Neuropsychological function improving agent

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

Technical Field

[0001] The present invention relates to a neuropsychological function improving agent having a preventive and / or ameliorating effect on symptoms and diseases caused by the decline of neuropsychological functions such as Alzheimer-type dementia (AD) and depression. More specifically, the present invention relates to a neuropsychological function improving agent containing soybean peptide and γ-aminobutyric acid as active ingredients, which can be safely and easily ingested and can prevent and / or improve the decline of neuropsychological functions.

Background Art

[0002] In recent years, the rapid increase in the number of elderly people with dementia due to the global aging has become a major problem in increasing the social security burden. Also, even in the healthy senior population, improvement of the decline of brain function due to aging is desired. Therefore, a preventive method that does not reduce brain function, particularly cognitive function, is also socially demanded. In particular, in Japan, it is predicted that one in four people aged 65 or older will develop dementia, and more than 60% of them are estimated to have Alzheimer-type dementia (AD) (Non-Patent Document 1).

[0003] It has been clarified that in the early stage of AD, deposition of amyloid-β (Aβ), which is the main component of senile plaques in the brain, occurs. After the accumulation of Aβ, abnormal phosphorylation of Tau protein occurs, resulting in neurofibrillary tangles (NFT). This series of processes is called the amyloid cascade hypothesis (Non-Patent Document 2). And the hypothesis of intracerebral inflammation in AD, which has been proposed before, has been 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). Furthermore, in 1990, in rheumatoid patients who had been taking non-steroidal anti-inflammatory drugs (NSAIDs) for a long time, the risk of developing AD was reduced to one-sixth, and the importance of intracerebral inflammation in the development of AD was pointed out (Non-Patent Document 4).

[0004] In addition to cognitive impairment, primarily progressive memory loss, Alzheimer's disease (AD) is characterized by various behavioral and psychological symptoms (BPSD) during its course, one of the main symptoms of which is depression (Non-Patent Literature 5).

[0005] Studies have reported that patients with depression exhibit reduced hippocampal volume and impaired hippocampal function (Non-Patent Literature 6). The hippocampus is known as a brain region involved in cognitive functions such as memory and learning, but in patients with depression, 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), but in patients with depression, the HPA system is overactive, and impaired hippocampal function is considered a contributing factor.

[0006] Traditionally, the prevailing view was that nerve cells are newly generated during the embryonic and juvenile stages, and not during maturity. However, recent studies have revealed that in certain brain regions, such as the subventricular zone and the dentate gyrus of the hippocampus, nerve stem and progenitor cells exist even during maturity, and that these cells proliferate and differentiate to generate new nerve cells (Non-Patent Literature 7). Furthermore, it has been reported that nerve cells newly generated in the dentate gyrus of the hippocampus form neural networks and play important roles in memory formation (Non-Patent Literature 8). Recently, it has been reported that nerve cell generation in the hippocampus rapidly decreases as Alzheimer's disease (AD) progresses, and this may be related to the onset of AD (Non-Patent Literature 9).

[0007] In recent years, as our understanding of brain function has advanced, there has been a surge in efforts to discover substances that improve neuropsychological functions such as memory, and prevent or alleviate symptoms and diseases associated with a decline in neuropsychological function. As one example, there has been a great deal of research into whether naturally occurring substances derived from foods that can be consumed daily contain substances that improve cognitive function. For example, it has been disclosed that ingesting a compound of five amino acids consisting of arginine, citrulline, glycine, proline, and tyrosine enhances cognitive function (assessed by the Stroop test) (Patent Document 1), that oral intake of lipopolysaccharide derived from the wheat symbiotic bacterium Pantoea agglomerans significantly reduces the accumulation of Aβ peptide in the brain and improves learning function (Patent Document 2), and that ingesting chlorogenic acids, which are polyphenols found in coffee beans, potatoes, rice bran, etc., improves higher brain functions such as cognitive flexibility, executive function, and attention control (Patent Document 3).

[0008] Furthermore, gamma-aminobutyric acid (GABA) is known to be one of the most widespread and abundant neurotransmitters in the mammalian central nervous system, playing a major role in regulating brain stimuli (Patent Document 4). In addition, clinical trials have reported that oral intake of GABA has antidepressant effects and improves sleep, but since GABA cannot cross the blood-brain barrier, the mechanism of its action has remained unclear. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] Japanese Patent Publication No. 2019-112361 [Patent Document 2] Japanese Patent Publication No. 2018-199643 [Patent Document 3] Japanese Patent Publication No. 2018-39797 [Patent Document 4] Japanese Patent Application Publication No. 2-32029 [Non-patent literature]

[0010] [Non-Patent Document 1] Takeshi et al., Japanese Journal of Pharmacology, Vol. 150, pp. 141-147, 2017. [Non-Patent Document 2] Hardy JA et al.,Science,256(5054):184-185(1992) [Non-Patent Document 3] McGeer PL et al, Neurosci Lett, 79(1-2):195-200(1987) [Non-Patent Document 4] McGeer PL et al, Lancet, 335(8696):1037(1990) [Non-Patent Document 5] Katsuyoshi Mizukami, Journal of Psychiatry and Neurology, Vol. 115, No. 11, pp. 1122-1126 (2013) [Non-Patent Document 6] MacQueen GM et al., Proc Natl Acad Sci USA, 100(3):1387-1392(2003) [Non-Patent Document 7] Ming GL et l., Annu Rev Neurosci 28:223-250(2005) [Non-Patent Document 8] Aimone JB et al.,Trends Cogn Sci,14(7):325-337(2010) [Non-Patent Document 9] Moreno-Jimenez EP et al., Nat Med,25(4):554-560(2019) [Overview of the project] [Problems that the invention aims to solve]

[0011] The present invention aims to provide a neuropsychological function improving agent that has preventive and / or ameliorative effects on symptoms and diseases caused by a decline in neuropsychological function, such as Alzheimer's disease and depression.

[0012] Furthermore, the present invention aims to provide a pharmaceutical composition for improving psychological function and a food or drink composition for improving neuropsychological function, both containing the above-mentioned neuropsychological function improving agent, and a method for preventing and / or improving symptoms and / or diseases caused by reduced neuropsychological function using the above-mentioned neuropsychological function improving agent.

Means for Solving the Problems

[0013] As a result of intensive efforts to find a material that contributes to the improvement of neuropsychological function among the foods commonly consumed, the present inventors surprisingly found that when soybean peptide and GABA are used in combination, they have a synergistic effect of improving neuropsychological function, leading to the completion of the present invention.

[0014] The gist of the present invention is 〔1〕A neuropsychological function improving agent for preventing and / or improving symptoms and / or diseases caused by reduced neuropsychological function, containing soybean peptide and γ-aminobutyric acid (GABA) as active ingredients, 〔2〕The neuropsychological function improving agent according to 〔1〕 above, wherein the symptoms and / or diseases caused by reduced neuropsychological function are Alzheimer's dementia, depression, memory impairment due to aging, autism spectrum disorder, bipolar disorder, schizophrenia or chronic fatigue syndrome, 〔3〕The neuropsychological function improving agent according to 〔1〕 or 〔2〕 above, wherein the soybean peptide is a thermolysin digest, 〔4〕The neuropsychological function improving agent according to any one of 〔1〕 to 〔3〕 above, wherein the soybean peptide contains a peptide consisting of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1), 〔5〕A pharmaceutical composition for improving neuropsychological function, containing the neuropsychological function improving agent according to any one of 〔1〕 to 〔4〕 above, 〔6〕A food or drink composition for improving neuropsychological function, containing the neuropsychological function improving agent according to any one of 〔1〕 to 〔4〕 above, A method for preventing and / or improving symptoms and / or diseases caused by decreased neuropsychological function, comprising the step of administering the neuropsychological function improving agent according to any one of [1] to [4] to a patient or a reserve army who needs the neuropsychological function improving agent relates to

Effects of the Invention

[0015] According to the neuropsychological function improving agent of the present invention, the active ingredients, soybean peptide and GABA, are highly safe materials with a history of being used as food ingredients. By combining them, the effect of improving high neuropsychological function is achieved. Therefore, when the neuropsychological function improving agent of the present invention is administered to a subject who needs prevention or improvement (treatment) of a disease or condition (symptom) caused by decreased neuropsychological function, prevention or improvement (treatment) of such a disease or condition is expected without side effects.

Brief Description of the Drawings

[0016] [Figure 1] FIG. 1 is a diagram showing the core symptoms of dementia and behavioral and psychological symptoms (BPSD).<了 [Figure 2] FIG. 2 is a graph showing the results of the tail suspension test in Example 2. [Figure 3] FIG. 3 is a graph showing the results of the amount of brain-derived neurotrophic factor (mature BDNF) in the brain in Example 3.

Modes for Carrying Out the Invention

[0017] Hereinafter, specific embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments, and can be appropriately modified and implemented within the scope of the object of the present invention. Regarding parts where the description overlaps, the description may be omitted as appropriate, but it does not limit the present invention.

[0018] s The neuropsychological function improving agent of the present invention contains soy peptide and gamma-aminobutyric acid (GABA) as active ingredients and can be used to improve neuropsychological functions. In the present invention, "neuropsychological function" refers to a broad concept that includes not only general higher brain functions (hereinafter also called cognitive functions) such as intelligence, memory function, language function, attention, frontal lobe function, and executive function as shown in Table 1, but also psychological functions related to the degree of depression, anxiety, and sadness. The degree of improvement and / or enhancement of each of the above functions by taking the neuropsychological function improving agent of the present invention can be investigated by the tests shown in Table 1.

[0019] [Table 1]

[0020] Improvements in neuropsychological function include improvements in cognitive function and depressive symptoms, suppression of brain atrophy related to neuropsychological function, suppression of brain functional decline (strengthening of functional connections with the hippocampus), and improvement of nerve cell damage due to inflammation. Furthermore, symptoms and / or disorders resulting from a decline in neuropsychological function include Alzheimer's disease, depression, autism spectrum disorder, bipolar disorder, schizophrenia, or age-related conditions. Therefore, improving neuropsychological function includes addressing Alzheimer's disease, depression, age-related memory impairment, autism spectrum disorder, bipolar disorder, schizophrenia, and / or aging of brain function.

[0021] As shown in Figure 1, dementia, including Alzheimer's disease, has both core symptoms and behavioral / psychological symptoms. Core symptoms include memory impairment, disorientation, aphasia, apraxia, agnosia, and executive dysfunction. BPSD (Behavioral and Psychological Symptoms of Dementia) encompasses many symptoms, including wandering, agitation, violence, hallucinations, delusions, depression, and unhygienic behavior. These symptoms are thought to manifest in relation to the core cognitive impairment, influenced by the surrounding environment, personality, and psychological state.

[0022] [1] Soy peptide In the present invention, it is important that the soy peptide used is obtained by hydrolysis or other methods to a specific degree of degradation from soy protein. Hydrolysis can be performed on an aqueous dispersion containing soy protein. It is important that the hydrolysis of soy protein is carried out in a manner that results in a peptide mixture that provides the neuropsychological function improvement effect described in the present invention. In other words, enzymatic hydrolysis of soy protein by a protease (also called a protein-degrading enzyme) is preferred.

[0023] As for proteases, endo-proteases, which are enzymes that hydrolyze peptide bonds within proteins and peptides where amino acids are linked in a chain, into several peptides, are preferred. It is also possible to combine one or more exo-proteases, which are enzymes that sequentially cleave amino acids and peptides from the amino and carboxyl terminals located at the ends of proteins and peptides. Any type of endo-protease and exo-protease that is active in the solution environment of soy protein material can be used, and for example, proteases derived from microorganisms such as Bacillus are preferably used. Examples of proteases derived from Bacillus include "Samoase (registered trademark) PC10F" (manufactured by Amano Enzyme Co., Ltd.), "Protin SD-AY10" (manufactured by Amano Enzyme Co., Ltd.), "Protin SD-NY10" (manufactured by Amano Enzyme Co., Ltd.), and "Protamex" (manufactured by Novozymes Japan Co., Ltd.).

[0024] In particular, thermolysin digests are preferred from the viewpoint of the potency of the neuropsychological function-improving effect. Thermolysin is a known protease derived from the thermoresistant bacterium Bacillus thermoproteolyticus (EC3.4.24.4, EC3.4.24.27). Thermolysin can be used as a food additive in Japan. Commercially available thermolysin of food additive grade (for example, the aforementioned "Samoase (registered trademark) PC10F" (manufactured by Amano Enzyme Co., Ltd.)) can be used.

[0025] The substrates hydrolyzed by thermolysin are not particularly limited as long as they contain soybean beta-conglycinin (β-CG) protein. Examples include soybeans themselves, soybean meal (also called defatted soybeans) left over after extracting soybean oil, concentrated soybean protein obtained by removing sugars and ash from defatted soybeans, isolated soybean protein (Soy Protein Isolate: SPI) obtained by separating only the protein from defatted soybeans, and purified β-CG protein. The hydrolysis reaction with thermolysin is carried out under conditions that yield peptides of about 10 amino acid residues. The reaction temperature can be appropriately selected from 30-70°C, 40-70°C, 50-65°C, etc. The reaction time can be appropriately selected from about 30 minutes to 48 hours, about 1-10 hours, or about 2-8 hours, etc. The pH of the reaction can be appropriately selected from about pH 6.5-8.5 or about pH 7-8, etc. 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 (particularly around pH 7.5). Alternatively, if necessary, the thermolysin may be deactivated by heating to a temperature that deactivates it (for example, heating at a temperature above 80°C for about 5 to 60 minutes). The reaction product obtained by hydrolysis can be used as is, or, if necessary, the hydrolyzed product obtained above can be further fractionated by molecular weight using means such as gel filtration or membrane filtration, or by fractionation using adsorption properties such as adsorption resins or ion exchange resins to obtain fractions with molecular weights of 300 to 1500, preferably 500 to 1300, more preferably 700 to 1100.

[0026] In particular, from the viewpoint of producing an agent that has a high neuropsychological function-improving effect, it is preferable that the soybean peptide includes a peptide consisting of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1). The soy peptide with a known amino acid sequence as described above may be a synthetic product obtained using a known chemical synthesis method, or it may be a derivative if it provides the desired effect as a soy peptide.

[0027] [2] Gamma-aminobutyric acid (GABA) The GABA used in this invention may be isolated from natural products or obtained by industrial methods such as fermentation. However, since it has certain properties regardless of its origin, it is not limited by its origin and various types can be used. Specific examples include GABA derived from natural products such as brown rice, and GABA that has undergone fermentation by microorganisms such as lactic acid bacteria. Intermediate products containing GABA can also be used. These intermediate products are crude products obtained during the isolation and purification of GABA from natural products or fermented products, or fermented products by microorganisms such as lactic acid bacteria, and are safe for consumption. The various types of GABA described above may be used individually or in mixtures of two or more.

[0028] [3] Neuropsychological function enhancers The neuropsychological function improving agent of the present invention contains both soy peptide and GABA as active ingredients, thereby exhibiting a synergistic effect in improving neuropsychological function. Here, a synergistic effect means that a higher neuropsychological function improving effect can be obtained by using both soy peptide and GABA together than by using each of them individually. In particular, among the neuropsychological function improving agents of the present invention, the type of peptide that is most likely to exhibit the aforementioned synergistic effect is the soy peptide, which consists of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1).

[0029] In the neuropsychological function improving agent of the present invention, the ratio of soy peptide to GABA (soy peptide / GABA, weight ratio) is not limited as long as a synergistic effect in improving neuropsychological function is obtained, but is preferably 1 to 1000, more preferably 1 to 500, and even more preferably 1 to 200. Hereinafter, a mixture containing the two components soy peptide and GABA will be referred to as "soy-GABA compound".

[0030] For example, in the case of a solid neuropsychological function improving agent, the content of the soybean-GABA compound may be 100% by weight, or if additional components described later are included, it may be 20% by weight or more, preferably 40% by weight or more, more preferably 60% by weight or more, and even more preferably 80% by weight or more. Furthermore, in the case of a solution-type neuropsychological function improving agent in which the soybean-GABA compound is dispersed and dissolved in a medium such as water, the content of the soybean-GABA compound may be 2% by weight or more.

[0031] The neuropsychological function improving agent of the present invention may further contain polysaccharides as additional components, and may also contain, as necessary, components such as bulking agents, solubilizers, dispersants, suspending agents, emulsifiers, antioxidants, antibacterial agents, coloring agents, flavoring agents, and odoring agents. These additional components are not particularly limited as long as they are used in food, pharmaceuticals, or pharmaceutical components. 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, and even more preferably 20% by weight or less, based on 100% by weight of the dry weight of the "neuropsychological function improving agent".

[0032] The neuropsychological function improving agent of the present invention can be incorporated as an active ingredient and used as a food and beverage composition for the prevention and / or improvement of symptoms and / or diseases caused by a decline in neuropsychological function.

[0033] Symptoms and / or diseases resulting from a decline in neuropsychological function include Alzheimer's disease, depression, age-related memory impairment, autism spectrum disorder, bipolar disorder, and schizophrenia.

[0034] The aforementioned use refers to use in humans or non-human animals to which the product is applied, and may be therapeutic or non-therapeutic use. In this specification, "non-therapeutic" is a concept that does not include medical procedures, i.e., treatments performed on the human body. Furthermore, in this specification, “treatment” means restoring a disease or symptom that has developed in the subject area to its pre-onset state. In this specification, “prevention” means preventing or delaying the onset of a disease in the subject area, or reducing the risk of developing the disease or symptom in the subject area. In this specification, “improvement” means an improvement in a disease, symptom, or condition; prevention or delay of the worsening of a disease, symptom, or condition, or reversal, prevention, or delay of the progression of a disease or symptom.

[0035] The food and beverage composition containing the neuropsychological function improving agent of the present invention as an active ingredient can be ingested by animals, including humans, and used in methods to prevent the onset of diseases or symptoms related to a decline in neuropsychological function, or to improve or treat diseases or symptoms.

[0036] Intracerebral inflammation refers to a condition in which inflammatory cytokines are released excessively in the brain beyond physiological limits and duration. Intracerebral inflammation has been implicated in the development of Alzheimer's disease, depression, schizophrenia, chronic fatigue syndrome, and other conditions. Microglia, which are glial cells that support nerve cells, are thought to play a central role in intracerebral inflammation because they produce and release inflammatory cytokines in response to infection, tissue damage, neurodegeneration, etc. The function of normal microglia is essential for maintaining brain homeostasis, but excessively activated microglia release large amounts of inflammatory cytokines, causing intracerebral inflammation. Microglia are also activated by the accumulation of Aβ and tau proteins, which are important in the pathogenesis of Alzheimer's disease. The hippocampus, the memory center, is one of the brain regions with the highest concentration of microglia and is strongly affected by intracerebral inflammation. The neuropsychological function improving agent of the present invention, when containing soy peptide as an active ingredient, is thought to contribute to the improvement of diseases and / or symptoms involving a decline in neuropsychological function by suppressing intracerebral inflammation.

[0037] Brain-derived neurotrophic factor (BDNF) is one of the neurotrophic factors that plays a fundamental role in the expression of higher brain functions, such as memory and learning. Because BDNF is involved in the expression of various physiological functions in the brain and nervous system, it is known that decreased BDNF expression is observed in various brain and nervous system diseases, including Alzheimer's disease and depression. Furthermore, it is known that increasing BDNF expression may improve brain function that has been impaired by mental illnesses such as depression. Therefore, 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 combining soy peptide and GABA, it is possible to increase BDNF expression in the brain and is thought to contribute to the improvement of diseases and / or symptoms related to impaired neuropsychological function.

[0038] Examples of the aforementioned food and beverage compositions include functional foods, foods for sick people, and foods for specified health uses, which are based on the concept of preventing, improving, or treating various symptoms or diseases caused by a decline in neuropsychological function, etc.

[0039] The aforementioned food and beverage compositions include, regardless of whether they are in liquid, paste, solid, or powder form, tablets, liquid foods, animal feed (including pet feed), as well as, for example, wheat flour products, instant foods, processed agricultural products, processed marine products, processed livestock products, milk and dairy products, oils and fats, basic seasonings, compound seasonings and foods, frozen foods, confectionery, beverages, and other commercially available foods.

[0040] For example, wheat flour products include bread, macaroni, spaghetti, noodles, cake mix, fried chicken batter, breadcrumbs, etc. Instant foods include instant noodles, cup noodles, retort / prepared foods, canned prepared foods, microwaveable foods, instant soups / stews, instant miso soup / clear soup, canned soups, freeze-dried foods, and other instant foods. For example, processed agricultural products include canned agricultural products, canned fruit, jams / marmalades, pickles, boiled beans, dried agricultural products, cereals (grain processed products), etc. Processed marine products include canned marine products, fish ham / sausages, processed marine products, marine delicacies, tsukudani (simmered seafood), etc. Processed livestock products include canned livestock products, pastes, meat ham, sausages, etc.

[0041] For example, the milk and dairy products include processed milk, milk beverages, yogurts, lactic acid bacteria beverages, cheese, ice cream, powdered milk, cream, and other dairy products. The oils and fats include butter, margarine, and vegetable oil. The basic seasonings include soy sauce, miso, sauces, tomato-based seasonings, mirin, and vinegars. The compound seasonings and foods include cooking mixes, curry bases, sauces, dressings, noodle soup bases, spices, and other compound seasonings. The frozen foods include frozen raw materials, semi-cooked frozen foods, and cooked frozen foods.

[0042] For example, the aforementioned confectionery items include gummies, jellies, caramels, candies, chewing gum, chocolates, cookies, biscuits, cakes, pies, snacks, crackers, Japanese sweets, rice sweets, bean sweets, dessert sweets, and other confectionery. The aforementioned beverages include carbonated drinks, natural fruit juices, fruit juice drinks, fruit juice-containing soft drinks, fruit pulp drinks, fruit juice drinks with fruit pulp, vegetable drinks, soy milk, soy milk drinks, coffee drinks, tea drinks, powdered drinks, concentrated drinks, sports drinks, nutritional drinks, alcoholic beverages, and other beverages for enjoyment. Other commercially available foods include baby food, furikake (rice seasoning), and tea-soaked seaweed.

[0043] Furthermore, the neuropsychological function improving agent of the present invention can be used in combination with other pharmaceutical ingredients as an active ingredient in pharmaceutical compositions such as human or animal pharmaceuticals and quasi-drugs for the prevention, improvement, and / or treatment of diseases, disorders, and symptoms involving the aforementioned decline in neuropsychological function.

[0044] The pharmaceutical composition containing the neuropsychological function improving agent of the present invention as an active ingredient may be administered orally or parenterally, but oral administration is preferred. Examples of oral dosage forms include tablets, capsules, lozenges, syrups, granules, powders, and ointments. During formulation, ingredients such as excipients, pH adjusters, colorants, and flavorings commonly used in pharmaceutical formulations can be used. Furthermore, known or potentially discovered functional ingredients with muscle synthesis-promoting effects can also be used in combination.

[0045] The frequency and dosage of administration of the neuropsychological function improving agent of the present invention can be appropriately adjusted according to the recipient, age, sex, condition, etc., as long as an amount of soy peptide and GABA that can produce the desired effect can be administered to the recipient. For example, the total content of soy peptide and GABA in the pharmaceutical composition is preferably at least 0.001% by mass or more relative to the final formulation. The intake or dosage of soy peptide and GABA varies depending on the species, age, symptoms, etc. of the organism being administered, but is usually 0.001 to 8000 mg / kg body weight / day, preferably 0.01 to 6000 mg / kg body weight / day, most preferably 0.01 to 4000 mg / kg body weight / day, and may be administered in one to three divided doses per day. The intake or dosage for humans is 0.001 to 1500 mg / kg body weight / day, preferably 0.01 to 1000 mg / kg body weight / day, most preferably 0.01 to 500 mg / kg body weight / day.

[0046] Furthermore, the dosage of soy peptides and GABA for administration to humans can be calculated using the conversion formula based on "HED (Human Equivalent Dose) exchange from animals based on body surface area" (see, for example, Reference 1 below). HED = [Dosage to animals (mg / kg body weight)] × {[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. STEP 2:HUMAN EQUIVALENT DOSE CALCULATION, July 2005, Pharmacology and Toxicology, p.6-7 / US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER)

[0047] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. [Examples]

[0048] [Example 1] Preparation of soybean peptide Soybean peptides were prepared as follows. That is, 0.5 kg of soy protein isolate (SPI, Spro 661, DuPont) was suspended and dissolved in 4.5 kg of water. The resulting mixture was heated to 60 °C while stirring, and after adding 10 M sodium hydroxide solution to adjust the pH to 7.0 (±0.1), 5 g of Sumizyme (registered trademark) PC10F (manufactured by Amano Enzyme Inc.) was added, and the reaction was carried out at 60 °C for 5 hours while stirring. During the reaction, the pH was measured every 30 minutes, and 10 M sodium hydroxide solution was added to adjust the pH to 7.0 (±0.1). After the reaction, the temperature of the reaction solution was raised to 90 °C and kept warm for 1 hour to inactivate the enzyme, and then dried with a spray dryer to obtain soybean peptide powder (Soylax).

[0049] Under the following measurement conditions, the content of decapeptide LSSTQAQQSY (SEQ ID NO: 1; Soy-deprestatin) contained in the soybean peptide powder (Soylax) was measured. <LC-MS / MS Analysis Conditions> The HPLC apparatus and mass spectrometer used were Alliance 2695 HPLC system (Waters) and 3200 Q Trap (AB SCIEX Co., Ltd.), respectively. The column used was Capcell PAK C18 UG80 (2.0×150 mm, 5 μm) (manufactured by Osaka Soda Co., Ltd.). The eluents were Solution A: 0.1 v / v% formic acid in water and Solution B: acetonitrile containing 0.1 v / v% formic acid. The gradient conditions were 0 min - 15 min (0 - 70 v / v% B) → 15 min - 20 min (70 v / v% B - 70 v / v% B) → 20 min - 25 min (70 v / v% B - 100 v / v% B) → 25 min - 35 min (100 v / v% B) → 35 min - 35.01 min (100 - 0 v / v% B) v / v% B) → 10 min - 10.01 min (100 v / v% B - 10 v / v% B) → 10.01 min - 11 min (10 v / v% B). The flow rate was 0.2 mL / min. The MRM method (multiple reaction monitoring) was used for the detection method, and the ionization method was carried out in the ESI (positive mode). The precursor ion: 1112.7 (m / z) and product ion: 101.1 (m / z) were detected. <Reagents> Standard samples of the decapeptide LSSTQAQQSY (SEQ ID NO: 1) were synthesized by the Fmoc method and purified by reverse-phase HPLC. A calibration curve was created by dissolving them in peptone water (0.1% aqueous solution of bacto peptone). <Sample> The prepared soy peptide was dissolved in peptone water at a concentration of 10 mg / ml, and 10 μL was injected for analysis.

[0050] Quantitative analysis revealed that the concentration of the decapeptide LSSTQAQQSY in the manufactured soy peptide powder (Soylax) was 0.97 mg / g.

[0051] [Example 2] Comparison of the effects of soy peptide powder (Soylax), GABA, and their combined use. Eight-week-old Slc:ddY mice (Slc Japan Co., Ltd.) were administered a mixed powder containing 10 mg / kgBW of soy peptide powder (Soylax), 0.025 mg / kgBW of GABA (γ-aminobutyric acid, Kochi Trading Co., Ltd.), and 5 mg / kgBW of Soylax, mixed with 0.025 mg / kgBW of GABA. This mixed powder was dissolved in water and administered via gastric tube. The control group received only water via tube.

[0052] Forty-five minutes after administration, the mice were suspended by their tails taped to a horizontally positioned rod. Observation of the mice's behavior began immediately after suspension, and the period of immobility during the six minutes was measured. The percentage of immobility in relation to the total measured time was calculated using the formula: immobility (seconds) / 360 (seconds) × 100. It should be noted that administering a substance with antidepressant effects reduces this period of immobility. Therefore, a decrease in immobility can be evaluated as an indication of an antidepressant-like effect. Immobility is considered a state of despair, and a decrease in immobility is an indicator of improvement in the state of despair, i.e., an increase in motivation.

[0053] The results are shown in Figure 2. The percentage of immobility time was approximately 14.1% in the control group compared to approximately 13.7% in the group treated with Soylax alone, indicating that Soylax did not exhibit any antidepressant effects. On the other hand, the immobility period with GABA alone was 8.2% at 0.025 mg / kgBW, indicating that GABA has an antidepressant effect. In contrast, the idle time when Soylax 5 mg / kgBW and GABA 0.025 mg / kgBW were included was 3.2%, indicating that the antidepressant effect of GABA was further enhanced by Soylax. Furthermore, since no antidepressant effect was observed even at 10 mg / kgBW of Soylax, we believe that the antidepressant effect observed when the soy peptide of the present invention and GABA are used in combination is a synergistic effect that the inventors have discovered for the first time.

[0054] As mentioned above, the mechanism by which soy peptides, which do not have antidepressant effects on their own, exert a synergistic effect when used in combination with GABA is not fully understood. However, the inventors have confirmed that soy peptides have an anti-inflammatory effect on the brain by examining the amount of interleukin-6 in the brains of mice that were given soy peptides. Recent research has revealed that neuroinflammation, including intracranial inflammation, is deeply involved in the onset and progression of central nervous system diseases such as Alzheimer's disease (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"), and further, it has been revealed that intracranial inflammation caused by repeated stress is deeply involved in the induction of depression (for example, 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, are primarily responsible for triggering inflammatory responses, and cytokines such as IFNγ, IL1β, IL-6, and TNF-α produced by active microglia are known to suppress neurogenesis on their own (e.g., Folia Pharmacol. Jpn. 140, pp. 216-220 (2012), Japanese Journal of Psychiatry and Neurology (2012) Vol. 114 No. 2, pp. 124-133). Therefore, it is thought that the neuropsychological function improving agent of the present invention may have a more pronounced antidepressant effect due to the suppression of neuroinflammation such as intracranial inflammation by containing soy peptides. Furthermore, since soy peptides have the effect of suppressing intracranial inflammation as described above, it is thought that the neuropsychological function improving agent of the present invention is effective not only for functional mental disorders such as depression and schizophrenia, but also for neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

[0055] [Example 3] Effects of Soylax and GABA administration on the amount of brain-derived neurotrophic factor (mature BDNF) in the brain Similar to Example 2, Soylax 10 mg / kgBW (alone), GABA 0.025 mg / kgBW (alone), and then a mixture of Soylax 5 mg / kgBW and GABA 0.025 mg / kgBW were administered to mice via gastric tube. Water was administered to the control group via gastric tube. Forty-five minutes after administration, brains were collected and frozen at -80°C. The frozen brains were thawed, homogenized in 1.5 ml of RIPA buffer (containing a protease inhibitor cocktail), and the amount of mature BDNF in the supernatant obtained by centrifugation (25,000 × g, 10 min, 4°C) was measured using Human / Mouse BDNF DuoSet ELISA (R&D Systems). The mature BDNF value was calculated as the concentration per unit of protein. The results are shown in Figure 3. As a result, the mature BDNF level in the control group was 537 pg / mg protein, in the Soylax monotherapy group it was 605 pg / mg protein, and in the GABA monotherapy group it was 565 pg / mg protein. The Soylax monotherapy group showed an increase in mature BDNF levels compared to the control group, while the GABA monotherapy group did not show an increase. In contrast, the mature BDNF level when Soylax and GABA were administered together was 631 pg / mg protein, which was significantly higher than the control group. Furthermore, when comparing the group administered a mixture of Soylax 5 mg / kgBW and GABA 0.025 mg / kgBW with the group administered Soylax 10 mg / kgBW alone, the amount of mature BDNF increased in the group administered the mixture with GABA, even though the amount of Soylax was halved, indicating a synergistic effect. The additive effect of the neuropsychological function-improving agent of the present invention on promoting BDNF expression is something that the inventors have demonstrated for the first time. The long-term increase in mature BDNF in the brain shown in the above results is thought to have a significant effect on the prevention and treatment of various neurodegenerative diseases, even in small amounts.

[0056] For example, BDNF, a member of the neurotrophic factor family, is a crucial factor that plays a fundamental role in the expression of higher brain functions such as memory and learning, and a decrease in BDNF expression levels is observed in mental illnesses such as depression and Alzheimer's disease, as well as in neurodegenerative diseases. Here, it has become clear that neuroinflammation is deeply involved in the onset and progression of central nervous system diseases such as Alzheimer's disease (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"). In central nervous system tissue, including the brain, microglia, which are responsible for immunity, are mainly responsible for causing inflammatory responses, and cytokines such as IFNγ, IL1β, IL-6, and TNF-α produced by active microglia are known to suppress neurogenesis on their own (for example, Japanese Journal of Pharmacology 140, pp. 216-220 (2012), Japanese Journal of Psychiatry and Neurology (2012) Vol. 114 No. 2, pp. 124-133). Furthermore, in genetically modified rats from which central nervous system progenitor cells (NG2 glia), a type of glial cell, were removed from the brain, microglia were activated, leading to excessive neuroinflammation. This resulted in damage to hippocampal neurons involved in memory and spatial learning, and significant atrophy of hippocampal tissue. It has also been suggested that NG2 glia suppress neuroinflammation and protect the hippocampus by supplying HGF, a stem cell growth factor (e.g., Scientific Reports 7. 42041 (2017)). Furthermore, it has been reported that neurogenesis in the hippocampus is reduced in Alzheimer's patients (Nature medicine, 25, 554-560 (2019)), and that inflammation is harmful to neurogenesis in the hippocampus (PNAS, 100(23), 13632-13637 (2003)). Furthermore, while the prevailing view has been that nerve cells are newly generated during the embryonic and juvenile stages and not during maturity, recent studies have revealed that in certain brain regions such as the subventricular zone and the hippocampal dentate gyrus, neural stem and progenitor cells exist even during maturity, and that these cells proliferate and differentiate to generate new nerve cells (Ming GL et l., Annu Rev Neurosci 28:223-250 (2005)). It has also been reported that nerve cells newly generated in the hippocampal dentate gyrus form neural networks and play important roles 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 decreases sharply as Alzheimer's disease (AD) progresses, suggesting that a decrease in brain neurogenesis may be involved in the onset of AD (Moreno-Jimenez EP et al., Nat Med, 25(4):554-560 (2019)). Therefore, based on the above results, the neuropsychological function improving agent of the present invention, when used in combination with a small amount of GABA and soy peptide, further enhances the mature BDNF-increasing effect of Soylax, resulting in a positive effect. Thus, it is thought that it may be effective in preventing or improving neurodegenerative diseases such as depression and Alzheimer's disease.

Claims

1. This is a neuropsychological function improving agent containing soy peptide and gamma-aminobutyric acid (GABA) as active ingredients, for the prevention and / or improvement of symptoms and / or diseases caused by neuropsychological dysfunction. Soy peptides are thermolysin digests of soy protein. A neuropsychological function enhancer for which symptoms and / or diseases resulting from a decline in neuropsychological function are Alzheimer's disease or depression.

2. The neuropsychological function improving agent according to claim 1, wherein the soybean peptide comprises a peptide consisting of the amino acid sequence LSSTQAQQSY (Sequence ID 1).

3. The neuropsychological function improving agent according to claim 1 or 2, wherein the weight ratio of soy peptide to GABA is 1 to 1000.

4. A pharmaceutical composition for improving neuropsychological function, comprising a neuropsychological function improving agent according to any one of claims 1 to 3, for the prevention and / or improvement of symptoms and / or diseases caused by a decline in neuropsychological function, wherein the symptoms and / or diseases caused by a decline in neuropsychological function are Alzheimer's disease or depression.

5. A food and beverage composition for improving neuropsychological function, comprising a neuropsychological function improving agent according to any one of claims 1 to 3, wherein the symptoms and / or diseases caused by the decline in neuropsychological function are Alzheimer's disease or depression.

6. A method for preventing and / or improving symptoms and / or diseases caused by a decline in neuropsychological function, comprising the step of administering a neuropsychological function improving agent described in any one of claims 1 to 3 to a non-human animal that requires the neuropsychological function improving agent, wherein the symptoms and / or diseases caused by a decline in neuropsychological function are Alzheimer's disease or depression.

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