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WO2022186015A1 - Agent améliorant la fonction neuropsychologique - Google Patents

Agent améliorant la fonction neuropsychologique 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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Prior art keywords
neuropsychological function
neuropsychological
improving
function
symptoms
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English (en)
Japanese (ja)
Inventor
康浩 鹿島
琢和 安田
泰治 松川
健二 長田
泰正 山田
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Uha Mikakuto Co Ltd
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Uha Mikakuto Co Ltd
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Priority to JP2023503742A priority Critical patent/JPWO2022186015A1/ja
Publication of WO2022186015A1 publication Critical patent/WO2022186015A1/fr
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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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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 OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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 or 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.

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Abstract

La présente invention concerne un agent améliorant la fonction neuropsychologique permettant de prévenir et/ou d'améliorer des symptômes et/ou des maladies provoqués par la détérioration de la fonction neuropsychologique, ledit agent contenant un peptide de soja et de l'acide γ-aminobutyrique (GABA) en tant que principes actifs. Les symptômes et/ou maladies provoqués par la détérioration de la fonction neuropsychologique comprennent la démence de type Alzheimer, la dépression, les troubles mnésiques dus au vieillissement, les troubles du spectre autistique, les troubles bipolaires, la schizophrénie ou le syndrome de fatigue chronique.
PCT/JP2022/007377 2021-03-02 2022-02-22 Agent améliorant la fonction neuropsychologique Ceased WO2022186015A1 (fr)

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WO2024117210A1 (fr) * 2022-12-01 2024-06-06 国立大学法人京都大学 Composition contenant un peptidef

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023114846A1 (fr) * 2021-12-15 2023-06-22 Digestome Therapeutics, Inc. Utilisations de peptides thérapeutiques
WO2024117210A1 (fr) * 2022-12-01 2024-06-06 国立大学法人京都大学 Composition contenant un peptidef

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