Neuropsychological function improving agent containing soybean peptide and / or collagen peptide

Abstract

The present invention relates to: a neuropsychological function improver which contains, as an active ingredient, a dipeptide containing proline or a tripeptide containing glycine and proline; and a neuropsychological function improver which comprises a soybean peptide and / or a collagen peptide. The present invention also relates to: a pharmaceutical composition for improving a neuropsychological function or a food or beverage composition for improving a neuropsychological function, which contains the improver; and a method for preventing and / or ameliorating a condition and / or a disease associated with the deterioration in a neuropsychological function, the method comprising a step of administering the improver to a patient or a potential patient to whom the improver is needed.

Description

[Technical Field]

[0001] The present invention relates to a neuropsychological function improver that has a preventive and / or ameliorating effect on symptoms and diseases caused by a decline in neuropsychological function, such as Alzheimer's-type dementia (AD) and depression. More specifically, the present invention relates to a neuropsychological function improver that contains safe and easily ingestible soy peptides and / or collagen peptides as active ingredients and that can prevent and / or ameliorate a decline in neuropsychological function. [Background technology]

[0002] In recent years, the rapid increase in the number of elderly people with dementia due to the global aging population has led to a major problem of increased social security burdens. Furthermore, even healthy seniors are expected to improve the age-related decline in brain function. Therefore, there is a social demand for preventive methods that do not impair brain function, particularly cognitive function. In particular, in Japan, it is predicted that one in four people aged 65 or older will develop dementia, and more than 60% of these will have Alzheimer's disease (AD) (Non-Patent Document 1).

[0003] It has been shown that the early stage of AD involves the deposition of amyloid-β (Aβ), the main component of senile plaques, in the brain. After the accumulation of Aβ, abnormal phosphorylation of tau protein occurs, resulting in the formation of neurofibrillary tangles (NFTs). This series of events is known as the amyloid cascade hypothesis (Non-Patent Document 2). The previously proposed intracerebral inflammation hypothesis of AD has also attracted renewed attention. Specifically, in 1987, activated microglia were reported to accumulate around senile plaques in autopsy brains of AD patients (Non-Patent Document 3). Furthermore, in 1990, it was reported that rheumatoid arthritis patients who had long-term nonsteroidal anti-inflammatory drugs (NSAIDs) had a one-sixth reduction in the risk of developing AD, highlighting the importance of intracerebral inflammation in the development of AD (Non-Patent Document 4).

[0004] In addition to cognitive dysfunction, primarily progressive memory impairment, AD is associated with a variety of behavioral and psychological symptoms (behavioral psychological symptoms of dementia: BPSD) over the course of the disease, one of the major symptoms of which is depression (Non-Patent Document 5).

[0005] It has been reported that patients with depression have reduced hippocampal volume and hippocampal function (Non-Patent Document 6). The hippocampus is known to be a brain region involved in cognitive functions such as memory and learning, and patients with depression not only experience mood disorders but also impaired cognitive functions, including memory. Furthermore, the hippocampus negatively regulates the function of the hypothalamus-pituitary-adrenal axis (HPA axis). However, the HPA axis is overactive in patients with depression, and reduced hippocampal function is thought to be a contributing factor.

[0006] Previously, it was generally believed that neurons are generated during the fetal and juvenile periods but not during adulthood. However, recent studies have demonstrated that neural stem and progenitor cells exist even during adulthood in specific brain regions, such as the subventricular zone and the dentate gyrus of the hippocampus, and that these cells proliferate and differentiate to generate new neurons (Non-Patent Document 7). Furthermore, it has been reported that neurons generated in the dentate gyrus of the hippocampus play important roles, such as forming neural networks and participating in memory formation (Non-Patent Document 8). Recently, it has been reported that as AD progresses, neuronal generation in the hippocampus rapidly declines, suggesting that this may be related to the onset of AD (Non-Patent Document 9).

[0007] In recent years, advances in understanding brain function have led to active research into the discovery of substances that improve neuropsychological functions such as memory and prevent or ameliorate symptoms and diseases associated with impaired neuropsychological function. For example, active research has been conducted to identify natural food-derived substances that enhance or improve cognitive function. Studies have shown that ingestion of a blend of five amino acids (arginine, citrulline, glycine, proline, and tyrosine) improves cognitive function (evaluated using the Stroop test) (Patent Document 1). Oral ingestion of lipopolysaccharide derived from the wheat symbiotic bacterium Pantoea agglomerans significantly reduces Aβ peptide accumulation in the brain and improves learning function (Patent Document 2). Ingestion of chlorogenic acids, a polyphenol found in coffee beans, potatoes, rice bran, and other foods, improves higher brain functions such as cognitive flexibility, executive function, and attention control (Patent Document 3). [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Japanese Patent Application Publication No. 2019-112361 [Patent Document 2] Japanese Patent Application Publication No. 2018-199643 [Patent Document 3] Japanese Patent Application Publication No. 2018-39797 [Non-patent literature]

[0009] [Non-Patent Document 1] Takesu et al., Japanese Pharmacological Journal, 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) Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide a neuropsychological function improving agent that has a preventive and / or ameliorating effect on symptoms and diseases caused by a decline in neuropsychological function, such as Alzheimer's disease and depression.

[0011] Another object of the present invention is to provide a pharmaceutical composition and a food and beverage composition for improving neuropsychological function that contain the neuropsychological function improving agent, as well as a method for preventing and / or improving symptoms and / or diseases caused by neuropsychological function decline using the neuropsychological function improving agent. [Means for solving the problem]

[0012] The inventors made extensive efforts to find materials from among the foodstuffs ingested on a daily basis that contribute to the improvement of neuropsychological functions. As a result, they surprisingly discovered that administration of soy peptides and / or collagen peptides has the effect of improving neuropsychological functions, leading to the completion of the present invention.

[0013] 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 dysfunction, comprising a dipeptide containing proline or a tripeptide containing glycine and proline as an active ingredient; [2] The dipeptide containing proline or the tripeptide containing glycine and proline is hydroxyproline-proline, Proline-alanine, Proline-hydroxyproline, Proline-proline, Proline-serine, glycine-proline-alanine, glycine-proline-hydroxyproline, Glycine-Proline-Glutamine, glycine-proline-proline, glycine-proline-leucine, Glycine-Proline-Serine and Glycine-Proline-Cysteine The neuropsychological function improving agent according to [1] above, which is one or more selected from the group consisting of: [3] A neuropsychological function improving agent for preventing and / or improving symptoms and / or diseases caused by neuropsychological dysfunction, comprising soybean peptide and / or collagen peptide as an active ingredient. [4] The neuropsychological function improving agent according to [3], wherein the soybean peptide and the collagen peptide are blended in a ratio and content that provides a synergistic effect. [5] The neuropsychological function improving agent according to any one of [1] to [4] above, wherein the symptom and / or disease caused by a decline in neuropsychological function is Alzheimer's disease, depression, memory impairment due to aging, autism spectrum disorder, bipolar disorder, schizophrenia, or chronic fatigue syndrome. [6] The neuropsychological function improving agent according to any one of [3] to [5], wherein the soybean peptide is a thermolysin digest. [7] The neuropsychological function improving agent according to any one of [3] to [6], wherein the soybean peptide comprises a peptide consisting of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1), and the collagen peptide is a dipeptide containing proline or a tripeptide containing glycine and proline. [8] The neuropsychological function improving agent according to any one of [3] to [7], wherein the collagen peptide has an average molecular weight of 100 to 6000. [9] The collagen peptide, hydroxyproline-proline, Proline-alanine, Proline-hydroxyproline, Proline-proline, Proline-serine, glycine-proline-alanine, glycine-proline-hydroxyproline, Glycine-Proline-Glutamine, glycine-proline-proline, glycine-proline-leucine, Glycine-Proline-Serine and Glycine-Proline-Cysteine The neuropsychological function improving agent according to any one of [3] to [8] above, which is one or more selected from the group consisting of:

[10] A pharmaceutical composition for improving neuropsychological function, comprising the neuropsychological function improving agent according to any one of [1] to [9].

[11] A food or drink composition for improving neuropsychological function, comprising the neuropsychological function improver according to any one of [1] to [9].

[12] A method for preventing and / or ameliorating symptoms and / or diseases caused by neuropsychological dysfunction, comprising a step of administering the neuropsychological function improving agent according to any one of [1] to [9] to a patient in need of the neuropsychological function improving agent or a patient at risk of developing the neuropsychological function improving agent. Regarding. [Effects of the Invention]

[0014] According to the neuropsychological function improving agent of the present invention, the active ingredients, soybean peptides and / or collagen peptides, are highly safe ingredients that have a long history of use as food ingredients and are used in the diet. Furthermore, both have the effect of improving neuropsychological function, so it is expected that the agent will be able to prevent or improve (treat) diseases or conditions (symptoms) caused by a decline in neuropsychological function in subjects who need such prevention or improvement (treatment) without causing side effects. [Brief explanation of the drawings]

[0015] [Figure 1] Figure 1 shows the core symptoms of dementia and behavioral and psychological symptoms of dementia (BPSD). [Figure 2] FIG. 2 shows how the tail suspension test was performed. [Figure 3] FIG. 3 shows the results of the tail suspension test when synthetic soy-deprestatin or soybean peptide powder (Soylax) was administered. [Figure 4] FIG. 4 shows the results of the tail suspension test when GABA, theanine, or soybean peptide powder (Soylax) was administered. [Figure 5] FIG. 5 is a graph showing the amount of IL-6 in the brain when GABA, theanine, or soybean peptide powder (Soylax) was administered. [Figure 6] FIG. 6 shows the results of the tail suspension test when collagen peptide (PCT-A) was administered. [Figure 7] FIG. 7 is a graph showing the amount of BDNF in the brain when collagen peptide (PCT-A) was administered. [Figure 8]FIG. 8 shows the amount of HGF in the brain when collagen peptide (PCT-A) was administered. [Figure 9] FIG. 9 shows the results of a tail suspension test in which soybean peptide powder (Soylax) and collagen peptide (PCT-A) were administered alone or in combination. [Figure 10] FIG. 10 shows the results of a tail suspension test carried out in Example 8 when a dipeptide derived from a collagen peptide was administered in a single dose. [Figure 11] FIG. 11 shows the results of a tail suspension test carried out in Example 8, in which a dipeptide derived from a collagen peptide was administered for 5 days. [Figure 12] FIG. 12 shows the results of a tail suspension test carried out in Example 8 when a tripeptide derived from a collagen peptide was administered in a single dose. [Figure 13] FIG. 13 shows the results of the novel object recognition test carried out in Example 9. DETAILED DESCRIPTION OF THE INVENTION

[0016] Specific embodiments of the present invention will be described in detail below, but the present invention is not limited to the following embodiments and can be implemented with appropriate modifications within the scope of the object of the present invention. Note that duplicated explanations may be omitted as appropriate, but this does not limit the present invention.

[0017] The neuropsychological function improving agent of the present invention can be used to improve neuropsychological function. In the present invention, "neuropsychological function" refers to a broad concept that includes general higher brain functions (hereinafter also referred to as cognitive functions) such as intelligence, memory function, language function, attention, frontal lobe function, and executive function, as shown in Table 1, as well as psychological functions related to the degree of depression, anxiety, and depression. The improvement and / or degree of improvement in each of the above functions due to the administration of the neuropsychological function improving agent of the present invention can be examined by the various tests shown in Table 1.

[0018] [Table 1]

[0019] Improvements in neuropsychological function include improvements in cognitive function and depressive symptoms, as well as suppression of brain atrophy and brain function decline (strengthening of functional connections with the hippocampus) related to neuropsychological function, and improvement of neuronal damage caused by inflammation. Furthermore, symptoms and / or diseases caused by a decline in neuropsychological function include Alzheimer's disease, depression, autism spectrum disorder, bipolar disorder, schizophrenia, and those associated with aging. Therefore, improving neuropsychological function includes treatment of Alzheimer's disease, depression, memory impairment due to aging, autism spectrum disorder, bipolar disorder, schizophrenia, and / or functional aging of the brain.

[0020] As shown in Figure 1, the symptoms of dementia, including Alzheimer's disease, are divided into 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 unsanitary behavior. However, it is thought that the core symptom of cognitive dysfunction is related to the surrounding environment, personality, psychological state, and other factors.

[0021] [1] Soybean peptides The agent for improving neuropsychological function of the present invention contains soybean peptide as an active ingredient. It is important that the soybean peptide used in the present invention has soybean protein decomposed to a specific degree of decomposition. The hydrolysis treatment can be carried out on an aqueous dispersion containing soybean protein. It is important that the hydrolysis of soybean protein is carried out by a method that results in a peptide mixture that can achieve the neuropsychological function improving effect of the present invention. In other words, the hydrolysis of soybean protein is preferably carried out by enzymatic decomposition using a proteolytic enzyme (also called a protease).

[0022] Suitable proteases include, for example, endoproteases, which are enzymes that hydrolyze peptide bonds within proteins or peptides in which amino acids are linked in a chain to form several peptides. It is also possible to combine one or more exoproteases, which are enzymes that sequentially cleave amino acids or peptides from the amino and carboxy terminals of proteins or peptides. Any type of endoprotease or exoprotease can be used as long as it is active in the solution environment of soy protein materials. For example, proteases derived from microorganisms such as Bacillus are preferably used. Examples of proteases derived from Bacillus include "Thermoase (registered trademark) PC10F" (manufactured by Amano Enzyme Inc.), "Protin SD-AY10" (manufactured by Amano Enzyme Inc.), "Protin SD-NY10" (manufactured by Amano Enzyme Inc.), and "Protamex" (manufactured by Novozymes Japan Co., Ltd.).

[0023] Among these, a thermolysin digest is preferred from the viewpoint of the potency of the effect of improving neuropsychological function. Thermolysin is a known protease derived from the heat-resistant bacterium Bacillus thermoproteolyticus (EC3.4.24.4). Thermolysin can be used as a food additive in Japan. Thermolysin can be commercially available, such as food additive grade (for example, the aforementioned "Thermoase (registered trademark) PC10F" (manufactured by Amano Enzyme Inc.)).

[0024] The substrate to be hydrolyzed by thermolysin is not particularly limited as long as it contains soybean beta-conglycinin (β-CG) protein. Examples include soybeans themselves, soybean pomace (meal, also known as defatted soybeans) from which soybean oil is extracted, concentrated soy protein obtained by removing sugars and ash from defatted soybeans, soy protein isolate (SPI) obtained by separating only the protein from defatted soybeans, and purified β-CG protein. The hydrolysis reaction using thermolysin is carried out under conditions that yield a peptide of approximately 10 amino acid residues. The reaction temperature can be appropriately selected from 30 to 70°C, 40 to 70°C, 50 to 65°C, etc. The reaction time can be appropriately selected from approximately 30 minutes to 48 hours, approximately 1 to 10 hours, or approximately 2 to 8 hours, etc. The pH at which the reaction is carried out can be appropriately selected from approximately 6.5 to 8.5 or approximately 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 (particularly, about pH 7.5). If necessary, thermolysin can be inactivated by heating to a temperature at which it is inactivated (for example, heating at a temperature above 80°C for about 5 to 60 minutes). The hydrolysis reaction product can be used as is, or, if necessary, the hydrolysate obtained above can be further fractionated by molecular weight using means such as gel filtration or membrane filtration, or by fractionation using the adsorption properties of adsorption resins or ion exchange resins to obtain fractions with molecular weights of 300 to 1500, preferably 500 to 1300, and more preferably 700 to 1100.

[0025] In particular, from the viewpoint of producing an agent having a high effect of improving neuropsychological functions, the soybean peptide preferably includes a peptide consisting of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1). The soybean peptides having a known amino acid sequence as described above may be synthetic products obtained by known chemical synthesis methods, or may be derivatives as long as they can produce the desired effects as soybean peptides.

[0026] [2] Collagen peptide The neuropsychological function improving agent of the present invention contains collagen peptide as an active ingredient. The collagen peptide used in the present invention can be produced by known methods from raw materials containing the above-mentioned collagen or gelatin. In the present invention, "collagen peptide" refers to a degradation product of a collagen raw material that has been hydrolyzed to have an average molecular weight of 100 to 6000. In the present invention, by producing collagen peptides with the above average molecular weight, the collagen peptides are highly absorbable into the body when orally ingested, and the desired neuropsychological function improving effect of the present invention can be exerted in vivo. Note that using the collagen raw material as is or collagen peptides with an average molecular weight exceeding 6000 is undesirable because they are poorly absorbable into the body when orally ingested, preventing the efficient exertion of the neuropsychological function improving effect.

[0027] The collagen peptide used in the present invention is preferably a collagen peptide containing a tripeptide, a dipeptide, or an oligopeptide having about 4 to 12 amino acid residues. Examples of tripeptides include Gly-Pro-X (X may be any naturally occurring amino acid residue; the same applies below), Gly-Leu-X, and the like. Examples of dipeptides include Gly-Pro, Pro-X, and X-Gly.

[0028] Among these, dipeptides containing proline or tripeptides containing glycine and proline are preferred from the viewpoint of excellent effect of improving the desired neuropsychological function. Examples of the proline-containing dipeptide include hydroxyproline (Hyp)-Pro, Pro-Ala, Pro-Hyp, Pro-Pro, and Pro-Ser. Examples of the tripeptide containing glycine and proline include Gly-Pro-Ala, Gly-Pro-Hyp, Gly-Pro-Gln, Gly-Pro-Pro, Gly-Pro-Leu, Gly-Pro-Ser, and Gly-Pro-Cys. Examples of oligopeptides include those consisting of about 4 to 12 amino acid residues, and among these, n(Gly-Pro-X)n (n represents an integer of 2 to 4) is preferred. The tripeptide, dipeptide or oligopeptide may be obtained by enzymatically digesting collagen or gelatin to contain a dipeptide, or may be further purified, isolated or synthesized from amino acids.

[0029] The total content of tripeptides, dipeptides and oligopeptides contained in the collagen peptide is preferably 5 to 25% by weight, more preferably 8 to 20% by weight, and most preferably 13 to 20% by weight. Collagen peptides with a clear amino acid sequence as described above may be synthetic products obtained using known chemical synthesis methods, or may be derivatives as long as they can produce the desired effects as collagen peptides.

[0030] Furthermore, the collagen used as the raw material for collagen peptides is not particularly limited, and any of types I to XIII collagen can be used, and mixed collagen, which is a mixture of these, can also be used. In reality, it is expected that mixed collagen obtained from various animals and fish will be used, but the type of animal (e.g., cow, pig, etc.) or fish (e.g., flounder, salmon, sardine, tuna, etc.) from which this collagen is sourced, and the part from which collagen is extracted can also be bone, skin, tendon, swim bladder (fish), etc.

[0031] Collagen can be extracted and purified from these components using commonly known methods. Specifically, for example, collagen-containing tissues such as bones, skin, tendons, and swim bladder tissues can be crushed, washed with water, extracted with a dilute salt solution, extracted with an acid or alkaline solution, or extracted with an enzyme such as pepsin, trypsin, or hyaluronidase, and then purified and obtained by known purification methods such as salting out or dialysis. It is also possible to obtain "regenerated collagen" using commonly known methods. Commercially available collagen can also be used as a raw material.

[0032] Gelatin is a water-soluble protein obtained by extracting the above-mentioned collagen with water by heating. In the present invention, gelatin produced by a commonly known method can be used as a raw material, and commercially available products can also be used.

[0033] The collagen peptide used in the present invention can be produced by allowing the collagen or gelatin obtained as described above to react with an enzyme such as a crude enzyme derived from a natural plant, collagenase, modified collagenase, prolyl endopeptidase, or a modified enzyme thereof. The enzyme is not particularly limited. For example, plant raw materials for crude enzymes derived from natural plants include pineapple, kiwi, ginger, etc. Furthermore, the collagenase is not particularly limited, and may be derived from bacteria such as Clostridium histolyticum or Streptomyces parvulus, actinomycetes, or fungi, and specifically cleaves the amino terminal side of the glycine residue in the collagen-specific amino acid sequence [(Gly-AB)n (wherein A and B represent amino acid residues excluding glycine residues and may be the same or different, and n represents a positive integer); hereinafter, this amino acid sequence will also be referred to as the "specific amino acid sequence"]. By using such a collagenase, it is possible to obtain a collagenase digestion product rich in peptides of this specific amino acid sequence.

[0034] The types of amino acid residues other than glycine residues that can be represented by A and B above are not particularly limited, and typically may be any amino acid residue of a naturally occurring amino acid (other than glycine), specifically, any amino acid residue of alanine residue, valine residue, leucine residue, isoleucine residue, proline residue, hydroxyproline residue, phenylalanine residue, tryptophan residue, methionine residue, serine residue, threonine residue, cysteine ​​residue, glutamine residue, asparagine residue, tyrosine residue, lysine residue, arginine residue, histidine residue, aspartic acid residue, or glutamic acid residue.

[0035] The collagen peptide used in the present invention can be produced by conventional methods, such as those described in Japanese Patent Application Laid-Open Nos. 7-82299 and 9-176196, by contacting collagenase, either free or immobilized on an immobilization carrier such as chitobal, with the collagen or gelatin using a batch method, a column method, or a combination of these methods under optimal pH and temperature conditions for the enzyme used (for typical enzyme preparations, the optimal conditions described in the pamphlet will suffice). After hydrolysis, the mixture is typically heated to 85°C or higher and maintained for approximately 30 minutes to inactivate the enzyme and terminate the hydrolysis reaction. After the reaction is terminated, the raw material residue is separated by filtration. The degree of purification can be increased by using a filter aid such as diatomaceous earth. Adsorbents such as activated carbon may also be used for decolorization and deodorization. The resulting filtrate is sterilized and dried to obtain a collagen peptide dry powder. Drying methods include spray drying, heated vacuum drying, freeze drying, and drum drying. Furthermore, a fraction with an increased concentration of low molecular weight peptides can also be obtained by purifying collagen peptides by a method of precipitating and separating them using an organic solvent or an inorganic salt.

[0036] When collagen or gelatin is decomposed with collagenase using the above-mentioned methods and purified by various techniques, it is sufficient to contain 50% by weight or more of collagen peptides with a molecular weight of 6000 or less from various viewpoints, such as increasing the absorption rate and absorption rate of collagen peptides in the digestive tract, improving their permeability through the blood-brain barrier, improving their stability against heat and proteases, increasing the activity of the peptide itself, and increasing the number of moles per unit weight. The average molecular weight of collagen peptides can be measured by conventional methods, such as gel filtration chromatography or gel permeation chromatography. The average molecular weight is calculated as the weight-average molecular weight.

[0037] Spray drying refers to a method of producing a dry powder by spraying a liquid into a gas and rapidly drying it. Heat-reduced-pressure drying refers to a method of evaporating and drying with less energy by reducing the pressure inside a heating device to lower the boiling point and promote drying. Freeze-drying refers to a method of first freezing, then lowering the boiling point of the frozen dried product in a vacuum to sublimate the water content of the dried product and dry it. All of these drying methods can be performed using known drying devices. The temperature conditions during drying can be set to an appropriate temperature range depending on the drying method. For example, the outlet temperature can be adjusted to 50 to 100°C for spray drying, 20 to 100°C for heat-reduced-pressure drying, and 20 to 60°C for freeze-drying, but are not particularly limited.

[0038] Commercially available collagen peptides may also be used, such as "Nippi Peptide (registered trademark) PCT-A" (manufactured by Nippi Corporation), "Nippi Peptide FCP-EX" (manufactured by Nippi Corporation), "Nippi Peptide FCP-AS" (manufactured by Nippi Corporation), "Nippi Peptide FCP-AK" (manufactured by Nippi Corporation), "Nippi Peptide FCP-AM," and "Nippi Peptide FCP-DP" (manufactured by Nippi Corporation). The commercially available products are collagen peptides containing tripeptides, dipeptides, oligopeptides, etc. For example, "Nippi Peptide (registered trademark) PCT-A" contains a relatively large amount of collagen peptides beginning with Gly, and has a tripeptide content of 13 to 20% by weight.

[0039] [3] Dipeptide containing proline or tripeptide containing glycine and proline The neuropsychological function improving agent of the present invention contains a dipeptide containing proline or a tripeptide containing glycine and proline as an active ingredient. Examples of the proline-containing dipeptide include hydroxyproline (Hyp)-Pro, Pro-Ala, Pro-Hyp, Pro-Pro, and Pro-Ser. Examples of the tripeptide containing glycine and proline include Gly-Pro-Ala, Gly-Pro-Hyp, Gly-Pro-Gln, Gly-Pro-Pro, Gly-Pro-Leu, Gly-Pro-Ser, and Gly-Pro-Cys. The dipeptide containing proline or the tripeptide containing glycine and proline may be obtained by digesting collagen or gelatin and then purifying it, or may be obtained by amino acid synthesis.

[0040] [4] Neuropsychological function improvers The first neuropsychological function improving agent of the present invention (hereinafter referred to as the first embodiment of the neuropsychological function improving agent) contains a dipeptide containing proline or a tripeptide containing glycine and proline as an active ingredient. The dipeptide containing proline or the tripeptide containing glycine and proline includes: Hydroxyproline-proline (Hyp-Pro), Proline-alanine (Pro-Ala), Proline-hydroxyproline (Pro-Hyp), Proline-proline (Pro-Pro), Proline-serine (Pro-Ser), Glycine-Proline-Alanine (Gly-Pro-Ala), Glycine-proline-hydroxyproline (Gly-Pro-Hyp), Glycine-Proline-Glutamine (Gly-Pro-Gln), glycine-proline-proline (Gly-Pro-Pro), Glycine-Proline-Leucine (Gly-Pro-Leu), Glycine-Proline-Serine (Gly-Pro-Ser) and Glycine-Proline-Cysteine ​​(Gly-Pro-Cys) It is preferable that the material is one or more selected from the group consisting of:

[0041] Here, the neuropsychological function improving effect is expected to be an effect of improving symptoms and / or diseases caused by a decline in neuropsychological function, specifically, an effect of improving Alzheimer's disease, depression, autism spectrum disorder, bipolar disorder, schizophrenia, or chronic fatigue syndrome.

[0042] The second neuropsychological function improving agent of the present invention (hereinafter referred to as the neuropsychological function improving agent of the second embodiment) contains either or both of the soybean peptide and the collagen peptide as active ingredients.

[0043] In particular, a neuropsychological function improving agent containing both the soybean peptide and the collagen peptide as active ingredients exhibits a "synergistic effect" in improving neuropsychological function. Here, the synergistic effect means that a combination of the soybean peptide and the collagen peptide provides a greater neuropsychological function improving effect than the sum of the neuropsychological function improving effects when either is used alone. For example, in the neuropsychological function improving agent of the second aspect, examples of types of peptides that are likely to exhibit neuropsychological improving function and the synergistic effect include soybean peptides that contain a peptide consisting of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1) and collagen peptides that are dipeptides containing proline or tripeptides containing glycine and proline.

[0044] In the neuropsychological function improving agent of the second embodiment, the blending ratio of soybean peptide to collagen peptide (soybean peptide:collagen peptide, weight ratio) is not limited as long as a "synergistic effect" in improving neuropsychological function is obtained, but is usually 10-90:90-10, preferably 20-80:80-20, more preferably 30-70:70-30, more preferably 40-60:60-40, even more preferably 40-60:60-40, even more preferably 45-55:55-45, and most preferably 50:50. Hereinafter, a blend of the two components, soybean peptide and collagen peptide, will be referred to as a "soybean-collagen peptide blend."

[0045] For example, in the case of a solid neuropsychological function improving agent, the content of the soybean-collagen peptide blend may be 100% by weight, or when additional components described below are contained, the content 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. In the case of a solution-type neuropsychological function improving agent in which the soybean-collagen peptide blend is dispersed or dissolved in a medium such as water, the content of the soybean-collagen peptide blend may be 2% by weight or more.

[0046] The neuropsychological function improving agent of the first or second aspect may further contain a polysaccharide as an additional component, and may further contain components such as a bulking agent, solubilizer, dispersant, suspending agent, emulsifier, antioxidant, bacteria inhibitor, colorant, flavoring agent, and odorant, as necessary. These additional components are not particularly limited as long as they are all used in foods, pharmaceuticals, and medical materials. 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."

[0047] The neuropsychological function improving agent of the first or second aspect can be formulated as an active ingredient and used as a food or drink composition for preventing and / or improving symptoms and / or diseases caused by a decline in neuropsychological function.

[0048] Symptoms and / or diseases resulting from a decline in neuropsychological function include Alzheimer's disease, depression, memory impairment due to aging, autism spectrum disorder, bipolar disorder, and schizophrenia.

[0049] The use may be in a human or non-human animal, and may be therapeutic or non-therapeutic. In this specification, the term "non-therapeutic" does not include medical procedures, i.e., treatment of the human body by therapy. Furthermore, as used herein, "treatment" refers to restoring an onset disease or symptom in a subject to its pre-onset state. As used herein, "prevention" refers to preventing or delaying the onset of a disease in a subject, or reducing the risk of onset of a disease or symptom in the subject. As used herein, "improvement" refers to improving a disease, symptom, or condition; preventing or delaying the worsening of a disease, symptom, or condition, or reversing, preventing, or delaying the progression of a disease or symptom.

[0050] The food and beverage composition containing the neuropsychological function improving agent of the first or second embodiment as an active ingredient can be ingested by animals, including humans, and used in methods for preventing the onset of diseases or symptoms associated with a decline in neuropsychological function, or for improving or treating diseases or symptoms.

[0051] According to the latest findings, neurogenesis is observed in the hippocampus of the human brain throughout life, but it is known that in patients with Alzheimer's disease, neurogenesis rapidly declines as Alzheimer's disease progresses. When the neuropsychological function improving agent of the first or second aspect contains a proline-containing dipeptide, a glycine and proline-containing tripeptide, or a collagen peptide as an active ingredient, it is thought to promote neurogenesis and thereby contribute to the improvement of diseases and / or symptoms associated with a decline in neuropsychological function.

[0052] Brain inflammation refers to the excessive release of inflammatory cytokines in the brain beyond physiological limits and duration. Brain inflammation has also been implicated in the pathogenesis of Alzheimer's disease, depression, schizophrenia, and chronic fatigue syndrome. Microglia, glial cells that support neurons, are thought to play a central role in brain inflammation by producing and releasing inflammatory cytokines in response to infection, tissue injury, and neurodegeneration. Normal microglial function is essential for maintaining brain homeostasis, but overactivated microglia release large amounts of inflammatory cytokines, causing brain 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, the memory center, is one of the brain regions with the highest microglia population and is therefore strongly affected by brain inflammation. When the neuropsychological function improving agent of the second aspect contains soybean peptide as an active ingredient, it is thought to suppress inflammation in the brain, thereby contributing to the improvement of diseases and / or symptoms associated with a decline in neuropsychological function.

[0053] Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor 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, decreased BDNF expression is known to be observed in various brain and nervous system disorders, including Alzheimer's disease and depression. Furthermore, results have shown that increasing BDNF expression may improve brain function impaired by psychiatric disorders such as depression. Based on these findings, substances that increase the amount of BDNF may contribute to the prevention and / or improvement of Alzheimer's disease and depression. The neuropsychological function improving agent of the second aspect, when used in combination with soy peptides and collagen peptides, is thought to contribute to the improvement of diseases and / or symptoms associated with impaired neuropsychological function by increasing BDNF expression in the brain.

[0054] Examples of the food and drink compositions include functional foods, foods for the sick, 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.

[0055] The food and drink compositions may be in any form, such as liquid, paste, solid, or powder, and may include tablet confectionery, liquid food, feed (including for pets), and the like, as well as, for example, flour products, instant foods, processed agricultural products, processed marine products, processed livestock products, milk and dairy products, oils and fats, basic seasonings, complex seasonings and foods, frozen foods, confectionery, beverages, and other commercially available foods.

[0056] Examples of the wheat flour products include bread, macaroni, spaghetti, noodles, cake mix, fried chicken flour, breadcrumbs, etc. Examples of the instant foods include instant noodles, cup noodles, retort pouches and prepared foods, canned foods, microwaveable foods, instant soups and stews, instant miso soup and clear soups, canned soups, freeze-dried foods, and other instant foods. Examples of the processed agricultural products include canned agricultural products, canned fruit, jams and marmalades, pickles, boiled beans, dried agricultural products, cereals (processed grain products), etc. Examples of the processed seafood products include canned seafood, fish ham and sausage, fish paste products, seafood delicacies, and tsukudani (simmered foods). Examples of the processed livestock products include canned livestock products and pastes, livestock ham and sausage, etc.

[0057] For example, the milk and dairy products include processed milk, milk drinks, yogurts, lactic acid bacteria drinks, cheese, ice cream, infant formula, cream, and other dairy products. The fats and oils include butter, margarines, and vegetable oils. The basic seasonings include soy sauce, miso, sauces, tomato-processed seasonings, mirin, and vinegars. The complex seasonings and foods include cooking mixes, curry bases, sauces, dressings, noodle soups, spices, and other complex seasonings. The frozen foods include frozen ingredient foods, semi-cooked frozen foods, and cooked frozen foods.

[0058] Examples of the confectioneries include gummies, jellies, caramels, candies, chewing gum, chocolates, cookies, biscuits, cakes, pies, snacks, crackers, Japanese sweets, rice snacks, bean snacks, dessert snacks, and other confectioneries. Examples of the beverages include carbonated drinks, natural fruit juices, fruit juice drinks, soft drinks containing fruit juice, fruit pulp drinks, fruit drinks containing fruit particles, vegetable drinks, soy milk, soy milk drinks, coffee drinks, tea drinks, powdered drinks, concentrated drinks, sports drinks, nutritional drinks, alcoholic drinks, and other beverages. Examples of commercially available foods other than those mentioned above include baby food, furikake rice seasoning, and ochakukenori seaweed.

[0059] Furthermore, the neuropsychological function improving agent of the first or second embodiment can be used in combination with other medicinal ingredients as an active ingredient in human or veterinary medicines, quasi-drugs, etc. for the prevention, amelioration, and / or treatment of diseases, disorders, and symptoms associated with the aforementioned decline in neuropsychological function, etc.

[0060] The pharmaceuticals and quasi-drugs containing the neuropsychological function improving agent of the first or second aspect as an active ingredient may be administered either orally or parenterally, but oral administration is preferred. Dosage forms for oral administration include tablets, capsules, lozenges, syrups, granules, powders, ointments, etc. When formulating, ingredients commonly used in formulations such as excipients, pH adjusters, colorants, flavoring agents, etc. It is also possible to use functional ingredients that have known or will be discovered in the future and have the effect of promoting muscle synthesis.

[0061] The administration frequency and dosage of the neuropsychological function improving agent of the first or second aspect may be adjusted appropriately depending on the recipient's age, sex, condition, etc., as long as a proline-containing dipeptide or glycine, proline-containing tripeptide, soybean peptide, collagen peptide, etc. is administered to the recipient in an amount sufficient to exert the desired effect. For example, the total content of proline-containing dipeptides or glycine, proline-containing tripeptides, soybean peptides, and collagen peptides in the pharmaceuticals, quasi-drugs, etc. is preferably at least 0.001% by mass or more of the final formulation. The intake or administration amount of proline-containing dipeptides or glycine, proline-containing tripeptides, soybean peptides, and collagen peptides varies depending on the species, age, symptoms, etc. of the recipient, but is usually 0.001 to 8000 mg / kg body weight / day, preferably 0.01 to 6000 mg / kg body weight / day, and most preferably 0.01 to 4000 mg / kg body weight / day, and may be administered once to three times a day. The intake or administration amount for humans is 0.001 to 1500 mg / kg body weight / day, preferably 0.01 to 1000 mg / kg body weight / day, and most preferably 0.01 to 500 mg / kg body weight / day.

[0062] The dose of proline-containing dipeptides or glycine, proline-containing tripeptides, soybean peptides, and collagen peptides administered to humans can be calculated using a conversion formula based on the "Human Equivalent Dose (HED) exchange from animals based on body surface area" (see, for example, Reference 1 below). HED = [Animal dose (mg / kg body weight)] × {[Animal body weight (kg)] ÷ [Human body weight (kg)]} 0.33 Human weight: 60 kg 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)

[0063] The present invention will be explained in more detail below by way of examples, but the present invention is not limited to these examples. [Example]

[0064] Example 1: Preparation of soybean peptides Soybean peptides were prepared as follows: 0.5 kg of soy protein isolate (SPI, Supro 661, DuPont) was suspended and dissolved in 4.5 kg of water. The 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). 5 g of Thermoase® PC10F (Amano Enzyme Inc.) was then added, and the mixture was allowed to react for 5 hours with stirring at 60°C. The pH was measured every 30 minutes during the reaction, and 10 M sodium hydroxide solution was added to adjust the pH to 7.0 (±0.1). After the reaction was completed, the temperature of the reaction mixture was raised to 90°C and kept at that temperature for 1 hour to inactivate the enzyme. The mixture was then dried in a spray dryer to obtain soybean peptide powder (Soylax).

[0065] 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> The HPLC apparatus and the mass spectrometer used were the Alliance 2695 HPLC system (Waters) and the 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 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 performed in the ESI (positive mode). The precursor ion: 1112.7 (m / z) and the product ion: 101.1 (m / z) were detected. <Reagents> The standard product 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 prepare a calibration curve. <Samples> The produced soy peptide was dissolved in peptone water at a concentration of 10 mg / ml, and 10 μL was injected for analysis.

[0066] As a result of quantification, the concentration of the decapeptide LSSTQAQQSY in the produced soy peptide powder (Soylax) was 0.97 mg / g.

[0067] 〔Example 2〕Comparison of the effects of soy peptide powder (Soylax) and synthetic decapeptide (Soy-deptrestatin) Eight-week-old Slc:ddY mice (Japan SLC, Inc.) were administered the chemically synthesized decapeptide LSSTQAQQSY (SEQ ID NO: 1; soy-deptrestatin) at 0.1 mg / kg body weight or soy peptide powder (Soylax) containing the same amount of soy-deptrestatin as above at 0.1 mg / kg body weight via the stomach tube. The control group received the solvent (water) via the stomach tube.

[0068] Thirty minutes after administration, as shown in Figure 2, the rats were suspended by fixing their tails with tape to a horizontally placed rod. Observation of the rats' behavior began immediately after hanging, and the immobility time was measured over a 6-minute period. The percentage of immobility time relative to the total measured time was calculated using the formula: immobility time (seconds) / 360 (seconds) x 100. Administration of substances with antidepressant effects reduces this immobility time. Therefore, a decrease in immobility time can be evaluated as the presence of an antidepressant-like effect. Since immobility is considered a state of despair, a decrease in immobility time is an indicator of an improvement in despair, i.e., an increase in motivation.

[0069] The results are shown in Figure 3. The percentage of immobility time was approximately 32.5% for the control, approximately 22.6% (no significant difference) for the chemically synthesized decapeptide LSSTQAQQSY (SEQ ID NO: 1; Soy-deptrestatin), and approximately 10.1% (P<0.05) for soy peptide powder (Soylax), confirming that soy peptide powder has a superior antidepressant effect to soy-deptrestatin.

[0070] [Example 3] Comparison of the antidepressant effects of soy peptides with other antidepressant functional ingredients Seven-week-old male Slc:ddY mice were administered GABA (1 mg / kg body weight), theanine (1 mg / kg body weight), and soy peptide powder (Soylax) at doses of 100 mg / kg body weight (equivalent to 0.1 mg / kg body weight of soy-deptrestatin) or 500 mg / kg body weight (equivalent to 0.5 mg / kg body weight of soy-deptrestatin) via gastric tube. At 0.5 hours after administration, lipopolysaccharide (LPS) was intraperitoneally injected at 1 mg / kg body weight. The same doses of the same substances were administered via gastric tube at 5, 11, 17, and 23 hours after LPS injection. An equal volume of water was administered as a control. Following the same procedure as in Example 2, 30 minutes after the final sample administration, the mice were suspended by their tails. Measurements were initiated immediately after suspension, and the immobility time was counted during the 6-minute period. The percentage of immobility time was calculated as follows: total immobility time (seconds) / 360 seconds x 100 (%). The results of the tail suspension test are shown in Figure 4. As is clear from Figure 4, in the soy peptide powder (Soylax) group, even when administered an amount equivalent to soy-deptrestatin (0.1 mg / kg BW), which is one-tenth the dose of soy-deptrestatin administered in the GABA and theanine groups, the percentage of immobility time was reduced more than in the GABA and theanine groups, confirming a strong antidepressant effect.

[0071] [Example 4] Anti-cerebral inflammation effect of soybean peptides To investigate the anti-inflammatory effect of soybean peptides in the brain, we measured the amount of interleukin-6 (IL-6) in the brains of mice. Forty minutes after the final sample administration in Example 3, mouse 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 centrifuged (25,000 × g, 10 min, 4°C). The amount of IL-6 in the supernatant was measured using a Quantikine IL-6 ELISA kit (R&D Systems). The protein concentration in the supernatant was also measured using a BCA protein assay kit. The measurement results are shown in Figure 5. In this experiment, a lower amount of IL-6 indicates a stronger anti-cerebral inflammatory effect of the administered drug. As is clear from Figure 5, a significant decrease in the amount of IL-6 in the brain was observed in the soy peptide powder (Soylax) administration group compared to the control group, demonstrating that soy peptide powder (Soylax) has the effect of suppressing inflammation in the brain.

[0072] Recent research findings 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-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer's disease"). It is known that in the brain and other central nervous tissues, microglia, which are responsible for the immune system, primarily cause inflammatory responses, and that cytokines such as IFNγ, IL1β, IL-6, and TNF-α produced by activated microglia independently suppress neurogenesis (e.g., Folia Pharmacol. Jpn. 140, pp. 216-220 (2012); Journal of Psychiatry and Neurology (2012) Vol. 114, No. 2, pp. 124-133). Therefore, soy peptides may be effective in suppressing neuroinflammation, such as inflammation in the brain, and in treating not only functional psychiatric disorders such as depression and schizophrenia, but also neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.

[0073] [Example 5] Antidepressant effect of collagen peptides Collagen peptide (Nippi Peptide (registered trademark) PCT-A, manufactured by Nippi Corporation, 10 mg, 100 mg, 500 mg, 1000 mg / kg body weight) was administered to 7-week-old Slc:ddY mice (male) via stomach tube. Water was administered as a control. 30 minutes after administration of the sample, the mice were suspended by their tails. Measurement was started immediately after suspension, and the immobility time was counted over a 6-minute period. The percentage of immobility time was calculated as the total immobility time (seconds) / 360 seconds x 100 (%). The results of the tail suspension test described above are shown in Figure 6. As is clear from Figure 6, the immobility time was significantly reduced in a concentration-dependent manner at collagen peptide concentrations of 100 mg / kg BW or more. This result indicates that collagen peptide has an antidepressant effect.

[0074] [Example 6] Effect of collagen peptide administration on brain BDNF and HGF levels For the collagen peptide-administered mice in Example 5, brains were collected 40 minutes after collagen peptide administration and cryopreserved at -80°C. The cryopreserved brains were thawed, homogenized in 1.5 ml of RIPA buffer (containing a protease inhibitor cocktail), and centrifuged (25,000 × g, 10 min, 4°C). The BDNF level in the supernatant was measured using a Total BDNF Quantikine ELISA kit (R&D Systems). Similarly, the HGF level after administration of collagen peptide (100 mg / kg BW) was measured using a Mouse / Rat HGF Quantikine ELISA Kit. The protein concentration in the supernatant was also measured using a BCA protein assay kit (Thermo). Total BDNF and HGF levels were calculated as concentrations per protein. The results of the total BDNF measurement are shown in Figure 7, and the results of the HGF measurement are shown in Figure 8. The results in Figure 7 show that a significant increase in total BDNF levels was observed in the collagen peptide (100 and 500 mg / kg BW) administration groups compared to the control group. This indicates that collagen peptide intake increases BDNF expression levels. Similarly, the results in Figure 8 show that in measuring brain HGF, the group administered 100 mg / kg BW of collagen peptide showed a significant increase in HGF levels compared to the control group. These results indicate that collagen peptide has the ability to induce the expression of both BDNF, a neurotrophic factor, and HGF, a hepatocyte growth factor. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, is an important factor that plays a fundamental role in the expression of higher brain functions such as memory and learning, and reduced BDNF expression levels are observed in psychiatric disorders such as depression and Alzheimer's disease and neurodegenerative diseases.

[0075] Neuroinflammation has been shown to be 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 the brain and other central nervous tissues, it is known that microglia, which are responsible for immunity, primarily cause inflammatory responses, and that cytokines such as IFNγ, IL1β, IL-6, and TNF-α produced by activated microglia independently suppress neurogenesis (for example, Japanese Pharmacology Journal 140, pp. 216-220 (2012); Japanese Journal of Psychiatry and Neurology (2012) Vol. 114, No. 2, pp. 124-133). Furthermore, in genetically modified rats in which central neural progenitor cells (NG2 glia), a type of glial cell, have been removed from the brain, microglia become activated, causing excessive neuroinflammation, which damages hippocampal neurons involved in memory and spatial learning and leads to 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 hippocampal neurogenesis is reduced in Alzheimer's patients (Nature medicine, 25, 554-560(2019)), and inflammation is harmful to hippocampal neurogenesis (PNAS, 100(23), 13632-13637 (2003)). Although it was previously thought that neurons are generated during fetal and juvenile periods but not during adulthood, recent studies have demonstrated that neural stem and progenitor cells exist even during adulthood in specific brain regions, such as the subventricular zone and the dentate gyrus of the hippocampus, and that these cells proliferate and differentiate to generate new neurons (Ming GL et al., Annu Rev Neurosci 28:223-250(2005)). Furthermore, it has been reported that neurons generated in the dentate gyrus of the hippocampus 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 as AD progresses, neurogenesis in the hippocampus rapidly declines, suggesting that a decline 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, collagen peptides are thought to be effective in improving mental illnesses such as depression and Alzheimer's disease, as they induce the expression of both BDNF and HGF.

[0076] [Example 7] Synergistic effect of soybean peptide and collagen peptide Eight-week-old Slc:ddY mice were administered a 1:1 mixture (by weight) of soy peptide (Soylax, UHA Mikakuto Co., Ltd.) and collagen peptide (PCT-A) dissolved in an equal volume of water to achieve an intake of 20 mg / kg body weight (1:1 mixture of Soylax:PCT-A (10 mg + 10 mg / kg body weight)) or 10 mg / kg body weight (1:1 mixture of Soylax:PCT-A (5 mg + 5 mg / kg body weight)) via stomach tube. A control group received vehicle (water) via tube tube.

[0077] As shown in Figure 9, the measurement results showed that there was no significant change in immobility time in the Soylax (10 mg / kg BW) alone-administered group or the PCT-A (10 mg / kg BW) alone-administered group compared to the control group. On the other hand, a significant decrease in immobility time was observed in the Soylax:PCT-A mixture (5 mg + 5 mg / kg BW) (10 mg + 10 mg / kg BW)-administered group compared to the control group. Furthermore, a significant decrease in immobility time was observed in the PCT-A:Soylax mixture (5 mg + 5 mg / kg BW)-administered group compared to the PCT-A group (10 mg / kg BW).

[0078] From the above, it was found that the mixture of soybean peptide and collagen peptide has a synergistic effect of improving depressive symptoms compared to when soybean peptide or collagen peptide is used alone.

[0079] In particular, the results of Example 4 show that soybean peptides have an anti-cerebral inflammation effect, and the results of Example 6 show that the inclusion of collagen peptides has the effect of increasing the amount of BDNF and HGF in the brain. Therefore, it is thought that the neuropsychological function improving agent of the present invention containing these ingredients will have an improving effect on central nervous system diseases such as Alzheimer's disease, autism spectrum disorder, bipolar disorder, schizophrenia, or chronic fatigue syndrome, in particular Alzheimer's disease.

[0080] [Example 8] Effects of dipeptides and tripeptides derived from collagen peptides As dipeptides and tripeptides derived from collagen, Hydroxyproline-proline (OP), proline-alanine (PA), proline-hydroxyproline (PO), proline-proline (PP), proline-serine (PS), Glycine-Proline-Alanine (GPA), Glycine-Proline-Hydroxyproline (GPO), Glycine-Proline-Glutamine (GPQ), glycine-proline-proline (GPP), Glycine-Proline-Leucine (GPL), Glycine-Proline-Serine (GPS) and Glycine-proline-cysteine ​​(GPC) was prepared by amino acid synthesis. Next, 6-week-old Slc:ddY mice were administered a single dose of 1 mg / kg BW of each peptide dissolved in water via stomach tube. 45 minutes after administration, the tail suspension test was performed to measure the immobility time (seconds) during a 6-minute test period, and the immobility time (%) relative to the test period was calculated. Next, 6-week-old Slc:ddy mice were administered 1 mg / kg BW / day of each peptide dissolved in water via stomach tube for 5 days. 24 hours after the final administration, the immobility time (seconds) during a 6-minute test period was measured in a tail suspension test, and the immobility time (%) relative to the test time was calculated. The control group was administered only water.

[0081] As the results of the tail suspension test, the results of a single administration of the dipeptide are shown in FIG. 10, the results of 5-day administration of the dipeptide in FIG. 11, and the results of a single administration of the tripeptide in FIG. The results shown in Figures 10 and 12 indicate that the dipeptides and tripeptides used reduced the immobility time in the tail suspension test after a single administration compared to the control, and in particular, OP, PL, PO, PP, PS, GPA, GPO, GPW, GPP, GPL, GPS, and GPC showed significant differences compared to the control. Furthermore, it was clear that administration of PA for 5 days had the effect of reducing immobility time compared to the control. From the above, it was shown that the dipeptides and tripeptides used had antidepressant effects.

[0082] [Example 9] Evaluation test of suppression of cognitive decline using senescence-accelerated mice Rodents such as mice naturally approach an object they recognize as novel, engaging in exploratory behavior such as checking its shape and smelling it. However, they tend not to exploratory behavior toward objects they have already memorized, or they only explore them for a shorter period of time than toward novel objects. Taking advantage of this characteristic of mice, a novel object recognition test is known as a method for evaluating the effects of memory retention and cognitive function in mice, and the effects of soy peptides and collagen peptides were investigated.

[0083] Twenty-week-old senescence-accelerated mice (SAMP8) were divided into a control feed group (normal feed "AIN-93M", 8 mice) and a test feed group (normal feed mixed with 2.5% Soylax and 2.5% collagen peptide, 8 mice). They were given 6g of feed per day and allowed free access to drinking water for 20 weeks.

[0084] The suppression of cognitive decline was assessed by a novel object recognition test, which was performed as follows. That is, the mouse was placed in a plastic cage measuring 38 cm in length, 55 cm in width, and 27 cm in height, and allowed to acclimate to the environment for 10 minutes (acclimation trial). The next day, the same objects (A1 and A2: both triangular prisms) were placed in the cage, and the mice were allowed to freely explore the objects for 5 minutes, and their behavior was recorded on video (training trial). One hour after removing the mouse from its cage, one of the objects was replaced with a new object (B: cylinder), and the trained mouse was returned to its cage. Five minutes of exploratory behavior was recorded on video (acquisition trial). The number of times the mouse poked its nose at object A (familiar object) or object B (novel object) during the acquisition trial was counted using a counter as the number of explorations. The ratio of the number of searches for novel objects to the total number of searches for objects was calculated from the measured values, and this was taken as the novel object recognition rate. This test was conducted before the intake of the control or test feed, and the rats were divided into groups so that the novel object recognition rate was average in both groups. The test was then conducted 4, 8, 12, 16, and 20 weeks after the intake of the control or test feed.

[0085] The results are shown in Figure 13. At all test occasions except before the test, the novel object recognition rate was higher in the test diet group than in the control diet group. Furthermore, the age-related decline in novel object recognition rate observed in both groups was more gradual in the test diet group than in the control diet group. These results show that continuous intake of soy peptides and collagen peptides can suppress memory impairment caused by aging and maintain cognitive function.

Claims

1. A neuropsychological function improving agent for preventing and / or improving symptoms and / or diseases caused by neuropsychological function decline, comprising a dipeptide containing proline or a tripeptide containing glycine and proline as an active ingredient, The dipeptide containing proline or the tripeptide containing glycine and proline is hydroxyproline-proline, Proline-proline, Proline-serine, glycine-proline-proline, and Glycine-Proline-Leucine A neuropsychological function improving agent, which is one or more selected from the group consisting of:

2. Contains soy peptides and collagen peptides as active ingredients, The soybean peptide comprises a peptide consisting of the amino acid sequence LSSTQAQQSY (SEQ ID NO: 1), and the collagen peptide comprises hydroxyproline-proline, Proline-proline, Proline-serine, glycine-proline-proline, and Glycine-Proline-Leucine and one or more selected from the group consisting of: A neuropsychological function improving agent for preventing and / or improving symptoms and / or diseases caused by neuropsychological dysfunction, wherein the collagen peptide has an average molecular weight of 100 to 6000 and the tripeptide content is 13 to 20% by weight.

3. 3. The neuropsychological function improving agent according to claim 2, wherein the soybean peptide and the collagen peptide are blended in a ratio and content that produces a synergistic effect.

4. The neuropsychological function improving agent according to any one of claims 1 to 3, wherein the symptom and / or disease caused by a decline in neuropsychological function is Alzheimer's disease, depression, memory impairment due to aging, autism spectrum disorder, bipolar disorder, schizophrenia, or chronic fatigue syndrome.

5. The neuropsychological function improving agent according to any one of claims 2 to 4, wherein the soybean peptide is a thermolysin digest.

6. A pharmaceutical composition for improving neuropsychological function, comprising the neuropsychological function improving agent according to any one of claims 1 to 5.

7. A food and drink composition for improving neuropsychological function, comprising the neuropsychological function improver according to any one of claims 1 to 5.

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