterial agents, coloring agents, flavoring agents, flavoring agents and the like may also be included. Any of these additional ingredients are not particularly limited as long as they are used in foods, medicines, or medicinal products. The total amount of these additional components is 80% by weight or less, preferably 60% by weight or less, more preferably 40% by weight or less, still more preferably 20% by weight, based on 100% by weight of the dry weight of the "neuropsychological function improving agent" % by weight or less.
　本発明の神経心理学的機能改善剤を有効成分として配合し、神経心理学的機能の低下に起因する症状及び／又は疾患の予防及び／又は改善用飲食品組成物として使用することができる。 The neuropsychological function-improving agent of the present invention can be blended as an active ingredient and used as a food and drink composition for preventing and/or improving symptoms and/or diseases caused by decreased neuropsychological function.
　神経心理学的機能の低下に起因する症状及び／又は疾患としては、アルツハイマー型認知症、うつ病、老化による記憶障害、自閉症スペクトラム障害、双極性障害、及び統合失調症等が挙げられる。 Symptoms and/or diseases caused by decreased neuropsychological function include Alzheimer's dementia, depression, memory impairment due to aging, autism spectrum disorder, bipolar disorder, and schizophrenia.
　前記使用とは、適用対象であるヒト若しくは非ヒト動物における使用をいい、また治療的使用であっても非治療的使用であってもよい。本明細書において、「非治療的」とは、医療行為、すなわち治療による人体への処置行為を含まない概念である。
　また、本明細書において、「治療」とは、適用対象において発症した疾患若しくは症状を発症前の状態に戻すことをいう。本明細書において「予防」とは、適用対象において疾患の発症の防止又は遅延、或いは適用対象の疾患若しくは症状の発症の危険性を低下させることをいう。本明細書において、「改善」とは、疾患、症状又は状態の好転；疾患、症状又は状態の悪化の防止、遅延若しくは疾患又は症状の進行の逆転、防止又は遅延をいう。 Said use refers to use in a human or non-human animal to which it is applied, and may be therapeutic or non-therapeutic. As used herein, the term "non-therapeutic" is a concept that does not include medical treatment, that is, the treatment of the human body by therapy.
As used herein, the term “treatment” refers to restoring a disease or symptom that has developed in an application subject to the pre-development state. As used herein, "prevention" means preventing or delaying the onset of a disease in a subject, or reducing the risk of developing a disease or condition in a subject. As used herein, "amelioration" refers to amelioration of a disease, symptom or condition; prevention or delay of worsening of a disease, symptom or condition or reversal, prevention or delay of progression of a disease or condition.
　本発明の神経心理学的機能改善剤を有効成分として含有する前記飲食品組成物は、ヒトを含む動物が摂取して、神経心理学的機能の低下が関与する疾病又は症状の発現を予防したり、疾患や症状の改善や治療等を図るための方法に使用したりすることができる。 The food and drink composition containing the neuropsychological function-improving agent of the present invention as an active ingredient is ingested by animals including humans to prevent the development of diseases or symptoms associated with deterioration of neuropsychological functions. Also, it can be used in a method for improving or treating a disease or symptom.
　脳内炎症とは、脳内で炎症性サイトカインが生理的な範囲・期間を超えて過剰に放出された状態をいう。アルツハイマー病、うつ病、統合失調症、慢性疲労症候群等の発症過程にも脳内炎症が関与することが指摘されている。神経細胞を支えるグリア細胞であるミクログリアは感染、組織損傷、神経変性等に応答して炎症性サイトカインを産生・放出することから脳内炎症に中心的な役割を果たすと考えられている。正常なミクログリアの機能は、脳の恒常性維持に必須であるが、過剰に活性化したミクログリアは、大量の炎症性サイトカインを放出し、脳内炎症を引き起こす。ミクログリアは、アルツハイマー型認知症の病態に重要なＡβやタウ蛋白の蓄積によっても活性化される。記憶中枢である海馬は脳内でもミクログリアが最も多い脳部位の一つであり、脳内炎症を通しての影響を強く受ける。本発明の神経心理学的機能改善剤は、大豆ペプチドを有効成分として含有する場合に、脳内炎症を抑制することにより、神経心理学的機能の低下が関与する疾病及び／又は症状の改善に寄与すると考えられる。 Cerebral inflammation refers to a state in which inflammatory cytokines are excessively released in the brain beyond the physiological range and duration. It has been pointed out that intracerebral inflammation is involved in the onset process of Alzheimer's disease, depression, schizophrenia, chronic fatigue syndrome, and the like. Microglia, which are glial cells that support nerve cells, are thought to play a central role in brain inflammation because they produce and release inflammatory cytokines in response to infection, tissue damage, neurodegeneration, and the like. Normal microglia function is essential for maintaining brain homeostasis, but hyperactivated microglia release large amounts of pro-inflammatory cytokines, leading to intracerebral inflammation. Microglia are also activated by the accumulation of Aβ and tau proteins, which are important in the pathology of Alzheimer's disease. The hippocampus, a memory center, is one of the brain regions with the highest number of microglia in the brain and is strongly affected through intracerebral inflammation. The neuropsychological function-improving agent of the present invention, when containing soybean peptide as an active ingredient, suppresses brain inflammation, thereby improving diseases and / or symptoms associated with deterioration of neuropsychological function. considered to contribute.
　脳由来神経栄養因子（Ｂｒａｉｎ－Ｄｅｒｉｖｅｄ　Ｎｅｕｒｏｔｒｏｐｈｉｃ　Ｆａｃｔｏｒ：ＢＤＮＦ）は、記憶や学習に代表される高次脳機能発現において根幹的な役割を果たす神経栄養因子の１つである。ＢＤＮＦは、脳・神経系において多彩な生理機能発現に関わることから、アルツハイマー病やうつ病等を含む様々な脳・神経系の疾患において、ＢＤＮＦ発現の低下が認められることが知られている。また、ＢＤＮＦ発現を増加させることにより、うつ病等の精神疾患により低下した脳機能を改善する可能性を示す結果も知られている。以上より、ＢＤＮＦの量を増加させる物質が、上記アルツハイマーやうつ病の予防及び／又は改善に寄与する可能性がある。本発明の神経心理学的機能改善剤では、大豆ペプチド及びＧＡＢＡを併用することで、脳内のＢＤＮＦの発現を高めることができ、神経心理学的機能の低下が関与する疾病及び／又は症状の改善に寄与すると考えられる。 Brain-Derived Neurotrophic Factor (BDNF) is one of the neurotrophic factors that plays a fundamental role in the expression of higher brain functions represented by memory and learning. Since BDNF is involved in the expression of various physiological functions in the brain and nervous system, it is known that BDNF expression is reduced in various brain and nervous system diseases including Alzheimer's disease and depression. In addition, results are also known that show the possibility of improving brain function that has been reduced due to mental disorders such as depression by increasing BDNF expression. From the above, substances that increase the amount of BDNF may contribute to the prevention and/or improvement of Alzheimer's disease and depression. In the neuropsychological function improving agent of the present invention, by using soybean peptide and GABA in combination, the expression of BDNF in the brain can be enhanced, and the disease and / or symptoms associated with the deterioration of neuropsychological function It is thought that this will contribute to improvement.
　前記飲食品組成物としては、神経心理学的機能の低下等によって引き起こされる各種症状又は疾患等の予防、改善又は治療をコンセプトとする機能性表示食品、病者用食品、特定保健用食品等が挙げられる。 Examples of the food and drink compositions include foods with functional claims, foods for sick people, foods for specified health uses, etc., based on the concept of prevention, improvement or treatment of various symptoms or diseases caused by deterioration of neuropsychological functions. mentioned.
　前記飲食品組成物として、液状、ペースト状、固体、粉末等の形態を問わず、錠菓、流動食、飼料（ペット用を含む）等のほか、例えば、小麦粉製品、即席食品、農産加工品、水産加工品、畜産加工品、乳・乳製品、油脂類、基礎調味料、複合調味料・食品類、冷凍食品、菓子類、飲料類、これら以外の市販食品等が挙げられる。 The food and drink composition may be liquid, paste, solid, powder, or the like, and may be tablet confectionery, liquid food, feed (including pet food), or, for example, wheat flour products, instant foods, processed agricultural products, etc. , processed marine products, processed livestock products, milk and dairy products, oils and fats, basic seasonings, compound seasonings/foods, frozen foods, confectionery, beverages, and other commercially available foods.
　例えば、前記小麦粉製品として、パン、マカロニ、スパゲッティ、めん類、ケーキミックス、から揚げ粉、パン粉等が挙げられる。前記即席食品として、即席めん、カップめん、レトルト・調理食品、調理缶詰め、電子レンジ食品、即席スープ・シチュー、即席みそ汁・吸い物、スープ缶詰め、フリーズ・ドライ食品、その他の即席食品等が挙げられる。例えば、前記農産加工品として、農産缶詰め、果実缶詰め、ジャム・マーマレード類、漬物、煮豆類、農産乾物類、シリアル（穀物加工品）等が挙げられる。前記水産加工品として、水産缶詰め、魚肉ハム・ソーセージ、水産練り製品、水産珍味類、つくだ煮類等が挙げられる。前記畜産加工品として、畜産缶詰め、ペースト類、畜肉ハム、ソーセージ等が挙げられる。 For example, the flour products include bread, macaroni, spaghetti, noodles, cake mixes, fried chicken powder, and bread crumbs. Examples of the instant foods include instant noodles, cup noodles, retort/cooked foods, cooked canned foods, microwave oven foods, instant soups/stews, instant miso soups/soups, canned soups, freeze-dried foods, and other instant foods. Examples of processed agricultural products include canned agricultural products, canned fruits, jams and marmalades, pickles, boiled beans, dried agricultural products, and cereals (processed grain products). Examples of the processed marine products include canned marine products, fish hams and sausages, fish paste products, marine delicacies, and tsukudani. Examples of the processed livestock products include canned livestock products, pastes, livestock hams, sausages, and the like.
　例えば、前記乳・乳製品として、加工乳、乳飲料、ヨーグルト類、乳酸菌飲料類、チーズ、アイスクリーム類、調製粉乳類、クリーム、その他の乳製品等が挙げられる。前記油脂類として、バター、マーガリン類、植物油等が挙げられる。前記基礎調味料として、しょうゆ、みそ、ソース類、トマト加工調味料、みりん類、食酢類等が挙げられる。前記複合調味料・食品類として、調理ミックス、カレーの素類、たれ類、ドレッシング類、めんつゆ類、スパイス類、その他の複合調味料等が挙げられる。前記冷凍食品として、素材冷凍食品、半調理冷凍食品、調理済冷凍食品等が挙げられる。 For example, the milk/dairy products include processed milk, milk drinks, yogurts, lactic acid beverages, cheese, ice creams, prepared milk powders, cream, and other dairy products. Examples of the fats and oils include butter, margarines, and vegetable oils. Examples of basic seasonings include soy sauce, miso, sauces, processed tomato seasonings, mirin, and vinegar. Examples of the complex seasonings/foods include cooking mixes, curry bases, sauces, dressings, noodle soups, spices, and other complex seasonings. Examples of the frozen food include material frozen food, semi-cooked frozen food, and cooked frozen food.
　例えば、前記菓子類として、グミ、ゼリー、キャラメル、キャンディー、チューインガム、チョコレート、クッキー、ビスケット、ケーキ、パイ、スナック、クラッカー、和菓子、米菓子、豆菓子、デザート菓子、その他の菓子等が挙げられる。前記飲料類として、炭酸飲料、天然果汁、果汁飲料、果汁入り清涼飲料、果肉飲料、果粒入り果実飲料、野菜系飲料、豆乳、豆乳飲料、コーヒー飲料、お茶飲料、粉末飲料、濃縮飲料、スポーツ飲料、栄養飲料、アルコール飲料、その他の嗜好飲料等が挙げられる。上記以外の市販食品として、ベビーフード、ふりかけ、お茶潰けのり等が挙げられる。 For example, the confectionery includes gummy, jelly, caramel, candy, chewing gum, chocolate, cookie, biscuit, cake, pie, snack, cracker, Japanese confectionery, rice confectionery, bean confectionery, dessert confectionery, and other confectionery. Examples of the beverages include carbonated drinks, natural fruit juices, fruit juice drinks, soft drinks containing fruit juice, pulp drinks, fruit drinks containing fruit, vegetable drinks, soy milk, soy milk drinks, coffee drinks, tea drinks, powdered drinks, concentrated drinks, and sports drinks. Beverages, nutritional beverages, alcoholic beverages, other beverages for taste, and the like. Examples of commercial foods other than the above include baby food, furikake (furikake), and tea-soaked seaweed.
　また、本発明の神経心理学的機能改善剤は、前記のような神経心理学的機能の低下等が関与する疾病、疾患や症状のための予防、改善及び／又は治療のための、ヒト用若しくは動物用の医薬品、医薬部外品等の医薬組成物の有効成分として、他の医薬成分とともに配合して使用可能である。 In addition, the neuropsychological function-improving agent of the present invention is for human use for prevention, improvement and / or treatment of diseases, diseases and symptoms involving deterioration of neuropsychological functions as described above. Alternatively, it can be used as an active ingredient of pharmaceutical compositions such as veterinary medicines and quasi-drugs by blending it with other pharmaceutical ingredients.
　本発明の神経心理学的機能改善剤を有効成分として含有する前記医薬組成物は、経口投与及び非経口投与の何れでもよいが、経口投与が望ましい。経口投与の剤形として、錠剤、カプセル剤、トローチ剤、シロップ剤、顆粒剤、散剤、軟膏等が挙げられる。
　製剤化に際しては、通常製剤化に用いられている賦形剤、ｐＨ調整剤、着色剤、矯味剤等の成分を用いることができる。また、公知の又は将来的に見出される筋合成促進作用を有する機能性成分を併用することも可能である。 The pharmaceutical composition containing the neuropsychological function-improving agent of the present invention as an active ingredient may be administered orally or parenterally, but is preferably administered orally. Dosage forms for oral administration include tablets, capsules, troches, syrups, granules, powders, ointments and the like.
For formulation, ingredients such as excipients, pH adjusters, colorants, and corrigents that are commonly used for formulation can be used. In addition, it is possible to use functional ingredients that are known or will be found in the future to promote muscle synthesis.
　本発明の神経心理学的機能改善剤の投与頻度や投与量は、投与対象、年齢、性別、状態等に応じて適宜調整すればよく、所望の効果を発揮できる量の大豆ペプチド及びＧＡＢＡを投与対象へ投与できればよい。
　例えば、前記医薬組成物における大豆ペプチド及びＧＡＢＡの合計含有量は、製剤の最終物に対し、少なくとも０．００１質量％以上であることが好ましい。
　大豆ペプチド及びＧＡＢＡの摂取量又は投与量は、投与対象の生物種、年齢、症状等により異なるが、通常、０．００１～８０００ｍｇ／ｋｇ体重／日、好ましくは０．０１～６０００ｍｇ／ｋｇ体重／日、最も好ましくは０．０１～４０００ｍｇ／ｋｇ体重／日であり、１日１回から３回に分けて投与してもよい。ヒトに対する摂取量又は投与量は、０．００１～１５００ｍｇ／ｋｇ体重／日、好ましくは０．０１～１０００ｍｇ／ｋｇ体重／日、最も好ましくは０．０１～５００ｍｇ／ｋｇ体重／日である。 The administration frequency and dosage of the agent for improving neuropsychological function of the present invention may be appropriately adjusted according to the subject, age, sex, condition, etc., and the amount of soybean peptide and GABA that can exhibit the desired effect is administered. It suffices if it can be administered to a subject.
For example, the total content of soybean peptide and GABA in the pharmaceutical composition is preferably at least 0.001% by mass or more relative to the final product.
The intake or dosage of soybean peptide and GABA varies depending on the species, age, symptoms, etc. of the administration target, but is usually 0.001 to 8000 mg/kg body weight/day, preferably 0.01 to 6000 mg/kg body weight/day. daily, most preferably 0.01 to 4000 mg/kg body weight/day, and may be administered in 1 to 3 divided doses per day. The intake or dosage for humans is 0.001-1500 mg/kg body weight/day, preferably 0.01-1000 mg/kg body weight/day, most preferably 0.01-500 mg/kg body weight/day.
　なお、大豆ペプチド及びＧＡＢＡのヒトへの投与の際の用量は、『体表面積に基づく動物からのＨＥＤ（Ｈｕｍａｎ　Ｅｑｕｉｖａｌｅｎｔ　Ｄｏｓｅ）交換』（例えば、以下の参考文献１を参照）による換算式から算出することができる。
  ＨＥＤ＝［動物への投与量（ｍｇ／ｋｇ体重）］×｛［動物の体重（ｋｇ）］÷［ヒトの体重（ｋｇ）］｝０．３３
  ヒトの体重：６０ｋｇ
  ラットの体重：２００ｇ
参考文献１：Ｇｕｉｄａｎｃｅ　ｆｏｒ　Ｉｎｄｕｓｔｒｙ，　Ｅｓｔｉｍａｔｉｎｇ　ｔｈｅ　Ｍａｘｉｍｕｍ　Ｓａｆｅ　Ｓｔａｒｔｉｎｇ　Ｄｏｓｅ　ｉｎ　Ｉｎｉｔｉａｌ　Ｃｌｉｎｉｃａｌ　Ｔｒｉａｌｓ　ｆｏｒ　Ｔｈｅｒａｐｅｕｔｉｃｓ　ｉｎ　Ａｄｕｌｔ　Ｈｅａｌｔｈｙ　Ｖｏｌｕｎｔｅｅｒｓ，　Ｖ．　ＳＴＥＰ　２：ＨＵＭＡＮ　ＥＱＵＩＶＡＬＥＮＴ　ＤＯＳＥ　ＣＡＬＣＵＬＡＴＩＯＮ，　Ｊｕｌｙ　２００５，　Ｐｈａｒｍａｃｏｌｏｇｙ　ａｎｄ　Ｔｏｘｉｃｏｌｏｇｙ，　ｐ．６－７　／　Ｕ．Ｓ．　Ｄｅｐａｒｔｍｅｎｔ　ｏｆ　Ｈｅａｌｔｈ　ａｎｄ　Ｈｕｍａｎ　Ｓｅｒｖｉｃｅｓ，　Ｆｏｏｄ　ａｎｄ　Ｄｒｕｇ　Ａｄｍｉｎｉｓｔｒａｔｉｏｎ，　Ｃｅｎｔｅｒ　ｆｏｒ　Ｄｒｕｇ　Ｅｖａｌｕａｔｉｏｎ　ａｎｄ　Ｒｅｓｅａｒｃｈ　（ＣＤＥＲ）　  The dose of soybean peptide and GABA when administered to humans is calculated from the conversion formula by "HED (Human Equivalent Dose) exchange from animals based on body surface area" (see, for example, the following reference 1). be able to.
HED = [Dose to animal (mg/kg body weight)] x {[Animal body weight (kg)] ÷ [Human body weight (kg)]} 0.33
Human weight: 60kg
Rat weight: 200g
Reference 1: Guidance for Industry, Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, V.E. STEP 2: HUMAN EQUIVALENT DOSE CALCULATION, July 2005, Pharmacology and Toxicology, p. 6-7 / U.S.A. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER)
　以下、実施例を挙げて本発明を更に具体的に説明するが、本発明はこれらの実施例に限定されるものではない。 The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.
〔実施例１〕大豆ペプチドの調製
　以下のようにして、大豆ペプチドを調製した。すなわち、０．５ｋｇの大豆分離タンパク（ＳＰＩ、スプロ６６１、デュポン株式会社）を４．５ｋｇの水に懸濁・溶解させた。得られた混合液を攪拌しながら６０℃に加温し、ｐＨ７．０（±０．１）になるように１０Ｍ 水酸化ナトリウム溶液を添加した後、サモアーゼ（登録商標）ＰＣ１０Ｆ（天野エンザイム株式会社製）を５ｇ添加し、６０℃にて攪拌しながら５時間反応させた。反応中、３０分毎に、ｐＨを測定し、ｐＨ７．０（±０．１）になるように１０Ｍ水酸化ナトリウム溶液を添加した。反応終了後、反応液の温度を９０℃に上げ、そのまま１時間保温し、酵素を失活させた後スプレードライヤーにて乾燥し、大豆ペプチド粉末（Ｓｏｙｌａｘ）を得た。 [Example 1] Preparation of soybean peptide A soybean peptide was prepared as follows. That is, 0.5 kg of isolated soybean protein (SPI, Spro 661, DuPont) was suspended and dissolved in 4.5 kg of water. The resulting mixture was heated to 60° C. with stirring, and 10 M sodium hydroxide solution was added to adjust the pH to 7.0 (±0.1). ) was added, and the reaction was allowed to proceed for 5 hours while stirring at 60°C. During the reaction, the pH was measured every 30 minutes, and 10M sodium hydroxide solution was added to adjust the pH to 7.0 (±0.1). After completion of the reaction, the temperature of the reaction solution was raised to 90° C. and maintained for 1 hour to deactivate the enzyme, followed by drying with a spray dryer to obtain soybean peptide powder (Soylax).
　以下の測定条件により、大豆ペプチド粉末（Ｓｏｙｌａｘ）中に含まれるデカペプチドＬＳＳＴＱＡＱＱＳＹ（配列番号１；Ｓｏｙ－ｄｅｐｒｅｓｔａｔｉｎ）の含有量を測定した。
＜ＬＣ－ＭＳ／ＭＳ分析条件＞
  ＨＰＬＣ装置及び質量分析装置は、それぞれＡｌｌｉａｎｃｅ　２６９５　ＨＰＬＣシステム（Ｗａｔｅｒｓ）及び３２００　Ｑ　Ｔｒａｐ（株式会社エービー・サイエックス）を使用した。カラムはＣａｐｃｅｌｌ ＰＡＫ　Ｃ１８　ＵＧ８０（２．０×１５０ｍｍ，５μｍ）（株式会社大阪ソーダ製）を使用した。溶離液は、Ａ液：０．１ｖ／ｖ％ギ酸水、Ｂ液：０．１ｖ／ｖ％ギ酸含有アセトニトリルを用い、グラジエント条件を０分～１５分（０～７０ｖ／ｖ％Ｂ）→１５分～２０分（７０ｖ／ｖ％Ｂ～７０ｖ／ｖ％Ｂ）→２０分～２５分（７０ｖ／ｖ％Ｂ～１００ｖ／ｖ％Ｂ）→２５分～３５分（１００ｖ／ｖ％Ｂ）→３５分～３５．０１分（１００～０ｖ／ｖ％Ｂ）ｖ／ｖ％Ｂ）→１０分～１０．０１分（１００ｖ／ｖ％Ｂ～１０ｖ／ｖ％Ｂ）→１０．０１分～１１分（１０ｖ／ｖ％Ｂ）とした。流速は０．２ｍＬ／分とした。検出方法にはＭＲＭ法（多重反応モニタリング）を用い、イオン化法はＥＳＩ（ポジティブモード）で行い、プレカーサーイオン：１１１２．７（ｍ／ｚ）、プロダクトイオン：１０１．１（ｍ／ｚ）で検出した。
＜試薬類＞
　デカペプチドＬＳＳＴＱＡＱＱＳＹ（配列番号１）の標準品はＦｍｏｃ法により合成し、逆相ＨＰＬＣにより精製した。ペプトン水（Ｂａｃｔｏ　ｐｅｐｔｏｎｅの０．１％水溶液）に溶解し検量線を作成した。
＜サンプル＞
　製造した大豆ペプチドをペプトン水に１０ｍｇ／ｍｌの濃度に溶解し、１０μＬを注入して分析した。 The content of decapeptide LSSTQAQQSY (SEQ ID NO: 1; Soy-deprestatin) contained in soybean peptide powder (Soylax) was measured under the following measurement conditions.
<LC-MS/MS analysis conditions>
Alliance 2695 HPLC system (Waters) and 3200 Q Trap (AB Sciex Co., Ltd.) were used as the HPLC device and the mass spectrometer, respectively. Capcell PAK C18 UG80 (2.0×150 mm, 5 μm) (manufactured by Osaka Soda Co., Ltd.) was used as the column. Eluent, A solution: 0.1 v / v% formic acid water, B solution: acetonitrile containing 0.1 v / v% formic acid, gradient conditions from 0 minutes to 15 minutes (0 to 70 v / v% B) → 15 Minutes to 20 minutes (70v/v%B to 70v/v%B) → 20 minutes to 25 minutes (70v/v%B to 100v/v%B) → 25 minutes to 35 minutes (100v/v%B) → 35 minutes to 35.01 minutes (100 to 0 v/v% B) v/v% B) → 10 minutes to 10.01 minutes (100 v/v% B to 10 v/v% B) → 10.01 minutes to 11 minutes (10 v/v % B). The flow rate was 0.2 mL/min. The MRM method (multiple reaction monitoring) is used as the detection method, the ionization method is performed in ESI (positive mode), and precursor ions: 1112.7 (m/z) and product ions: 101.1 (m/z) are detected. did.
<Reagents>
A standard of the decapeptide LSSTQAQQSY (SEQ ID NO: 1) was synthesized by the Fmoc method and purified by reverse-phase HPLC. It was dissolved in peptone water (0.1% aqueous solution of Bacto peptone) to create a calibration curve.
<Sample>
The prepared soybean peptide was dissolved in peptone water to a concentration of 10 mg/ml, and 10 μL was injected for analysis.
　定量した結果、製造した大豆ペプチド粉末（Ｓｏｙｌａｘ）中のデカペプチドＬＳＳＴＱＡＱＱＳＹの濃度は０．９７ｍｇ／ｇであった。 As a result of quantification, the concentration of decapeptide LSSTQAQQSY in the produced soybean peptide powder (Soylax) was 0.97 mg/g.
〔実施例２〕大豆ペプチド粉末（Ｓｏｙｌａｘ）、ＧＡＢＡ及びこれらを併用した場合の効果の比較
　８週齢のＳｌｃ：ｄｄＹマウス（日本エスエルシー株式会社）に、大豆ペプチド粉末（Ｓｏｙｌａｘ）を１０ｍｇ／ｋｇＢＷ、ＧＡＢＡ（γ-アミノ酪酸、株式会社公知貿易）０．０２５ｍｇ／ｋｇＢＷ、Ｓｏｙｌａｘ５ｍｇ／ｋｇＢＷとＧＡＢＡ０．０２５ｍｇ／ｋｇＢＷになるように混合した混合粉末を水に溶解し、胃ゾンデで投与した。なお対照群には溶媒（水）をゾンデ投与した。 [Example 2] Comparison of the effects of soybean peptide powder (Soylax), GABA, and their combined use Eight-week-old Slc:ddY mice (Japan SLC Co., Ltd.) were given soybean peptide powder (Soylax) at 10 mg/kg BW. , GABA (γ-aminobutyric acid, known trade Co., Ltd.) 0.025 mg/kg BW, Soylax 5 mg/kg BW and GABA 0.025 mg/kg BW. To the control group, a solvent (water) was administered to the sonde.
　投与４５分後、ネズミの尾を水平に設置した棒にテープで固定することでネズミを吊り下げて、吊るした直後からネズミの様子の観測を開始し、６分間中の無動時間を計測し、総計測時間に占める無動時間の割合（％）を、無動時間（秒）／３６０（秒）×１００の計算式により算出した。なお、抗うつ効果のある物質を投与すると、この無動の時間が減少する。そのため、無動時間の減少が見られた場合、抗うつ様作用ありとして評価することができる。無動状態は絶望状態と考えられ、無動時間の減少は絶望状態の改善、すなわち意欲向上の指標ともなる。 Forty-five minutes after administration, the mouse was suspended by fixing its tail to a horizontally placed rod with tape, and immediately after hanging, the state of the mouse was observed, and the immobility time during the 6-minute period was measured. , The ratio (%) of motionless time to the total measured time was calculated by the formula: motionless time (seconds)/360 (seconds) x 100. In addition, administration of substances with antidepressant effects reduces this immobility time. Therefore, when a decrease in immobility time is observed, it can be evaluated as having an antidepressant-like effect. A state of immobility is considered to be a state of despair, and a decrease in the period of immobility is an index of improvement of the state of despair, that is, improvement of motivation.
　結果を図２に示した。
　無動時間の割合は、対照群が約１３．７％であったのに対して、Ｓｏｙｌａｘ単独では約１４．１％でほぼ同じであり、Ｓｏｙｌａｘには抗うつ作用は見られなかった。
　一方、ＧＡＢＡ単独での無動時間は０．０２５ｍｇ／ｋｇＢＷで８．２％となり、ＧＡＢＡには抗うつ作用は見られた。
　これに対して、Ｓｏｙｌａｘ５ｍｇ／ｋｇＢＷとＧＡＢＡ０．０２５ｍｇ／ｋｇＢＷとを含有した場合の無働時間は３．２％となり、ＧＡＢＡが有する抗うつ作用がＳｏｙｌａｘによってより促進されたことがわかる。また、Ｓｏｙｌａｘには、１０ｍｇ／ｋｇＢＷでも抗うつ作用が見られないことから、本発明の大豆ペプチドとＧＡＢＡとを併用した場合に見られる抗うつ作用は、本発明者らが初めて見出した相乗効果であると考える。 The results are shown in FIG.
The rate of immobility time was about 13.7% in the control group, while that of Soylax alone was about 14.1%, which was almost the same, and Soylax had no antidepressant effect.
On the other hand, the immobility time with GABA alone was 8.2% at 0.025 mg/kg BW, indicating that GABA has an antidepressant effect.
On the other hand, when Soylax 5 mg/kg BW and GABA 0.025 mg/kg BW were contained, the non-work time was 3.2%, indicating that the antidepressant effect of GABA was enhanced by Soylax. In addition, since Soylax does not show an antidepressant effect even at 10 mg/kg BW, the antidepressant effect seen when the soybean peptide of the present invention and GABA are used in combination is a synergistic effect that the present inventors have discovered for the first time. I believe that.
　なお、前記のように、単独では抗うつ作用がない大豆ペプチドが、ＧＡＢＡと併用した場合に相乗効果を発揮するメカニズムについて、詳細は不明であるが、本発明者らは、大豆ペプチドを摂取させたマウスの脳内のインターロイキン－６量を調べることで、大豆ペプチドとには抗脳内炎症効果を有することを確認している。
　近年の研究結果から、脳内炎症を含む神経炎症は、アルツハイマー型認知症等の中枢神経疾患の発症や進行に深く関わっていることが明らかになっており（例えば、ＢＭＣ Ｎｅｕｒｏｓｃｉｅｎｃｅ　２０、１３（２０１９）「Amyloid-βplaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer’s disease」）、さらに、反復ストレスによって引き起こされる脳内炎症が抑うつの誘導に深く関わっていることも明らかにされている（例えば、Ｎｅｕｒｏｎ　９９、４６４（２０１８）「The innate immune receptors TLR2/4 mediate repeated social defeat stress-induced social avoidance through prefrontal microglial activation」）。脳をはじめとする中枢神経組織では、免疫を担うミクログリアが主に炎症反応を引き起こすこと、そして活性型ミクログリアが産生するＩＦＮγ, ＩＬ１β, ＩＬ－６, ＴＮＦ－α等のサイトカインは単独で神経新生を抑制することが知られている（例えば、日本薬理学雑誌（Folia Pharmacol. Jpn.）140，216-220頁（2012）、精神神経学雑誌（2012）114巻2号、124-133頁）。
　したがって、本発明の神経心理学的機能改善剤では、大豆ペプチドを含有することで、脳内炎症のような神経炎症を抑えることにより、ＧＡＢＡが奏する抗うつ効果がより顕著に発揮された可能性があると考えられる。また、大豆ペプチドは、前記のように脳内炎症を抑える効果があることから、本発明の神経心理学的機能改善剤には、うつ病や統合失調症等の機能性精神疾患に加えて、アルツハイマー病やパーキンソン病のような神経変性疾患にも有効であると考えられる。 As described above, the mechanism by which soybean peptide, which has no antidepressant effect by itself, exerts a synergistic effect when used in combination with GABA, is unknown in detail. By examining the amount of interleukin-6 in the brain of a mouse, it was confirmed that soybean peptide has an anti-inflammatory effect in the brain.
Recent research results have revealed that neuroinflammation, including intracerebral inflammation, is deeply involved in the onset and progression of central nervous system diseases such as Alzheimer's disease (e.g., BMC Neuroscience 20, 13 (2019 ) "Amyloid-βplaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer's disease"). (eg, Neuron 99, 464 (2018) "The innate immune receptors TLR2/4 mediate repeated social defeat stress-induced social avoidance through prefrontal microglial activation"). In the central nervous system, including the brain, microglia, which are responsible for immunity, mainly cause inflammatory reactions, and cytokines such as IFNγ, IL1β, IL-6, and TNF-α produced by active microglia independently induce neurogenesis. It is known to suppress (for example, Folia Pharmacol. Jpn. 140, pp. 216-220 (2012), Psychiatry and Neurology (2012) Vol. 114, No. 2, pp. 124-133).
Therefore, in the neuropsychological function improving agent of the present invention, by containing soybean peptide, neuroinflammation such as intracerebral inflammation is suppressed, so that the antidepressant effect of GABA may have been exhibited more remarkably. It is thought that there is In addition, since soybean peptide has the effect of suppressing inflammation in the brain as described above, the neuropsychological function improving agent of the present invention is useful for functional psychiatric disorders such as depression and schizophrenia. It is also believed to be effective in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
〔実施例３〕Ｓｏｙｌａｘ及びＧＡＢＡの投与が脳内脳由来神経栄養因子（ｍａｔｕｒｅ　ＢＤＮＦ）量に及ぼす影響
　実施例２と同様に、Ｓｏｙｌａｘ１０ｍｇ／ｋｇＢＷ（単独）、ＧＡＢＡ０．０２５ｍｇ／ｋｇＢＷ（単独）、さらにＳｏｙｌａｘ　５ｍｇ／ｋｇＢＷ及びＧＡＢＡ０．０２５ｍｇ／ｋｇＢＷとなるように混合した後マウスに胃ゾンデ投与した。対照群には水を胃ゾンデ投与した。投与してから４５分後、脳を採取し、－８０℃で凍結保存した。凍結保存した脳を解凍し、ＲＩＰＡバッファー（プロテアーゼインヒビターカクテル含有）１．５ｍｌ中でホモジナイズし、遠心分離（２５，０００×ｇ，１０ｍｉｎ，４℃）した上清中のｍａｔｕｒｅ　ＢＤＮＦ量を、Ｈｕｍａｎ/Ｍｏｕｓｅ　ＢＤＮＦ　ＤｕｏＳｅｔ　ＥＬＩＳＡ（Ｒ＆Ｄシステムズ）を用いて測定した。ｍａｔｕｒｅ　ＢＤＮＦの値は、タンパク質量あたりの濃度で算出した。得られた結果を図３に示す。
　その結果、対照群のｍａｔｕｒｅ　ＢＤＮＦ値は５３７ｐｇ／ｍｇ　ｐｒｏｔｅｉｎ、Ｓｏｙｌａｘ単独投与群のｍａｔｕｒｅ　ＢＤＮＦ値は６０５ｐｇ／ｍｇ　ｐｒｏｔｅｉｎ、ＧＡＢＡの単独投与群のｍａｔｕｒｅ　ＢＤＮＦ値は５６５ｐｇ／ｍｇ　ｐｒｏｔｅｉｎであり、Ｓｏｙｌａｘ単独投与群では対照群と比較してｍａｔｕｒｅ　ＢＤＮＦ値の増加が認められ、ＧＡＢＡ単独投与群では増加は認められなかった。これに対し、ＳｏｙｌａｘとＧＡＢＡを混合して投与した場合のｍａｔｕｒｅ　ＢＤＮＦ値は６３１ｐｇ／ｍｇ　ｐｒｏｔｅｉｎであり、対照群と比較して有意に高い値を示した。
　また、Ｓｏｙｌａｘ５ｍｇ／ｋｇＢＷとＧＡＢＡ０．０２５ｍｇ／ｋｇＢＷの混合群投与群を、Ｓｏｙｌａｘ１０ｍｇ／ｋｇＢＷ単独投与群と比較すると、Ｓｏｙｌａｘ量投与量が１／２になっているにもかかわらず、ＧＡＢＡとの混合物投与群でのｍａｔｕｒｅＢＤＮＦ量が上昇しており、相乗効果があることがわかる。
　本発明の神経心理学的機能改善剤が奏するＢＤＮＦ発現促進に関する相加効果は、本発明者らが初めて示したものであり、上記の結果に示されたｍａｔｕｒｅＢＤＮＦの脳内での長期的な増加は、微量であっても各種神経変性疾患の予防・治療に際し大きな効果があるものと考えられる。 [Example 3] Effect of administration of Soylax and GABA on the amount of brain-derived neurotrophic factor (mature BDNF) in the brain After mixing Soylax at 5 mg/kg BW and GABA at 0.025 mg/kg BW, mice were administered a gastric tube. A control group was given water via a gastric tube. Forty-five minutes after dosing, brains were harvested and stored frozen at -80°C. The cryopreserved brain was thawed, homogenized in 1.5 ml of RIPA buffer (containing protease inhibitor cocktail), and centrifuged (25,000×g, 10 min, 4° C.). Measured using the Mouse BDNF DuoSet ELISA (R&D Systems). The value of mature BDNF was calculated as the concentration per amount of protein. The results obtained are shown in FIG.
As a result, the mature BDNF value of the control group was 537 pg/mg protein, the mature BDNF value of the Soylax single administration group was 605 pg/mg protein, the mature BDNF value of the GABA single administration group was 565 pg/mg protein, and the Soylax single administration group , an increase in the mature BDNF value was observed compared to the control group, and no increase was observed in the GABA single administration group. In contrast, when Soylax and GABA were mixed and administered, the mature BDNF value was 631 pg/mg protein, which was significantly higher than that of the control group.
In addition, when comparing the mixed group administration group of Soylax 5 mg / kg BW and GABA 0.025 mg / kg BW with the Soylax 10 mg / kg BW single administration group, the Soylax dose is halved, but the mixture administration with GABA It can be seen that the amount of mature BDNF is increased in the group and that there is a synergistic effect.
The additive effect on BDNF expression promotion exhibited by the neuropsychological function-improving agent of the present invention was first shown by the present inventors, and the long-term increase in the brain of mature BDNF shown in the above results is considered to have a great effect in the prevention and treatment of various neurodegenerative diseases even in a very small amount.
　例えば、神経栄養因子ファミリーの一員であるＢＤＮＦは、記憶や学習に代表される高次脳機能発現において根幹的な役割を果たす重要な因子であり、うつ病やアルツハイマー病等の精神疾患や神経変性疾患において、ＢＤＮＦ発現レベルの低下が認められる。
　ここで、神経炎症は、アルツハイマー型認知症等の中枢神経疾患の発症や進行に深く関わっていることが明らかになっており（例えば、ＢＭＣ Ｎｅｕｒｏｓｃｉｅｎｃｅ　２０、１３（２０１９）「Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer’s disease」）、脳をはじめとする中枢神経組織では、免疫を担うミクログリアが主に炎症反応を引き起こすこと、そして活性型ミクログリアが産生するＩＦＮγ, ＩＬ１β, ＩＬ－６, ＴＮＦ－α等のサイトカインは単独で神経新生を抑制することが知られている（例えば、日本薬理学雑誌140，216-220頁（2012）、精神神経学雑誌（2012）114巻2号、124-133頁）。
　また、脳内からグリア細胞の一種である中枢神経前駆細胞（ＮＧ２グリア）を除去した遺伝子改変ラットにおいて、ミクログリアが活性化し、過剰な神経炎症が引き起こされることで、記憶や空間学習に関わる海馬の神経細胞が障害を受け、海馬組織が著しく委縮すること、そしてＮＧ２グリアが幹細胞増殖因子であるＨＧＦを供給することで、神経炎症を抑制し、海馬を保護していることも示唆されている（例えば、Ｓｃｉｅｎｔｉｆｉｃ　Ｒｅｐｏｒｔｓ　７.　４２０４１（２０１７））。
　さらには、アルツハイマー患者で海馬での神経新生が低下すること（Ｎａｔｕｒｅ ｍｅｄｉｃｉｎｅ, ２５, ５５４-５６０（２０１９））、炎症は海馬での神経新生に対して有害であること（ＰＮＡＳ, １００（２３）, １３６３２-１３６３７ （２００３））が報告されている。
　また、従来、神経細胞は胎生期、幼若期に新生され、成熟期では新生されないという考え方が主流であったが、近年では側脳室下帯や海馬歯状回といった特定の脳領域においては、成熟期においても神経幹・前駆細胞が存在し、それらが増殖、分化することにより神経細胞が新生されることが明らかにされている（Ｍｉｎｇ　ＧＬ　ｅｔ　ｌ．，　Ａｎｎｕ　Ｒｅｖ　Ｎｅｕｒｏｓｃｉ　２８：２２３－２５０（２００５））。そして、海馬歯状回で新生された神経細胞は、神経ネットワークを形成し、記憶形成に関わる等重要な役割を果たしていることが報告されている（Ａｉｍｏｎｅ　ＪＢ　ｅｔ　ａｌ．，Ｔｒｅｎｄｓ　Ｃｏｇｎ　Ｓｃｉ，１４（７）：３２５－３３７（２０１０））。最近、ＡＤが進行するにつれ、海馬における神経細胞新生が急激に低下していることが報告され、ＡＤ発症に脳神経細胞新生の低下が関わっている可能性が指摘されている（Ｍｏｒｅｎｏ－Ｊｉｍｅｎｅｚ　ＥＰ　ｅｔ　ａｌ．，Ｎａｔ　Ｍｅｄ，２５（４）：５５４－５６０（２０１９））。
　したがって、上記の結果より、本発明の神経心理学的機能改善剤は、微量のＧＡＢＡと大豆ペプチドを混合して使用することで、Ｓｏｙｌａｘのもつmature BDNF上昇効果が更に上乗せされるので、正の効果を持つことから、うつ病やアルツハイマー型認知症等の神経変性疾患の予防や改善に有効に作用することが考えられる。
  For example, BDNF, a member of the neurotrophic factor family, is an important factor that plays a fundamental role in the expression of higher brain functions represented by memory and learning. Decreased levels of BDNF expression are found in disease.
Here, it has been clarified that neuroinflammation is deeply involved in the onset and progression of central nervous system diseases such as Alzheimer's dementia (for example, BMC Neuroscience 20, 13 (2019) "Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer's disease"); Cytokines such as IFNγ, IL1β, IL-6, and TNF-α produced are known to suppress neurogenesis alone (for example, Japanese Pharmacological Journal 140, pp. 216-220 (2012), Psychiatry and Neurology Magazine (2012) Vol. 114, No. 2, pp. 124-133).
In addition, in genetically modified rats in which central nervous progenitor cells (NG2 glia), a type of glial cell, have been removed from the brain, microglia are activated and excessive neuroinflammation is induced, resulting in hippocampal involvement related to memory and spatial learning. It has also been suggested that nerve cells are damaged and the hippocampus tissue atrophies significantly, and that NG2 glia supply HGF, a stem cell growth factor, to suppress neuroinflammation and protect the hippocampus ( For example, Scientific Reports 7.42041 (2017)).
Furthermore, hippocampal neurogenesis is reduced in Alzheimer's patients (Nature medicine, 25, 554-560 (2019)), inflammation is detrimental to hippocampal neurogenesis (PNAS, 100 (23) , 13632-13637 (2003)) have been reported.
Conventionally, the mainstream idea was that neurons are generated during the embryonic and juvenile stages and not during the adult stage. , Neural stem/progenitor cells are present even in the maturation stage, and it has been clarified that neural cells are generated by their proliferation and differentiation (Ming GL et al., Annu Rev Neurosci 28: 223-250 (2005)). It has been reported that neurons generated in the hippocampal dentate gyrus form a neural network and play important roles such as being involved in memory formation (Aimone JB et al., Trends Cogn Sci, 14 ( 7): 325-337 (2010)). Recently, it has been reported that neurogenesis in the hippocampus rapidly declines as AD progresses, and it has been pointed out that the decline in brain neurogenesis may be involved in the onset of AD (Moreno-Jimenez EP et al. al., Nat Med, 25(4):554-560 (2019)).
Therefore, from the above results, the neuropsychological function improving agent of the present invention, by using a mixture of a trace amount of GABA and soybean peptide, further adds the mature BDNF raising effect of Soylax, so positive Since it is effective, it is considered that it acts effectively for prevention and improvement of neurodegenerative diseases such as depression and Alzheimer's dementia.

Claims (7)

  1. 　大豆ペプチド及びγアミノ酪酸（ＧＡＢＡ）を有効成分として含む、神経心理学的機能低下に起因する症状及び／又は疾患の予防及び／又は改善のための、神経心理学的機能改善剤。 A neuropsychological function-improving agent for the prevention and/or improvement of symptoms and/or diseases caused by decreased neuropsychological function, containing soybean peptide and γ-aminobutyric acid (GABA) as active ingredients.
  2. 　神経心理学的機能の低下に起因する症状及び／又は疾患が、アルツハイマー型認知症、うつ病、老化による記憶障害、自閉症スペクトラム障害、双極性障害、統合失調症又は慢性疲労症候群である、請求項１に記載の神経心理学的機能改善剤。 The symptoms and/or diseases resulting from decreased neuropsychological function are Alzheimer's dementia, depression, memory impairment due to aging, autism spectrum disorder, bipolar disorder, schizophrenia or chronic fatigue syndrome. The neuropsychological function improving agent according to claim 1.
  3. 　大豆ペプチドが、サーモリシン消化物である、請求項１又は２に記載の神経心理学的機能改善剤。 The neuropsychological function-improving agent according to claim 1 or 2, wherein the soybean peptide is a thermolysin digest.
  4. 　大豆ペプチドが、アミノ酸配列ＬＳＳＴＱＡＱＱＳＹ（配列番号１）から成るペプチドを含む、請求項１～３のいずれかに記載の神経心理学的機能改善剤。 The agent for improving neuropsychological function according to any one of claims 1 to 3, wherein the soybean peptide comprises a peptide consisting of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1).
  5. 　請求項１～４のいずれかに記載の神経心理学的機能改善剤を含む、神経心理学的機能改善用医薬組成物。 A pharmaceutical composition for improving neuropsychological function, comprising the agent for improving neuropsychological function according to any one of claims 1 to 4.
  6. 　請求項１～４のいずれかに記載の神経心理学的機能改善剤を含む、神経心理学的機能改善用飲食品組成物。 A food and drink composition for improving neuropsychological function, comprising the agent for improving neuropsychological function according to any one of claims 1 to 4.
  7. 　請求項１～４のいずれかに記載の神経心理学的機能改善剤を必要とする患者又は予備軍に、当該神経心理学的機能改善剤を投与する工程を含む、神経心理学的機能低下に起因する症状及び／又は疾患を予防及び／又は改善する方法。
          A step of administering the neuropsychological function-improving agent to a patient or potential patient in need of the neuropsychological function-improving agent according to any one of claims 1 to 4, for neuropsychological function deterioration A method of preventing and/or ameliorating the underlying symptoms and/or diseases.
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