JP7764992B2 - Neuropsychological function improving agent containing soybean peptide and/or collagen peptide - Google Patents

Description

The present invention relates to a neuropsychological function improver that has preventive and/or ameliorative effects 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 soy peptides and/or collagen peptides as active ingredients, which are safe and easy to ingest, and that can prevent and/or ameliorate a decline in neuropsychological function.

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 increase in the burden on social security, creating a major problem. Furthermore, even healthy seniors are seeking ways to improve the age-related decline in brain function. Therefore, there is a social demand for preventive methods to prevent the decline in brain function, particularly cognitive function. In Japan in particular, 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).

It is well known that the early stages of AD involve the deposition of amyloid-β (Aβ), the main component of senile plaques in the brain. Following 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, it was reported that activated microglia accumulated 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 use of non-steroidal 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).

In addition to cognitive impairment, primarily progressive memory loss, 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).

It has been reported that patients with depression have reduced hippocampal volume and impaired hippocampal function (Non-Patent Document 6). The hippocampus is known as 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 impaired hippocampal function is thought to be a contributing factor.

It was previously thought that neurons are generated during the fetal and juvenile periods, but not during adulthood. However, recent studies have shown 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 being involved in memory formation (Non-Patent Document 8). Recently, it has been reported that as AD progresses, neuron generation in the hippocampus rapidly declines, suggesting that this may be related to the onset of AD (Non-Patent Document 9).

As our understanding of brain function has progressed in recent years, there have been many attempts to discover substances that improve neuropsychological functions such as memory and prevent or ameliorate symptoms and diseases associated with declines in neuropsychological function. For example, active research is being conducted to determine whether natural foods that can be consumed on a daily basis contain substances that enhance or improve cognitive function. It has been shown that ingesting a blend of five amino acids—arginine, citrulline, glycine, proline, and tyrosine—improves cognitive function (assessed using the Stroop test) (Patent Document 1), that 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), and that ingesting chlorogenic acids, 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).

Japanese Patent Application Laid-Open No. 2019-112361 Japanese Patent Application Laid-Open No. 2018-199643 Japanese Patent Application Laid-Open No. 2018-39797

Takesu et al., Japanese Pharmacological Journal, Vol. 150, pp. 141-147, 2017 Hardy JA et al. , Science, 256(5054):184-185(1992) McGeer PL et al, Neurosci Lett, 79(1-2): 195-200 (1987) McGeer PL et al, Lancet, 335(8696):1037(1990) Katsuyoshi Mizukami, Journal of Psychiatry and Neurology, Vol. 115, No. 11, pp. 1122-1126 (2013) MacQueen GM et al. , Proc Natl Acad Sci USA, 100(3): 1387-1392 (2003) Ming GL et l. , Annu Rev Neurosci 28:223-250 (2005) Aimone JB et al. , Trends Cogn Sci, 14(7): 325-337 (2010) Moreno-Jimenez EP et al. , Nat Med, 25(4):554-560 (2019)

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.

The present invention also aims to provide a pharmaceutical composition and a food and beverage composition for improving neuropsychological function that contain the neuropsychological function improver, as well as a method for preventing and/or improving symptoms and/or diseases caused by neuropsychological function decline using the neuropsychological function improver.

The inventors made extensive efforts to find ingredients from commonly consumed foods that contribute to improving neuropsychological functions. As a result, they were surprised to discover that administration of soy peptides and/or collagen peptides has the effect of improving neuropsychological functions, leading to the completion of the present invention.

The gist of the present invention is
[1] A neuropsychological function improving agent for preventing and/or improving symptoms and/or diseases caused by neuropsychological 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,
The neuropsychological function improving agent according to [1] above, which is one or more selected from the group consisting of glycine-proline-serine and glycine-proline-cysteine.
[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 produce 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 6,000.
[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,
The neuropsychological function improving agent according to any one of [3] to [8] above, wherein the amino acid sequence is one or more selected from the group consisting of glycine-proline-serine and glycine-proline-cysteine.
[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] The present invention relates to 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 agent or a patient at risk of being in need of the agent.

The neuropsychological function improving agent of the present invention contains the active ingredients, soybean peptides and/or collagen peptides, which are highly safe ingredients with a long history of use as food ingredients. Furthermore, both have the effect of improving neuropsychological function. Therefore, 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 require such prevention or improvement (treatment) without causing side effects.

Figure 1 shows the core symptoms of dementia and behavioral and psychological symptoms (BPSD). FIG. 2 shows how the tail suspension test was performed. FIG. 3 shows the results of the tail suspension test when synthetic soy-deprestatin or soybean peptide powder (Soylax) was administered. FIG. 4 shows the results of the tail suspension test when GABA, theanine, or soybean peptide powder (Soylax) was administered. FIG. 5 shows the amount of IL-6 in the brain when GABA, theanine, or soybean peptide powder (Soylax) was administered. FIG. 6 shows the results of the tail suspension test when collagen peptide (PCT-A) was administered. FIG. 7 shows the amount of BDNF in the brain when collagen peptide (PCT-A) was administered. FIG. 8 shows the amount of HGF in the brain when collagen peptide (PCT-A) was administered. 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. FIG. 10 shows the results of the tail suspension test carried out in Example 8 when a dipeptide derived from a collagen peptide was administered in a single dose. 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. FIG. 12 shows the results of a tail suspension test performed in Example 8 when a tripeptide derived from a collagen peptide was administered in a single dose. FIG. 13 shows the results of the novel object recognition test carried out in Example 9.

Specific embodiments of the present invention are 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 invention. Note that redundant explanations may be omitted where appropriate, but this does not limit the present invention.

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 ingestion of the neuropsychological function improving agent of the present invention can be examined using the tests shown in Table 1.

Improvement in neuropsychological function includes improvement in cognitive function and depressive symptoms, suppression of brain atrophy related to neuropsychological function, suppression of brain function decline (strengthening of functional connectivity with the hippocampus), 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.

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 unclean behavior, but it is thought that the core symptom of cognitive dysfunction is related to the surrounding environment, personality, psychological state, etc.

[1] Soybean Peptide The neuropsychological function improving agent 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 decomposition level. 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 in a manner that results in a peptide mixture that can achieve the neuropsychological function improving effect of the present invention. That is, the hydrolysis of soybean protein is preferably carried out by enzymatic decomposition using a proteolytic enzyme (also called a protease).

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, thereby breaking down the peptide bonds into 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 at the ends 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 material. For example, proteases derived from microorganisms such as Bacillus are preferred. 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.).

Among these, thermolysin digests are preferred in terms of potency in 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. Commercially available food additive-grade thermolysin (e.g., the aforementioned "Thermoase (registered trademark) PC10F" (manufactured by Amano Enzyme Inc.)) can be used.

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, isolated soy 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 approximately 10 amino acid residues. The reaction temperature can be selected from 30-70°C, 40-70°C, 50-65°C, etc. The reaction time can be selected from approximately 30 minutes to 48 hours, approximately 1-10 hours, or approximately 2-8 hours, etc. The pH at which the reaction is carried out can be selected from approximately 6.5-8.5 or approximately 7-8. 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 may 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 an adsorption resin or ion exchange resin, to obtain a fraction having a molecular weight of 300 to 1500, preferably 500 to 1300, and more preferably 700 to 1100.

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.

[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 achieved 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 less absorbable into the body when orally ingested, preventing the efficient expression of the neuropsychological function improving effect.

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.

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 is 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.

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.

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

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 tissue can be crushed, washed with water, extracted with a dilute salt solution, extracted with an acid or alkaline solution, or extracted with enzymes 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.

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

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, but 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 an amino acid sequence specific to collagen [(Gly-A-B)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.

The types of amino acid residues other than glycine residues that A and B above can represent are not particularly limited, and typically may be any amino acid residue of a naturally occurring amino acid (other than glycine), specifically, 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.

The collagen peptides 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 under optimal pH and temperature conditions for the enzyme used (for typical enzyme preparations, the optimal conditions described in the pamphlet are sufficient), using a batch method, a column method, or a combination of these methods, and carrying out a hydrolysis reaction. 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 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.

When collagen or gelatin is degraded with collagenase using the methods described above and purified by various techniques, it is sufficient for the collagen peptide to contain 50% by weight or more of collagen peptides with a molecular weight of 6,000 or less, from various perspectives, such as increasing the absorption rate and absorption speed of collagen peptides in the digestive tract, improving blood-brain barrier permeability, improving 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 standard methods, such as gel filtration chromatography or gel permeation chromatography. The average molecular weight is calculated as the weight-average molecular weight.

Spray drying is a method of producing dry powder by spraying a liquid into a gas and rapidly drying it. Heat-reduced-pressure drying is a method of evaporating and drying with less energy by reducing the pressure inside a heating device to lower the boiling point and accelerate drying. Freeze-drying is a method of first freezing, then lowering the boiling point of the frozen dried product in a vacuum to sublimate the water in the dried product and dry it. Both of these drying methods can be performed using known drying equipment. 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 50-100°C for spray drying, 20-100°C for heat-reduced-pressure drying, and 20-60°C for freeze-drying, but there are no particular limitations.

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.

[3] Proline-containing dipeptide or glycine and proline-containing tripeptide The neuropsychological function improving agent of the present invention contains a proline-containing dipeptide or a glycine and proline-containing tripeptide 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.

[4] Neuropsychological function improving agent The neuropsychological function improving agent of the first aspect of the present invention (hereinafter referred to as the neuropsychological function improving agent of the first aspect) 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 polymer is one or more selected from the group consisting of:

Here, the effect of improving neuropsychological function 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.

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

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 include 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.

In the neuropsychological function improving agent of the second embodiment, the blending ratio of soy peptide to collagen peptide (soy peptide:collagen peptide, weight ratio) is not limited as long as a "synergistic effect" in improving neuropsychological function is obtained, but is typically 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, soy peptide and collagen peptide, will be referred to as a "soy-collagen peptide blend."

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 if the additional ingredients 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. Furthermore, 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.

The neuropsychological function improving agent of the first or second aspect may further contain polysaccharides as additional ingredients, and may further contain ingredients such as bulking agents, solubilizers, dispersants, suspending agents, emulsifiers, antioxidants, bacterial inhibitors, colorants, flavoring agents, and odorants, as necessary. There are no particular limitations on these additional ingredients, as long as they are all used in foods, pharmaceuticals, and medical components. The total amount of these additional ingredients 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 dry weight of the "neuropsychological function improving agent."

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

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

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 a disease or symptom that has developed 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 developing 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.

The food and beverage composition containing the neuropsychological function improving agent of the first or second aspect 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.

According to the latest findings, neuronal cell regeneration is observed in the hippocampus of the human brain throughout life, but it is known that in patients with Alzheimer's disease, neuronal cell regeneration 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 believed to promote neuronal regeneration and thereby contribute to the improvement of diseases and/or symptoms associated with a decline in neuropsychological function.

Brain inflammation refers to a condition in which inflammatory cytokines are released in excess of physiological limits and for a longer period of time. 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 concentration of microglia 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.

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 a variety of 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 the above, substances that increase the amount of BDNF may contribute to the prevention and/or improvement of Alzheimer's disease and depression. When used in combination with soy peptides and collagen peptides, the neuropsychological function improving agent of the second aspect is thought to contribute to the improvement of diseases and/or symptoms associated with impaired neuropsychological function by increasing BDNF expression in the brain.

Examples of the food and beverage 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.

The food and beverage compositions may be in any form, such as liquid, paste, solid, or powder, and may include tablet confectionery, liquid food, feed (including for pets), etc., as well as, for example, flour products, instant foods, processed agricultural products, processed seafood 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.

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/prepared foods, canned foods, microwave foods, instant soups/stews, instant miso soup/cleaning soups, canned soups, freeze-dried foods, and other instant foods. Examples of the processed agricultural products include canned agricultural products, canned fruit, jams/marmalades, pickles, boiled beans, dried agricultural products, cereals (processed grain products), etc. Examples of the processed seafood products include canned seafood, fish ham/sausage, fish paste products, seafood delicacies, and tsukudani (simmered foods). Examples of the processed livestock products include canned livestock products/pastes, livestock ham/sausage, etc.

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-based 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.

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 with fruit juice, fruit pulp drinks, fruit drinks with fruit pieces, 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 (green tea laver).

Furthermore, the neuropsychological function improving agent of the first or second aspect can be used in combination with other medicinal ingredients as an active ingredient in human or veterinary medicines, quasi-drugs, etc. for the prevention, improvement, and/or treatment of diseases, disorders, and symptoms involving the decline in neuropsychological function, etc., as described above.

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. Examples of dosage forms for oral administration include tablets, capsules, lozenges, syrups, granules, powders, ointments, etc.
When formulating the product, ingredients commonly used in formulations, such as excipients, pH adjusters, colorants, and flavoring agents, can be used. It is also possible to use functional ingredients that have a muscle synthesis promoting effect, either known or to be discovered in the future.

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. can be administered to the recipient in an amount sufficient to exert the desired effect.
For example, the total content of the proline-containing dipeptide or glycine, the proline-containing tripeptide, the soybean peptide, and the collagen peptide in the pharmaceutical product, quasi-drug, etc. is preferably at least 0.001% by mass or more relative to the final product of the preparation.
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 typically 0.001 to 8,000 mg/kg body weight/day, preferably 0.01 to 6,000 mg/kg body weight/day, and most preferably 0.01 to 4,000 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 1,500 mg/kg body weight/day, preferably 0.01 to 1,000 mg/kg body weight/day, and most preferably 0.01 to 500 mg/kg body weight/day.

The dose of proline-containing dipeptides or glycine, proline-containing tripeptides, soybean peptides, and collagen peptides when administered to humans can be calculated using a conversion formula based on "HED (Human Equivalent Dose) 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/U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER)

The present invention will be explained in more detail below using examples, but the present invention is not limited to these examples.

Example 1: Preparation of Soybean Peptides Soybean peptides were prepared as follows. Specifically, 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 Samoase® PC10F (Amano Enzyme Inc.) was then added, and the mixture was allowed to react for 5 hours with stirring at 60°C. 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 was completed, the temperature of the reaction solution was raised to 90°C and maintained at that temperature for 1 hour to inactivate the enzyme. The mixture was then dried using a spray dryer to obtain soybean peptide powder (Soylax).

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 and mass spectrometers used were Alliance 2695 HPLC system (Waters) and 3200 Q Trap (AB Sciex Co., Ltd.), respectively. The column used was a Capcell PAK C18 UG80 (2.0 × 150 mm, 5 μm) (Osaka Soda Co., Ltd.). The eluents used were 0.1 v/v% formic acid in water (Solution A) and 0.1 v/v% formic acid-containing acetonitrile (Solution B). The gradient conditions were as follows: 0 min to 15 min (0 to 70 v/v% B) → 15 min to 20 min (70 v/v% B to 70 v/v% B) → 20 min to 25 min (70 v/v% B to 100 v/v% B) → 25 min to 35 min (100 v/v% B) → 35 min to 35.01 min (100 to 0 v/v% B) → 10 min to 10.01 min (100 v/v% B to 10 v/v% B) → 10.01 min to 11 min (10 v/v% B). The flow rate was 0.2 mL/min. The detection method used was MRM (multiple reaction monitoring), the ionization method was ESI (positive mode), and detection was performed using precursor ion: 1112.7 (m/z) and product ion: 101.1 (m/z).
<Reagents>
A standard sample of decapeptide LSSTQAQQSY (SEQ ID NO: 1) was synthesized by the Fmoc method, purified by reversed-phase HPLC, and dissolved in peptone water (0.1% aqueous solution of Bacto peptone) to prepare a calibration curve.
<Sample>
The prepared soybean peptide was dissolved in peptone water to a concentration of 10 mg/ml, and 10 μL of the solution was injected for analysis.

Quantitation revealed that the concentration of decapeptide LSSTQAQQSY in the produced soybean peptide powder (Soylax) was 0.97 mg/g.

Example 2 Comparison of the Effects of Soybean Peptide Powder (Soylax) and Synthetic Decapeptide (Soy-deptrestatin) Eight-week-old Slc:ddY mice (Japan SLC Co., Ltd.) were administered 0.1 mg/kg body weight of the chemically synthesized decapeptide LSSTQAQQSY (SEQ ID NO: 1; Soy-deptrestatin) or soybean peptide powder (Soylax) adjusted to the same Soy-deptrestatin content of 0.1 mg/kg body weight using the stomach tube described above. The control group was administered the solvent (water) using the stomach tube.

Thirty minutes after administration, as shown in Figure 2, the rats were suspended by taping their tails to a horizontally placed rod. Observation of the rats' behavior began immediately after hanging, and the time spent immobile was measured over a six-minute period. The percentage of immobility time relative to the total time measured was calculated using the formula: time spent immobile (seconds) / 360 (seconds) x 100. Note that administration of substances with antidepressant effects reduces this time spent immobile. 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.

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 an antidepressant effect superior to that of soy-deptrestatin.

Example 3: Comparison of the antidepressant effects of soy peptides with other antidepressant functional ingredients. 7-week-old Slc:ddY mice (male) were administered GABA at 1 mg/kg body weight, theanine at 1 mg/kg body weight, and soy peptide powder (Soylax) at 100 mg/kg body weight (equivalent to soy-deptrestatin (0.1 mg/kg body weight)) or 500 mg/kg body weight (equivalent to soy-deptrestatin (0.5 mg/kg body weight)) via gastric tube. 0.5 hours after administration, lipopolysaccharide (LPS) was intraperitoneally injected at 1 mg/kg body weight. Five, 11, 17, and 23 hours after LPS injection, the same doses of the above were administered via gastric tube. As a control, an equal volume of water was administered as a solvent. Using the same procedure as in Example 2, 30 minutes after the final sample administration, the rats were suspended by their tails, and measurement was started immediately after suspension to count the immobility time during the 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 are shown in Figure 4.
As is clear from Figure 4, in the soy peptide powder (Soylax) administration group, even when an amount equivalent to soy-deptrestatin (0.1 mg/kg BW) was administered, which is one-tenth the dose of soy-deptrestatin administered in the GABA administration group and theanine administration group, the percentage of immobility time was reduced more than in the GABA administration group and theanine administration group, confirming a strong antidepressant effect.

Example 4 Anti-cerebral inflammation effect of soybean peptides To examine the anti-cerebral inflammation effect of soybean peptides, the amount of interleukin-6 (IL-6) in the brains of mice was measured.
Forty minutes after the final sample administration in Example 3, mouse brains were collected 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 x 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 FIG. 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 intracerebral inflammation.

Recent research has 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"). In the brain and other central nervous tissues, it is known that 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.

Example 5 Antidepressant Effect of Collagen Peptide Collagen peptide (Nippi Peptide (registered trademark) PCT-A, manufactured by Nippi Corporation, 10 mg, 100 mg, 500 mg, 1000 mg/kg BW) was administered to 7-week-old Slc:ddY mice (male) via stomach tube at doses of 10 mg, 100 mg, 500 mg, and 1000 mg/kg BW. Water was administered as a control. Thirty minutes after sample administration, the mice were suspended by their tails, and measurements were 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) measured/360 seconds x 100 (%). The results of the tail suspension test described above are shown in Figure 6.
6, the immobility time was significantly reduced in a concentration-dependent manner at 100 mg/kg BW or more of collagen peptide. This result indicates that collagen peptide has an antidepressant effect.

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 following 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). The values of total BDNF and HGF were calculated as concentrations per protein amount. The measurement results of the total BDNF amount are shown in Figure 7, and the measurement results of the HGF amount are shown in Figure 8.
The results in Figure 7 showed that the collagen peptide (100 and 500 mg/kg BW) administration groups showed a significant increase in total BDNF levels compared to the control group. It was shown that ingestion of collagen peptide increases BDNF expression levels. Similarly, the results in Figure 8 showed that in measuring intracerebral 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 indicated that collagen peptide has the ability to induce the expression of both the neurotrophic factor BDNF and the hepatocyte growth factor HGF.
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 and neurodegenerative diseases such as depression and Alzheimer's disease.

Neuroinflammation has been shown to be deeply involved in the onset and progression of central nervous system diseases such as Alzheimer's disease (see, 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, microglia, which are responsible for the immune system, are the primary cause of inflammatory responses, and cytokines such as IFNγ, IL1β, IL-6, and TNF-α produced by activated microglia independently suppress neurogenesis (see, 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 nervous system progenitor cells (NG2 glia), a type of glial cell, were removed from the brain, microglia became activated, causing excessive neuroinflammation, which damaged hippocampal neurons involved in memory and spatial learning and led to significant atrophy of the 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)).
In addition, it was previously thought that neurons are generated during the fetal and juvenile stages 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 (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, from the above results, it is thought that collagen peptides, which induce the expression of both BDNF and HGF, are effective in improving mental disorders such as depression and Alzheimer's disease.

Example 7: Synergistic effect of soy peptide and collagen peptide A 1:1 mixture (by weight) of soy peptide (Soylax, manufactured by UHA Mikakuto Co., Ltd.) and collagen peptide (PCT-A) was dissolved in an equal volume of water and administered to 8-week-old Slc:ddY mice via stomach tube to achieve an intake of 20 mg/kg body weight (a 1:1 mixture of Soylax:PCT-A (10 mg + 10 mg/kg body weight)) or 10 mg/kg body weight (a 1:1 mixture of Soylax:PCT-A (5 mg + 5 mg/kg body weight)). A control group received the solvent (water) via tube.

As shown in Figure 9, the measurement results showed that there was no significant change in immobility time compared to the control group in the Soylax (10 mg/kg BW) alone-administered group and the PCT-A (10 mg/kg BW) alone-administered 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).

From the above, it was found that a mixture of soy peptides and collagen peptides has a synergistic effect on improving depressive symptoms compared to using soy peptides or collagen peptides alone.

In particular, the results of Example 4 show that soybean peptides have an anti-cerebral inflammatory 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, particularly Alzheimer's disease.

[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) were 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, a 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.

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.
As can be seen from the results shown in Figures 10 and 12, the immobility time in the tail suspension test was reduced by a single administration of the dipeptides and tripeptides used compared to the control, and in particular, there was a significant difference compared to the control for OP, PL, PO, PP, PS, GPA, GPO, GPW, GPP, GPL, GPS, and GPC.
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.

Example 9: Evaluation test of suppression of cognitive decline using senescence-accelerated mice Rodents such as mice naturally engage in exploratory behavior such as approaching an object when it is recognized as novel, checking its shape, and sniffing it. When doing so, they tend not to exploratory behavior toward objects they have already memorized, or they tend to explore them for a shorter period of time than toward novel objects. Taking advantage of this mouse characteristic, 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.

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

The suppression of cognitive decline was assessed by a novel object recognition test, which was performed as follows.
That is, the mice were 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 the mouse was removed from the cage, one of the objects was replaced with a new object (B: cylinder), and the trained mouse was returned to the 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 feed or the test feed, and the rats were divided into groups so that the novel object recognition rate was average in both groups. The test was conducted 4, 8, 12, 16, and 20 weeks after the intake of the control feed or the test feed.

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 (7)

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,
A neuropsychological function improving agent which is one or more members selected from the group consisting of glycine-proline-proline and glycine-proline-leucine. 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. The neuropsychological function improving agent according to claim 2, characterized in that soybean peptides and collagen peptides are blended in a ratio and content that produces a synergistic effect. The neuropsychological function improving agent according to any one of claims 1 to 3, wherein the symptoms and/or diseases caused by a decline in neuropsychological function are Alzheimer's disease, depression, memory impairment due to aging, autism spectrum disorder, bipolar disorder, schizophrenia, or chronic fatigue syndrome. The neuropsychological function improving agent according to any one of claims 2 to 4, wherein the soybean peptide is a thermolysin digest. A pharmaceutical composition for improving neuropsychological function, comprising the neuropsychological function improving agent according to any one of claims 1 to 5 . A food or drink composition for improving neuropsychological function, comprising the neuropsychological function improver according to any one of claims 1 to 5 .