Composition for reducing persistence

Abstract

This invention relates to a composition for reducing persistence. [Solution] The composition of the present invention comprises at least one of a GLP-1 receptor agonist, a GLP-1 secretion promoter, or GLP-1.

Description

[Technical Field]

[0001] This invention relates to compositions for reducing persistence, etc. [Background technology]

[0002] Persistence The trait of strongly adhering to familiar and understandable behaviors is referred to as persistence, pickiness, obsessiveness, stubbornness, or bias of interest. These traits manifest, for example, as a strong adherence to personal rules, common regulations, or established routines; extreme bias in interests and concerns; panic when habits or routines are disrupted; and difficulty adapting to changing circumstances. In this specification, these traits are collectively referred to as "persistence."

[0003] When the degree of persistence is severe, it can cause difficulties in the individual's life and negatively impact those around them, making improvement desirable. In particular, persistent tendencies may be associated with certain diseases or symptoms such as dementia, autism spectrum disorder, schizophrenia, depression, and attention deficit hyperactivity disorder (ADHD). Persistence caused by such diseases or symptoms is difficult to reduce through environmental improvements or the individual's efforts. The development of compositions that reduce persistence is therefore highly desired.

[0004] GLP-1 The intestinal tract contains endocrine cells that secrete gastrointestinal hormones, which regulate the functions of other organs. Some of the gastrointestinal hormones secreted by enteroendocrine cells are also called incretins. They are secreted into the bloodstream in response to food intake and act on pancreatic β-cells (hereinafter referred to as "pancreatic β-cells") to promote insulin secretion. These incretins not only promote insulin secretion but also stimulate the regeneration of pancreatic β-cells and act on the central nervous system via the vagus nerve to suppress feeding behavior. Therefore, they are attracting attention as targets for the development of new therapeutic drugs for diabetes and obesity. There are two types of incretins: glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1).

[0005] GLP-1 is secreted from intestinal endocrine L cells (hereinafter referred to as "L cells") located in the lower small intestine. L cells face both the basement membrane side and the lumen side of the small intestinal mucosa and are called "open-type" endocrine cells. L cells possess sodium-dependent glucose transporters, which co-transport glucose and sodium from outside the cell, i.e., from within the lumen, into the cell. As a result, the membrane potential is depolarized, and voltage-dependent L-type Ca2+ is released. 2+ The channel is activated. This voltage-dependent L-type Ca 2+ Ca enters the cell from the channel 2+ Upon influx of these substances, GLP-1 is released in a glucose-dependent manner. Furthermore, L cells express G protein-coupled receptors (GPCRs) such as fatty acid receptors, bile acid receptors, and sweet taste receptors, and it is thought that these receptors sense lipids, bile acids, and glucose in the lumen, thereby releasing GLP-1.

[0006] The secreted GLP-1 acts on the β-cells of the islets of Langerhans in the pancreas, increasing insulin secretion and decreasing glucagon secretion. Increased insulin secretion inhibits acid secretion and gastric emptying, increasing satiety and thus reducing food intake.

[0007] Zheng et al., Molecular Metabolism 47(2021) 101180 (https: / / pubmed.ncbi.nlm.nih.gov / 33556642 / ) (Non-patent Literature 1) reported on the relationship between gastrointestinal hormones and higher-order mental activity, including the observation that GLP-1 receptor agonists improve cognitive ability in Alzheimer's disease model mice. It has been suggested that GLP-1 receptor agonists contribute to one of the neuroprotective roles in Alzheimer's disease. However, this literature does not mention any effect of GLP-1 receptor agonists on persistence.

[0008] Nauck et al., Molecular Metabolism 46 (2021) 101102 (https: / / www.sciencedirect.com / science / article / pii / S2212877820301769) (Non-Patent Literature 2) describes that several drugs, including GLP-1 receptor agonists, are marketed as treatments for type 2 diabetes. Furthermore, it describes that GLP-1 receptor agonists reduce weight and cardiovascular events (myocardial infarction, stroke, and associated mortality). However, similar to Non-Patent Literature 1, Non-Patent Literature 2 does not mention any effect of GLP-1 receptor agonists on persistence. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] Japanese Patent Publication No. 2020-097531 [Patent Document 2] WO2018 / 029150 A1 [Non-patent literature]

[0010] [Non-Patent Document 1] Zheng et al., Molecular Metabolism 47(2021) 101180(https: / / pubmed.ncbi.nlm.nih.gov / 33556642 / ) [Non-Patent Document 2] Nauck et al.,Molecular Metabolism 46(2021) 101102(https: / / www.sciencedirect.com / science / article / pii / S2212877820301769) [Non-Patent Document 3] Journal of the Japanese Society for Nutrition and Food Science, Vol. 77, No. 1, pp. 13-19 (2024) [Non-Patent Document 4] Okayama University Faculty of Education Research Journal, No. 125 (2004), pp. 35-42 [Non-Patent Document 5] "Attention Models and Reinforcement Learning - Learning Mechanisms of Attention in the Frontal Lobe and Basal Ganglia," Yamakawa et al., http: / / hymkw.com / researches / sig-cii-97 / paper.html [Non-Patent Document 6] NATURE COMMUNICATIONS | (2019)10:4007 | https: / / doi.org / 10.1038 / s41467-019-11978-0 [Non-Patent Document 7] Biochemical and Biophysical Research Communications,588,(2022),118-124 [Non-Patent Document 8] FEBS LETTERS 2023,597(5),https: / / doi.org / 10.1002 / 1873-3468.14580 [Non-Patent Document 9] Molecular Metabolism,2024,Dec 9:102072.,doi:10.1016 / j.molmet.2024.102072 [Non-Patent Document 10] Santos-Hernandez M et al.,Food Chem. 2023 Feb 15;402:134225. doi: 10.1016 / j.foodchem.2022.134225

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[0011] An object of the present invention is to provide a composition or the like for reducing tenacity. [Means for Solving the Problems]

[0012] The present inventors have found that tenacity is reduced by administering a GLP-1 receptor agonist or a GLP-1 secretion promoter, that is, by promoting the function of GLP-1 in vivo or by promoting the secretion of GLP-1, and have conceived the present invention.

[0013] The present invention includes, but is not limited to, the following aspects. [1] A composition for reducing tenacity, comprising at least one of a GLP-1 receptor agonist, a GLP-1 secretion promoter, or GLP-1. [2] The composition according to [1], wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, exenatide, liraglutide, lixisenatide, dulaglutide, tirzepatide, and retatrutide. [3] The aforementioned GLP-1 secretion-promoting agents include allulose, propionic acid, butyric acid, valeric acid, pantothenic acid, cholic acid, 3-aminoisobutyric acid, γ-aminobutyric acid, 2-aminobutyric acid, pipecolic acid, ornithine, citrulline, tyrosine methyl ester, piperidine, taurine, pyridoxal, pyridoxamine, pyridoxine, sarcosine, N,N-dimethylglycine, cytosine, 1,3-diaminopropane, nicotinic acid, indole-3-acetamide, and D-alamine. Nin, 5-hydroxylysine, 1-methylnicotinamide, thiamine, carnitine, gluconic acid, prostaglandin E2, methionine sulfoxide, spermidine and spermine, folic acid, caproic acid, lauric acid, pentadecanoic acid, oleic acid, vaccenic acid, linolenic acid, myristoleic acid, palmitoleic acid, arachidic acid, eicosenoic acid, eicosadienoic acid, dihomo-γ-linolenic acid, arachidonic acid, rumenic acid, 10-trans-12-cis Conjugated linoleic acid, antheisopentadecanoic acid, isopalmitic acid, antheisoheptadecanoic acid, isoheptadecanoic acid, palmitic acid amide, myristic acid amide, linoleic acid, 10-hydroxy-12-octadecenoic acid, docosahexaenoic acid, eicosapentaenoic acid, phenylalanine, tryptophan, proline, arginine, glutamine, metformin, deoxycholic acid, oxytocin, vasopressin, GPR40 receptor agonist, GPR120 receptor agonist, GPR40 receptor / GPR120 receptor dual agonist, WY The composition according to [1], which is a dipeptide that is FY, GW, KA, KF, NI, QL, QY, PM, WF, or WN; a peptide that is VAWRNRCKGTD, WRNRCKGTD, WIRGCRL, RYLGYLE, SRYPS, or LIVTQTM; a microorganism belonging to the genera Bifidobacterium, Citrobacter, or Lactobacillus that produces geraniol, citronellal, tryptophan-bound cholic acid, bile acid, and / or indolepropionic acid; and one or more substances selected from the group consisting of tryptophan-bound cholic acid, bile acid, indolepropionic acid, isoquercitrin, delphinidin 3-rutinoside, curcumin, berberine, [6]-Gingerol, quercetin, cinnamaldehyde, and capsaicin. [4] A composition according to any one of [1]-[3], wherein the persistence is based on one or more diseases or conditions selected from the group consisting of dementia, autism spectrum disorder, schizophrenia, depression, attention deficit hyperactivity disorder, obesity, diabetes, and aging. [5] A composition according to any one of items [1]-[3], which is a pharmaceutical composition, food, beverage, or supplement. [6] Use for the manufacture of compositions for reducing the persistence of GLP-1 receptor agonists, GLP-1 secretagogues, or GLP-1. [7] A screening method for GLP-1 secretagogues or GLP-1 receptor agonists, using the reduction of persistence as an indicator. [Effects of the Invention]

[0014] The composition of the present invention has the effect of reducing persistence. [Brief explanation of the drawing]

[0015] [Figure 1] Figure 1 shows an overview of the administration of GLP-1 receptor agonist (GLP-1RA) (semaglutide) or negative control (NC) to normal mice (WT) and obese mice (leptin receptor knockout mice (LepR-KO)). [Figure 2] Figure 2 shows the reagents administered to mice in the obsessive behavior test, as well as the test schedule. The substances were administered throughout the entire period: a 7-8 week pre-habituation period, a 3-week habituation period, and a 7-8 week obsessive behavior evaluation period. [Figure 3] Figure 3 shows the "behavior formation" process in preparation for the obsessive behavior test. [Figure 4] Figure 4 shows the "acquisition" of preparation for the obsessive behavior test. [Figure 5] Figure 5 shows an overview of the obsessive behavior test. [Figure 6]Figure 6 shows the evaluation method for obsessive behaviors in obsessive behavior tests. [Figure 7] Figure 7 shows the method for calculating the re-selection rate in the obsessive behavior test. [Figure 8] Figure 8 shows the effect of GLP-1RA (semaglutide) administration on reselectivity (persistence) in normal mice of the young (top), middle (middle), and aged (bottom) age groups. Black squares indicate results for the GLP-1RA-administered group. White circles indicate results for the NC-administered group. "Rev." means "reversal". [Figure 9] Figure 9 shows the reselection rates when NC was administered to normal mice (WT) (white circles) and obese mice (LepR-KO) (white squares). "Rev." means "reversal". [Figure 10] Figure 10 shows the reselection rates when GLP-1RA was administered to normal mice (WT) (black circles) and obese mice (LepR-KO) (black squares). "Rev." means "reversal". [Figure 11] Figure 11 compares the reselection rate of obese mice (LepR-KO) administered with GLP-1RA (black squares) with the reselection rate of the same mice administered with NC (white squares). "Rev." means "reversal." This figure shows the effect of semaglutide administration on the reselection rate (persistence) of the LepR-KO group. [Figure 12] Figure 12 shows the effects of administering a GLP-1 secretagogue to normal mice in the adult group. The black squares indicate the reselectivity rate when the GLP-1 secretagogue was administered, and the white circles indicate the reselectivity rate when physiological saline was administered. "Rev." means "reversal". [Figure 13] Figure 13 shows the reselection rates when allulose was administered to young, normal mice (WT) (white circles) and afferent vagus nerve-specific GLP-1 receptor-deficient mice (afferent vagus nerve-specific Glp1R-KO) (black squares). "Rev." means "reversal". [Figure 14]Figure 14 shows the effect on reselectivity (persistence) when GLP-1RA / GIPRA (tilzepatide) is administered to young, normal mice. Black triangles indicate the results for the GLP-1RA / GIPRA-administered group. White circles indicate the results for the vehicle-administered group. "Rev." means "reversal". [Figure 15] Figure 15 shows the effect on reselectivity (persistence) when GLP-1RA / GIPRA / GCGRA (letatrutide) is administered to young, normal mice. The black diamonds represent the results for the GLP-1RA / GIPRA / GCGRA administration group. The white circles represent the results for the vehicle administration group. "Rev." means "reversal". [Modes for carrying out the invention]

[0016] The present invention includes, but is not limited to, the following embodiments. Unless otherwise specified herein, the technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art. The substances, materials and examples disclosed herein are illustrative and not intended to limit them. Where the phrase "in one embodiment" is used herein, it means that the invention is not limited to that embodiment, i.e., it is not limited to that embodiment.

[0017] 1. Composition In one embodiment, the present invention relates to a composition for reducing persistence. The composition of the present invention comprises at least one of a GLP-1 receptor agonist, a GLP-1 secretagogue, or GLP-1.

[0018] "Persistence" is a characteristic of strongly adhering to familiar and understandable behaviors, and may also be referred to as obsession, compulsion, stubbornness, or a narrow range of interests. The characteristics of persistence can manifest as, for example, a strong adherence to personal rules, common regulations, or established procedures; extreme bias in interests and concerns; panic when habits or routines are disrupted; difficulty adapting to changing circumstances; inflexibility; becoming fixated on one thing and being unable to easily change it; and continuing to do the same thing indefinitely.

[0019] "Persistence" can be caused by certain diseases or symptoms. Non-limitingly, persistence is based on one or more diseases or symptoms selected from the group consisting of dementia, autism spectrum disorder, schizophrenia, depression, attention deficit hyperactivity disorder, obesity, diabetes, and aging. The age at which age-related persistence can occur varies by race, country, and era, similar to human life expectancy. For example, based on Japanese people in 2024, it is more likely to occur in old age, from around the late 60s onward. It can also occur in middle age, from around the late 30s to early 60s. On the other hand, younger people, younger than their early 30s, are more flexible and less prone to persistence compared to middle age and old age.

[0020] Alternatively, "persistence" may not be caused by a specific disease or symptom, but rather by an innate personality trait. The aforementioned composition may be applied for therapeutic purposes, particularly when the degree of persistence is significant, causing difficulties in the individual's life and negative impacts on those around them, and improvement is desired. Alternatively, it may be applied for preventive purposes to individuals with specific diseases or symptoms, such as dementia.

[0021] "Reducing persistence" means that when the composition is administered, the degree of persistence decreases compared to before administration. Alternatively, it means that when the composition is administered to a subject with a disease or symptoms that may cause persistent characteristics such as dementia, the persistent characteristics will not occur.

[0022] There are no particular limitations on the method for measuring the "degree of persistence." Non-restrictively, for example, the Wisconsin Card Sorting Test (WCST) can be used to objectively and quantitatively evaluate the "degree of persistence." Specifically, the WCST is a neuropsychological test that assesses the ability to cope with changes in a situation (set-shifting).

[0023] First, the examiner presents the subject with cards of the following types: (1) Colors of the shapes: red, green, yellow, blue; (2) Shapes of the shapes: circles, triangles, stars, crosses; (3) Number of shapes: cards containing 1 to 4 shapes. The examiner decides on three classification rules (for example, classifying by color) beforehand without telling the subject. The subject then classifies the cards one by one. The examiner only tells the subject whether their classification is correct or not. The subject tries to deduce the classification rules decided by the examiner from the information they are given about whether their classification is correct or not. After being told the success or failure of their classification results many times, the subject gradually comes to understand the classification rules decided by the examiner. As the test-taker understands the classification rules set by the examiner, their accuracy rate increases. However, the examiner suddenly changes the classification rules midway through (after about 10 correct answers). The examiner then decides on the new classification rules without informing the test-taker, and the test-taker then classifies the cards they are given one by one according to the new rules.

[0024] By repeatedly performing this task, the time it takes for a subject to learn a new classification rule and the number of errors made during learning can be analyzed and scored. The number of errors made, i.e., the subject's persistence in sticking to their own classification rule, can then be evaluated as persistence. A decrease in the number of errors can be objectively and quantitatively evaluated in humans as a decrease in persistence. This WCST is used as a frontal lobe function assessment method and is widely used clinically for patients with brain injury, neurodegenerative diseases, schizophrenia, depression, autism spectrum disorder, and other neuropsychiatric disorders (Okayama University Faculty of Education Research Report No. 125 (2004) 35-42) (Non-patent Literature 4). "Attention Model and Reinforcement Learning - Learning Mechanism of Attention in the Frontal Lobe and Basal Ganglia," Yamakawa et al., http: / / hymkw.com / researches / sig-cii-97 / paper.html (Non-patent Literature 5) describes that persistence can be evaluated using WCST.

[0025] GLP-1 is a glucagon-like peptide-1 (GLP-1), a gastrointestinal peptide hormone secreted from the mucosal epithelium of the gastrointestinal tract in response to orally ingested nutrients (carbohydrates, lipids, and proteins). Specifically, it is cleaved from preproglucagon as GLP-1(1-37) in the intestinal endocrine L cells ("L cells") located in the lower small intestine. Further cleavage of the N-terminal amino acid yields GLP-1(7-37) and GLP-1(7-36) amides, which possess strong physiological activity. In this specification, "GLP-1" refers to all or any of GLP-1(1-37), the physiologically active GLP-1(7-37), and GLP-1(7-36).

[0026] Secreted GLP-1 acts on the β-cells of the islets of Langerhans in the pancreas, increasing insulin secretion and decreasing glucagon secretion. Increased insulin secretion inhibits acid secretion and gastric emptying, increasing satiety and thus reducing food intake. In the central nervous system, GLP-1 production is known to occur in neurons of the nucleus tractus solitarius in the medulla oblongata that express leptin receptors (LepR), and these neurons are said to be the only GLP-1 producing neurons in the brain.

[0027] The present invention is based on the technical idea of ​​reducing persistence by promoting the function of GLP-1 in vivo or by promoting the secretion of GLP-1. Therefore, the type of GLP-1 receptor agonist, GLP-1 secretion promoter, or GLP-1 included in the composition of the present invention is not particularly limited.

[0028] A "GLP-1 receptor agonist" is a drug that acts by activating the GLP-1 receptor. GLP-1 receptor agonists are mainly used to treat type 2 diabetes. Because GLP-1 has a relatively short duration of action, GLP-1 receptor agonists that have been modified to overcome this limitation may be used as medications.

[0029] In a broad sense, glucagon-like peptide-1 receptor agonists include glucagon-like peptide-1 receptor agonists (also called "GLP-1 receptor agonists," "GLP-1 receptor agonists," or "GLP-1RAs"), agonists that act on both the GLP-1 receptor and the glucose-dependent insulin-stimulating polypeptide (GIP) receptor (also called "GIP / GLP-1 receptor agonists," "GIP / GLP-1RAs," or "GIP / GLP-1 receptor dual agonists"), GIP / GLP-1 / glucagon receptor agonists (also called "GIP / GLP-1 / glucagon agonists (GCG)" or "triple agonists"), and GLP-1 / amyrin receptor agonists. In this specification, the term "GLP-1 receptor agonist" is used to include any of the broad definitions of glucagon-like peptide-1 receptor agonists described above, unless otherwise specified and unless there is a technical inconsistency.

[0030] Non-limitingly, the GLP-1 receptor agonist is selected from the group consisting of semaglutide, exenatide, liraglutide, lixisenatide, dulaglutide, tilzepatide, and letatoltide. One GLP-1 receptor agonist may be used, or two or more GLP-1 receptor agonists may be used.

[0031] Semaglutide: CAS number 910463-68-2, trade names Ozempic (subcutaneous injection), Rybelsus (tablets); Exenatide: CAS number 141732-76-5, trade name Byetta (subcutaneous injection); Liraglutide: CAS number 204656-20-2, trade name Victoza (subcutaneous injection); Lixisenatide: CAS number 827033-10-3, trade name Lyxumia (subcutaneous injection); Dulaglutide: CAS number 923950-08-7, trade name Trulicity (subcutaneous injection); Chilzepatide: CAS number 2023788-19-2, trade names Zepbound (subcutaneous injection), Manjaro (subcutaneous injection); and Letatolchid: CAS number 2381089-83-2 The type of GLP-1 receptor agonist is not particularly limited. One type of GLP-1 receptor agonist may be used, or two or more types of GLP-1 receptor agonists may be used. Two or more GLP-1 receptor agonists may be contained in a single composition, or two or more compositions containing one type of GLP-1 receptor agonist may be administered simultaneously or sequentially.

[0032] The term "GLP-1 secretion promoter" is not particularly limited as long as it is an agent that has the effect of promoting the secretion of GLP-1. "GLP-1 secretion promotion" means that the secretion of GLP-1 from GLP-1 secreting cells is promoted when the GLP-1 secretion promoter is present compared to when it is not present. This also includes cases where, in the absence of the GLP-1 secretion promoter, the secretion of GLP-1 from GLP-1 secreting cells was not detected, but it becomes detectable in the presence of the GLP-1 secretion promoter. In cases where, in a living organism, the action of a first substance causes the production, activation, etc., of another second substance, and the secretion of GLP-1 is promoted by the second substance, the first substance, that is, a substance that has the effect of indirectly promoting the secretion of GLP-1, may also be included in the term "GLP-1 secretion promoter" as used herein.

[0033] Non-limitingly, the GLP-1 secretion-promoting agents include allulose, propionic acid, butyric acid, valeric acid, pantothenic acid, cholic acid, 3-aminoisobutyric acid, γ-aminobutyric acid, 2-aminobutyric acid, pipecolic acid, ornithine, citrulline, tyrosine methyl ester, piperidine, taurine, pyridoxal, pyridoxamine, pyridoxine, sarcosine, N,N-dimethylglycine, cytosine, 1,3-diaminopropane, nicotinic acid, indole-3-acetamide, D -Alanine, 5-hydroxylysine, 1-methylnicotinamide, thiamine, carnitine, gluconic acid, prostaglandin E2, methionine sulfoxide, spermidine and spermine, folic acid, caproic acid, lauric acid, pentadecanoic acid, oleic acid, vaccenic acid, linolenic acid, myristoleic acid, palmitoleic acid, arachidic acid, eicosenoic acid, eicosadienoic acid, dihomo-γ-linolenic acid, arachidonic acid, rumenic acid, 10-trans-12-cis One or more substances selected from the group consisting of conjugated linoleic acid (CLA), anteisopentadecanoic acid, isopalmitic acid, anteisoheptadecanoic acid, isoheptadecanoic acid, palmitic acid amide, myristic acid amide, linoleic acid, 10-hydroxy-12-octadecenoic acid, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), phenylalanine, tryptophan, proline, arginine, glutamine, metformin, deoxycholic acid, oxytocin, vasopressin, GPR40 receptor agonists, GPR120 receptor agonists, GPR40 receptor / GPR120 receptor dual agonists, and dipeptides that are WY, FY, GW, KA, KF, NI, QL, QY, PM, WF, or WN.

[0034] Non-limitingly, the GLP-1 secretion-promoting agent may be selected from the following: (1) Peptides derived from milk protein (casein, whey) and egg white protein (lysozyme) ·VAWRNRCKGTD (Sequence ID 1) ·WRNRCKGTD (Sequence ID 2) ·WIRGCRL (Sequence ID 3) ·RYLGYLE (Sequence ID 4) · SRYPS (Sequence ID 5) • LIVTQ™ (SEQ ID NO: 6) Santos-Hernandez M et al., Food Chem. 2023 Feb 15;402:134225. doi: 10.1016 / j.foodchem.2022.134225 (Non-patent Document 10) The milk protein and egg white protein mentioned above have the function of activating CaSR receptors or GPR93 receptors. Activation of CaSR receptors or GPR93 receptors promotes GLP-1 secretion.

[0035] (2) Rose and lemon scent compounds The following scent substances, such as those found in roses and lemons, promote GLP-1 secretion. Geraniol • Citronellal Kim KS, et al.,Sci Rep. 2017 Oct 25;7(1):13978. doi: 10.1038 / s41598-017-14086-5 (Non-patent document 11) (3) Microorganisms that produce tryptophan-bound cholic acid, bile acids, and / or indolepropionic acid, or metabolites produced by such microorganisms Microorganisms belonging to the genera Bifidobacterium, Citrobacter, or Lactobacillus produce metabolites such as tryptophan-binding cholic acid, bile acids, and indolepropionic acid. These metabolites promote GLP-1 secretion.

[0036] For example, the following Bifidobacteria and Lactobacillus species possess bile salt hydrolysates and transferases. ·Bifidobacterium adolescentis JC24-02, ·Bifidobacterium bifidum JC24-01, ·Bifidobacterium animalis subsp. lactis MN-Gup and JC24-02, ·Bifidobacterium longum B79 and BBMN68, ·Citrobacter freundii JC24-03, ·Enterococcus avium JC24-01, ·Lacticaseibacillus paracasei LC-19 The following metabolites are produced by bile salt hydrolysates and transferases.

[0037] Tryptophan-bound cholic acid ·Bile acids • Indolepropionic acid These metabolites have the effect of promoting GLP-1 secretion.

[0038] Therefore, by ingesting the above-mentioned Bifidobacterium and Lactobacillus microorganisms that possess bile salt hydrolysates and transferases, metabolites such as tryptophan-binding cholic acid increase in the body, leading to GLP-1 secretion.

[0039] Lin J, et al.,Cell. 2025 Aug 21;188(17):4530-4548.e25. doi: 10.1016 / j.cell.2025.05.010 (Non-patent document 12) (4) Polyphenols found in onions, buckwheat, etc. Isoquercitrin Zhang L, et al.,RSC Adv. 2018 Apr 19;8(27):14967-14974. doi: 10.1039 / c8ra00675j (Non-patent document 13) (5) Polyphenols contained in blackcurrant Delphinidin 3-rutinoside Kato M, et al.,PLoS One. 2015 May 11;10(5):e0126157. doi: 10.1371 / journal.pone.0126157 (Non-patent document 14) (6) Polyphenols contained in turmeric Curcumin Takikawa M, et al.,Biochem Biophys Res Commun. 2013 May 31;435(2):165-70. doi: 10.1016 / j.bbrc.2013.04.092 (Non-patent Document 15) (7) Yellow naturally occurring alkaloids found in plants such as Phellodendron amurense and Coptis japonica. Berberine Berberine is a type of benzylisoquinoline alkaloid found in plants such as Phellodendron amurense (Rutaceae), Coptis japonica (Buttercup), Phellodendron amurense, Oregon grape, Hydrastis, and Mahonia japonica.

[0040] Yu Y, et al.,Biochem Pharmacol. 2010 Apr 1;79(7):1000-6. doi: 10.1016 / j.bcp.2009.11.017 (Non-patent document 16) (8) The main pungent component of ginger ·[6]-Gingerol Samad MB, et al.,BMC Complement Altern Med. 2017 Aug 9;17(1):395. doi: 10.1186 / s12906-017-1903-0 (Non-patent document 17) (9) Flavonoids, which are abundant in onions (especially the peel), apples, broccoli, etc. • Quercetin Wang C, et al.,J. Mol Nutr Food Res. 2025 Aug;69(16):e70109. doi: 10.1002 / mnfr.70109 (Non-patent document 18) (10) The main components of cinnamon's aroma and taste (Cinnamaldehyde) and capsaicin Cinnamaldehyde Capsaicin Van Liefferinge E, et al.,Animals (Basel). 2021 Jul 30;11(8):2262. doi: 10.3390 / ani11082262 (Non-patent document 19) The GLP-1 secretion promoter also includes methods of orally administering these substances to a living organism by placing them in a carrier such as a capsule, or by orally administering precursors of these substances to a living organism to induce intestinal bacteria to produce these substances.

[0041] Allulose (CAS number 23140-52-5) is a monosaccharide classified as a hexasaccharide and ketose, also known as D-psicose. It is a rare sugar that exists only in very small amounts in nature. It has a GLP-1 secretion-promoting effect and is known to have effects such as suppressing the rise in postprandial blood glucose levels, anti-obesity, and prevention of arteriosclerosis.

[0042] In one embodiment, the GLP-1 secretion promoter includes one or more substances selected from the group consisting of propionic acid, butyric acid, valeric acid, pantothenic acid, cholic acid, 3-aminoisobutyric acid, γ-aminobutyric acid, 2-aminobutyric acid, pipecolic acid, ornithine, citrulline, tyrosine methyl ester, piperidine, taurine, pyridoxal, pyridoxamine, pyridoxine, sarcosine, N,N-dimethylglycine, cytosine, 1,3-diaminopropane, nicotinic acid, indole-3-acetamide, D-alanine, 5-hydroxylysine, 1-methylnicotinamide, thiamine, carnitine, gluconic acid, prostaglandin E2, methionine sulfoxide, spermidine, and spermine (Japanese Patent Application Publication No. 2020-097531).

[0043] Lipids such as caproic acid, lauric acid, pentadecanoic acid, oleic acid, vaccenic acid, linolenic acid, myristoleic acid, palmitoleic acid, arachidic acid, eicosenoic acid, eicosadienoic acid, dihomo-γ-linolenic acid, arachidonic acid, rumenic acid, 10-trans-12-cis-conjugated linoleic acid (CLA), anteisopentadecanoic acid, isopalmitic acid, anteisoheptadecanoic acid, isoheptadecanoic acid, palmitic acid amide, myristic acid amide, linoleic acid, 10-hydroxy-12-octadecenoic acid, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) are known to promote GLP-1 secretion. Regarding 10-trans-12-sys CLA, see, for example, NATURE COMMUNICATIONS | (2019)10:4007 | https: / / doi.org / 10.1038 / s41467-019-11978-0 (Non-Patent Literature 6).

[0044] Amino acids such as phenylalanine, tryptophan, proline, arginine, and glutamine have been reported to induce GLP-1 secretion (Biochemical and Biophysical Research Communications, 588, (2022), 118-124) (Non-Patent Literature 7).

[0045] The GLP-1 secretion-promoting effect of deoxycholic acid (DCA) is described, for example, in FEBS LETTERS 2023, 597(5), https: / / doi.org / 10.1002 / 1873-3468.14580 (Non-Patent Literature 8).

[0046] The GLP-1 secretion-promoting effects of hormones such as oxytocin and vasopressin are described, for example, in Molecular Metabolism, 2024, Dec 9:102072, doi:10.1016 / j.molmet.2024.102072 (Non-Patent Literature 9). These hormones are preferably administered by subcutaneous injection.

[0047] GPR40 agonists include, but are not limited to, GW9508 (CAS number: 885101-89-3), LY2922470 (CAS number: 1423018-12-5), SCO-267 (CAS number: 1656261-09-4), and Fasiglifam (CAS number: 1000413-72-8, an oral GPR40 receptor agonist). GPR120 agonists include, but are not limited to, TUG-891 (CAS number: 1374516-07-0). GPR40 / GPR120 dual agonists include, but are not limited to, DFL23916 (WO2018 / 029150 A1) and MEDICA16 (CAS number: 87272-20-6). GPR40 receptor agonists, GPR120 receptor agonists, and GPR40 receptor / GPR120 receptor dual agonists are mostly preferably administered parenterally, particularly by intravenous or subcutaneous injection. Fasiglifam is an orally administered GPR40 receptor agonist.

[0048] The Journal of the Japanese Society for Nutrition and Food Science, Vol. 77, No. 1, pp. 13-19 (2024), states that the following 11 dipeptides have a GLP-1 secretion-promoting effect. WY, FY, GW, KA, KF, NI, QL, QY, PM, WF, WN (single-letter abbreviation) In one embodiment, the GLP-1 secretion promoter is these dipeptides. In one embodiment, the GLP-1 secretion promoter is a dipeptide comprising WY.

[0049] One type of GLP-1 secretagogue may be used, or two or more types of GLP-1 secretagogues may be used. Two or more types of GLP-1 secretagogues may be contained in a single composition, or two or more compositions containing one type of GLP-1 secretagogue may be administered simultaneously or sequentially. "Sequential administration" means administering the two or more compositions in sequence within a time difference that allows them to interact. "A time difference that allows the two or more compositions to interact" is not limited to within 6 hours, within 3 hours, within 2 hours, within 1 hour, within 30 minutes, within 20 minutes, within 15 minutes, within 10 minutes, or within 5 minutes.

[0050] For example, powdered milk contains pantothenic acid, folic acid, pyridoxal, pyridoxamine, pyridoxine, etc., which have GLP-1 secretion-promoting effects. Therefore, powdered milk can be used as a composition containing a GLP-1 secretion promoter. Foods containing long-chain fatty acids such as linoleic acid, 10-hydroxy-12-octadecenoic acid, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) can also be used as a composition containing a GLP-1 secretion promoter.

[0051] One or more types of "GLP-1 receptor agonists" and one or more types of "GLP-1 secretion promoters" may be used. The "GLP-1 receptor agonist" and the "GLP-1 secretion promoter" may be contained in a single composition, or the composition containing the "GLP-1 receptor agonist" and the composition containing the "GLP-1 secretion promoter" may be administered simultaneously or sequentially. The significance of "sequential administration" is as described above.

[0052] In one embodiment, the composition contains GLP-1. When using "GLP-1" as the active ingredient, it is desirable to mimic the same conditions as when using a "GLP-1 receptor agonist," that is, to maintain a high concentration of GLP-1 in the target blood. Not limited to, in the case of GLP-1, it is preferable to administer it more frequently and multiple times than in the case of a "GLP-1 receptor agonist." In one embodiment, GLP-1 is administered daily. In one embodiment, GLP-1 is administered multiple times daily.

[0053] GLP-1 may be used in combination with a "GLP-1 receptor agonist" and / or a "GLP-1 secretion promoter." When "GLP-1," "GLP-1 receptor agonist," and / or a "GLP-1 secretion promoter" are used in combination, they may be contained in a single composition, or separate compositions containing each component may be administered simultaneously or sequentially. The significance of "sequential administration" is as described above.

[0054] In one embodiment, the composition is administered as a single dose. In another embodiment, the composition is administered two or more times in succession. The subjects to whom the composition is administered are not particularly limited, as long as they are animals in which persistence may be a problem. In one embodiment, the subject is a human. In another embodiment, the subject may be a non-human mammal. Examples include pets, farm animals, etc. Examples of non-human mammals include primates other than humans (monkeys, chimpanzees, gorillas, etc.), dolphins, sea lions, pigs, cattle, horses, sheep, dogs, cats, rats, mice, guinea pigs, rabbits, etc.

[0055] Unless otherwise specified, the information (including definitions) described in other sections shall also apply to the "Composition" section in this section. 2. Pharmaceutical Compositions In one embodiment, the composition of the present invention is a pharmaceutical composition. The pharmaceutical composition can be formulated according to standard techniques in the field of pharmaceuticals. See, for example, Alphonso Gennaro, ed., Remington's Pharmaceutical Sciences, 18th Ed., (1990) Mack Publishing Co., Easton, Pa.

[0056] The dosage form of the pharmaceutical composition is not particularly limited and can be appropriately selected according to the therapeutic purpose. Examples include liquids (e.g., injections), dispersants, suspensions, tablets, pills, powders, suppositories, powders, granules, capsules, syrups, lozenges, inhalants, ointments, eye drops, nasal drops, ear drops, poultices, etc. Formulation can be carried out by conventional methods, for example, by appropriately using excipients, binders, disintegrants, lubricants, solvents, solubilizers, colorants, flavoring and odor-correcting agents, stabilizers, emulsifiers, absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, etc.

[0057] Examples of ingredients used in formulation include, but are not limited to, purified water, saline solution, phosphate buffer, dextrose, glycerol, pharmaceutically acceptable organic solvents such as ethanol, animal and vegetable oils, lactose, mannitol, glucose, sorbitol, crystalline cellulose, hydroxypropyl cellulose, starch, corn starch, anhydrous silicic acid, aluminum magnesium silicate, collagen, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, sodium carboxymethylcellulose, sodium polyacrylate, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, methylcellulose, ethylcellulose, xanthan gum, acacia gum, tragacanth, casein, agar, polyethylene glycol, diglycerin, glycerin, propylene glycol, petrolatum, paraffin, octyldodecyl myristate, isopropyl myristate, higher alcohols, stearyl alcohol, stearic acid, human serum albumin, etc.

[0058] A composition containing the aforementioned pharmaceutical composition may also contain active ingredients other than the "GLP-1 receptor agonist," "GLP-1 secretion promoter," or "GLP-1." Additional active ingredients include, for example, active ingredients for diseases or symptoms such as dementia, autism spectrum disorder, schizophrenia, depression, attention deficit hyperactivity disorder, obesity, and diabetes. For example, active ingredients for dementia include donepezil, rivastigmine, galantamine, memantine, lecanemab, and donanemab. For example, active ingredients for diabetes include SGLT2 inhibitors and DPP-4 inhibitors. The additional active ingredients may be included in a single composition together with the "GLP-1 receptor agonist," "GLP-1 secretion promoter," or "GLP-1," or they may be combined in separate compositions to form a single kit.

[0059] The method of administering the pharmaceutical composition is not particularly limited and may be either oral or parenteral. In one embodiment, the pharmaceutical composition is administered subcutaneously. The dosage of the agent of the present invention is determined according to the patient's symptoms, weight, age, sex, etc., but generally, the amount of the active ingredient in a GLP-1 receptor agonist, GLP-1 secretagogue, or GLP-1 is in the range of approximately 0.05 μg / kg to 5000 mg / kg per day for adults, preferably in the range of approximately 0.1 μg / kg to 500 mg / kg, and more preferably in the range of approximately 1 μg / kg to 500 mg / kg. Not limited to, for example, if the active ingredient is "semaglutide", the range is approximately 1 μg / kg to 0.5 mg / kg per day for adults, preferably in the range of approximately 2 μg / kg to 0.25 mg / kg.

[0060] "Pharmaceutical compositions" include not only therapeutic drugs but also preventive drugs. Unless otherwise specified, the matters described in other sections (including definitions) also apply to "pharmaceutical compositions" in this section.

[0061] 3. Food, beverages, or supplements In one embodiment, the composition of the present invention is a food, beverage, or supplement. The aforementioned "GLP-1 receptor agonist," "GLP-1 secretion promoter," or "GLP-1" can be added to any food or beverage, and the type of food or beverage is not particularly limited.

[0062] "Food" can be used in all kinds of foods, including Japanese, Western, Chinese, and other Asian cuisines. For example, salads, stir-fries, simmered dishes, rice dishes, soups, pasta sauces, hot pots, stews, cheese, pudding, ice cream, etc. Foods to which the above composition can be applied include not only foods that the subject consumes on a daily basis, but also functional foods such as Foods for Specified Health Uses, Foods with Nutrient Function Claims, Foods for Special Dietary Uses, and Foods with Function Claims.

[0063] "Beverages" include, for example, dairy drinks, yogurt, fermented milk, lactic acid bacteria drinks, canned soups, soy milk, sports drinks, fruit juices, alcoholic beverages, black tea, oolong tea, coffee, green tea, cocoa, etc.

[0064] In addition, the aforementioned "GLP-1 receptor agonist," "GLP-1 secretion promoter," or "GLP-1" may be included in seasonings such as soy sauce, sauces, soup bases, mirin, and cooking sake.

[0065] The purpose of administering (ingesting) food, beverages, or supplements may be not only to reduce obsessive-compulsive disorder, but also to prevent it. Unless otherwise specified, the information (including definitions) described in other sections shall also apply to "foods, beverages, or supplements" in this section.

[0066] 4.Usage, method, etc. In one aspect, the present invention relates to the use of a composition for producing a GLP-1 receptor agonist, a GLP-1 secretagogue, or a composition for reducing the persistence of GLP-1.

[0067] In one aspect, the present invention relates to a GLP-1 receptor agonist, a GLP-1 secretagogue, or GLP-1 used for the production of a composition for reducing persistence. In one embodiment, the present invention relates to a GLP-1 receptor agonist, a GLP-1 secretagogue, or GLP-1 used to reduce persistence.

[0068] In one embodiment, the present invention relates to a method for reducing persistence, comprising the step of administering a GLP-1 receptor agonist, a GLP-1 secretagogue, or GLP-1 to a target. The "method for reducing persistence" includes preventing (preventing) the occurrence of persistence.

[0069] Unless otherwise specified, the matters described in other sections (including definitions) also apply to the "Usage and Method" section of this section. 5. Screening Methods In one embodiment, the present invention relates to a screening method for GLP-1 secretion promoters or GLP-1 receptor agonists, using whether or not they reduce persistence as an indicator.

[0070] In this invention, it has been found that various GLP-1 secretagogues or GLP-1 receptor agonists have the function of reducing persistence. It can be reasonably assumed that any substance that has the function of reducing persistence is highly likely to be a GLP-1 secretagogue or GLP-1 receptor agonist. Therefore, for target substances whose function as GLP-1 secretagogues or GLP-1 receptor agonists is unknown, it is possible to screen them as candidate substances for GLP-1 secretagogues or GLP-1 receptor agonists by using whether or not they reduce persistence as an indicator.

[0071] "Reducing persistence" means that when the target substance is administered, the degree of persistence decreases compared to before administration. Alternatively, it means that when the target substance is administered to a subject with a disease or symptoms that may cause the characteristic of persistence, such as dementia, the characteristic of persistence does not occur. The method for measuring the "degree of persistence" is not particularly limited, and methods such as those described in "1. Composition" can be used.

[0072] In a non-limiting sense, "using whether or not it reduces persistence as an indicator" means that if the degree of persistence decreases after administration of the target substance compared to before administration, or if the target substance does not cause the characteristic of persistence in subjects with diseases or symptoms that can cause the characteristic of persistence, such as dementia, then the target substance is selected as a candidate substance that has the function of promoting GLP-1 secretion or acting as a GLP-1 receptor agonist.

[0073] Further testing may be performed, if necessary, to determine whether the screened candidate substances truly function as GLP-1 secretagogues or GLP-1 receptor agonists. Such testing may include, for example, measuring plasma GLP-1 concentration by enzyme-linked immunosorbent assay (ELISA). Specifically, testing for function as a GLP-1 secretagogue or GLP-1 receptor agonist can be performed, for example, as follows: Before administering the substance to a human or non-human mammal, plasma is collected and the plasma GLP-1 concentration is measured by ELISA. Next, the substance is administered, and blood is collected and plasma is collected 15 and 30 minutes after administration, and the GLP-1 concentration is similarly measured by ELISA. If the plasma GLP-1 concentration at 15 and 30 minutes after administration is significantly higher than the plasma GLP-1 concentration before administration, the substance can be determined to be a GLP-1 secretagogue or GLP-1 receptor agonist.

[0074] Unless otherwise specified, the matters described in other sections (including definitions) also apply to the "Screening Method" section of this section. [Examples]

[0075] The present invention will be described in detail below based on examples, but the present invention is not limited to these examples. Those skilled in the art can easily modify and change the present invention based on the description herein, and such modifications are within the technical scope of the present invention.

[0076] Materials and Methods I Unless otherwise specified, the examples described herein were carried out using the following materials and methods.

[0077] 1. Laboratory animals (1) Normal mouse Male C57BL / 6JmsSlc mice were used in the behavioral studies. Male mice were purchased from Sankyo Labo Service (Tokyo, Japan) at 8 weeks of age for the young group, 32 weeks of age for the middle-aged group, and 55 weeks of age for the aged group.

[0078] The solutions for each reagent were administered starting one week after the reagents were purchased. The mice were housed individually in cages in a room with controlled light exposure (8am-8pm) for 17-19 weeks, including obsessive behavior tests.

[0079] The mice were fed CE-2 (CLEA Japan, Tokyo, Japan) and restricted feeding was implemented starting one week before the start of the obsessive behavior test. The restricted feeding was carried out to reduce each mouse's weight to approximately 80% of its weight before the restriction. Two days before the start of the obsessive behavior test, the mice were given 10 tablets of Purified Rodent Diet 5TUL 10mg (TestDiet, St. Louis, MO, USA) daily. Once the obsessive behavior test began, Purified Rodent Diet was given as a reward for completing tasks during the test, and more than one hour after the completion of a task, additional food necessary for weight maintenance was given using CE-2.

[0080] Body weight and food intake were measured five days a week after the first administration of each reagent. The diet consisted of CE-2. (2) Obese mice 8-week-old C57BLKS / J Iar -+Lepr db / +Lepr db Male mice were purchased from Sankyo Labo Service (Tokyo, Japan) and used in behavioral tests. These mice were single-recessive, hypereating, obese type 2 diabetic mice in which the leptin receptor (LepR-KO), a peptide hormone that plays a role in suppressing feeding and weight gain, was knocked out.

[0081] The preparation of the solutions for each reagent and the feeding of the mice were carried out in the same manner as for normal mice. 2. Approval of animal testing The animal experiments were conducted in compliance with the regulations stipulated in the "Act on the Protection and Management of Animals," the "University of Tokyo Animal Experiment Implementation Regulations," and the "University of Tokyo Animal Experiment Implementation Manual," with the approval of the Animal Experiment Committee of the Graduate School of Arts and Sciences, University of Tokyo (Approval No. 2020-4), and with strict adherence to rearing and storage conditions, reduction of suffering, minimization of the number of animals and stress on the animals, and careful consideration of the method of euthanasia.

[0082] 3. Reagents The following reagents were used. As a GLP-1 receptor agonist (hereinafter referred to as "GLP-1RA"), semaglutide (trade name: Ozempic) (NNC0113-0217, Novo Nordisk Inc., Copenhagen, Denmark); As a negative control (hereinafter referred to as "NC") for GLP-1 receptor agonists, NNC0113-0007 (recombinant protein of human GLP-1(7-37)-OH) (Novo Nordisk) is administered once a week, and D-allulose (hereinafter referred to as "allulose") is used as a GLP-1 secretion promoter (Matsutani Chemical Industry Co., Ltd.).

[0083] The protein used as NC, "NNC0113-0007," is a recombinant human GLP-1(7-37)-OH protein. 4. Administration of GLP-1 receptor agonists (GLP-1RAs) (1) C57BL / 6JmsSlc male mice (normal mice) were randomly divided at 9 weeks of age into a young group (GLP-1RA administration group, N=6) and an NC administration group (N=6). Similarly, at 33 weeks of age, they were randomly divided into a middle-aged group (GLP-1RA administration group, N=6) and an NC administration group (N=5). Similarly, at 56 weeks of age, they were randomly divided into a aged group (GLP-1RA administration group, N=4) and an NC administration group (N=6).

[0084] The young stage of a mouse corresponds to approximately the late teens to early 30s in humans, the middle stage to approximately the late 30s to early 60s in humans, and the old age to approximately the late 60s and older in humans. (The corresponding human ages are based on the age of Japanese people in 2024. However, like human lifespan, the corresponding human age may vary depending on race, country, era, etc.) C57BL / 6JmsSlc Male Mouse (Normal Mouse) Younger group: GLP-1RA administration group (N=6) and NC administration group (N=6) Middle-aged group: GLP-1RA administration group (N=6) and NC administration group (N=5) Elderly group: GLP-1RA administration group (N=4) and NC administration group (N=6) C57BLKS / J Iar -+Leprdb / +Leprdb male mice (obese mice) were randomly divided at 9 weeks of age into a group administered with a GLP-1 receptor agonist (hereinafter, GLP-1RA) (N=9) and a group administered with a negative control (hereinafter, NC) of a GLP-1 receptor agonist (N=9).

[0085] C57BLKS / J Iar -+Leprdb / +Leprdb Male Mouse (Obese Mouse) Younger group: GLP-1RA administration group (N=9) and NC administration group (N=9) (2) Administration of GLP-1 receptor agonists (GLP-1RAs) and negative controls (NCs) of GLP-1 receptor agonists In (1), the normal mice and obese mice were separated into two groups, and administration of GLP-1RA or NC was initiated as follows, and continued until the completion of the adherence test (Figure 1).

[0086] GLP-1RA (2.43 mM) or NC (2.43 mM) was dissolved in a pH 8 formulation vehicle (50 mM sodium phosphate, 70 mM sodium chloride, 0.007% polysorbate 20) to obtain the GLP-1RA solution and NC solution, respectively.

[0087] Each mouse was subcutaneously administered either GLP-1RA solution or NC solution at a dose of 40 μg / kg body weight using an insulin subcutaneous injection syringe (BD Lodose® 3 / 10 mL 29G, needle length 12.7 mm, Becton Dickinson Japan, Tokyo, Japan). The half-life of semaglutide is 8 hours.

[0088] For the mice used in the obsessive behavior test, administration was performed every Monday from 4 PM to 7 PM before the start of restricted feeding. After the start of restricted feeding, administration was performed every Friday from 4 PM to 7 PM. On the day the obsessive behavior test was performed, administration was performed at least one hour after the end of the test.

[0089] 5. Administration of GLP-1 secretagogues Male C57BL / 6JmsSlc mice were randomly divided into two groups: an allulose-administered group (N=9) and a saline-administered group (N=9) at 33 weeks of age, designated as the adult group. Administration of a GLP-1 secretagogue was initiated and continued until the completion of the selective testing.

[0090] Middle-aged group: Allulose administration group (N=9) and saline administration group (N=9) D-allulose (3 g / kg body weight) (3 g per kg of body weight) was dissolved in physiological saline to prepare the allulose solution. For each mouse, the allulose solution or physiological saline solution was administered to the stomach via a tube between 8:00 and 9:00 a.m. each day until the completion of the obsessive behavior test, to a concentration of 3 g / kg body weight.

[0091] 6. Preparation for the obsessive behavior test Figures 2-7 show an outline of the experimental design for administering GLP-1 receptor agonists (GLP-1RAs) or GLP-1 secretagogues.

[0092] (1) Experimental apparatus For the obsessive behavioral tests, a mouse touch panel operant experimental apparatus (O'Hara&Co., Ltd., Tokyo, Japan) was used. This apparatus was controlled using Operant Task Studio software (O'Hara&Co.,Ltd.).

[0093] (2) Acclimation Before beginning the detailed evaluation, a habituation period was first established to allow the mice to become accustomed to the touch panel operant experimental apparatus and the pellet dispenser. Each session lasted 30 minutes and 30 seconds, starting with a 15-minute waiting period with a small amount of reward food placed in front of the mouse. For the following 15 minutes, the mouse was given reward food from the dispenser once every 30 seconds. This was carried out for a minimum of two days per individual, continuing until all the food was consumed within the 30-minute period. In the examples described herein, this took up to four days.

[0094] (3) Behavior formation After acclimatization to the device, a period was set up for behavioral formation (behavior formation) in which the mice learned to receive food by touching (selecting) a spot on the touch panel (Figure 3). This rule was learned by utilizing the mice's spontaneous movements within the device and repeatedly causing them to accidentally touch the spots. For the first two days, only the upper right spot was lit, and a reward was given when that spot was selected. For the next four days, all four spots were lit, and a reward was given regardless of which spot was selected. Each session was configured to end after completing 100 trials or after 45 minutes had elapsed.

[0095] (4) Acquisition After behavior formation, the mice were trained on a behavioral sequencing task (Figure 4). During the acquisition phase, they learned that they would receive a reward for alternately selecting two specific spots on a diagonal in each trial. Four spots were lit, and the spot that yielded a reward (hereinafter sometimes referred to as the "correct answer") was set to alternate between two specific spots on a diagonal (hereinafter referred to as the "correct diagonal") in each trial. When the mouse selected the correct answer, it was given a reward and allowed to proceed to the next trial. If the mouse selected the wrong spot on the correct diagonal, or a spot on the diagonal where a reward could not be obtained (hereinafter referred to as the "incorrect diagonal"), the spot was temporarily hidden, and then the four spots were lit again. This trial continued until the mouse was able to select the correct answer. Once the mouse selected the correct answer and received a reward, in the next trial, the correct answer was changed to the other spot on the correct diagonal, and thereafter, the correct answer alternated between the correct diagonals in each trial. Each session was configured to end after completing 150 trials or after 60 minutes had elapsed. The learning phase consisted of one session per day for 10 sessions.

[0096] 7. Obsessive behavior test After completing the rule acquisition (approximately 2 weeks) as described in "6. Preparation for the Obsessive Behavior Test," the obsessive behavior test was conducted.

[0097] After mastering the action sequencing task, the correct and incorrect diagonals were reversed. Learning continued in this setting for two weeks (effectively 10 days) (Reversal 1 in Figure 5). From the following week, the pairs on the diagonal where the correct answer changes were reversed every week (effectively 5 days) (Reversal 2-4 in Figure 5). Each session continued until 150 trials were completed or 60 minutes had passed since the start of the trial. For example, in Reversal 1 in Figure 5, 2 (top left) and 4 (bottom right) are the "correct diagonals," and in Reversal 2, 1 (bottom left) and 3 (top right) are the "correct diagonals." If the same spot as the previous correct answer is re-selected (re-touched), it is judged to be a sign of high persistence. For example, this would occur if the user correctly selected 2 and then touched 2 again.

[0098] Figures 6 and 7 illustrate the evaluation method for specific choices. In Trial 1 in Figure 6, the correct answer is the upper right. In Trial 2, the correct answer is the lower left, which is diagonally opposite the upper right of the correct answer in Trial 1. If the upper right of the correct answer in Trial 2 is selected, it is judged that the same correct answer was selected immediately after the start of the trial, i.e., a "re-selection". If the upper left or lower right is selected, it is judged as "incorrect".

[0099] At the start of each trial (reversal), the "re-selection rate" was defined as the percentage of the total number of trials ("re-selection" + "correct answer" + "incorrect answer") in which the same spot as the previous correct answer was incorrectly selected. A high re-selection rate was evaluated as indicating a high level of adherence to the previous correct answer (Figure 7).

[0100] Example 1: Effect of GLP-1RA administration on age-related persistence In this example, the effects of administering GLP-1RA to normal mice in the young, middle-aged, and aged groups, as described in "4. Administration of GLP-1 receptor agonist (GLP-1RA)" above, were investigated. The comparative example was the NC administration group.

[0101] C57BL / 6JmsSlc Male Mouse (Normal Mouse) Younger group: GLP-1RA administration group (N=6) and NC administration group (N=6) Middle-aged group: GLP-1RA administration group (N=6) and NC administration group (N=5) Elderly group: GLP-1RA administration group (N=4) and NC administration group (N=6) The results are shown in Figure 8. In the younger group, no significant difference was observed between the reselection rate of the GLP-1RA administration group and the NC administration group. Furthermore, in the younger group, in both the GLP-1RA administration group and the NC administration group, the reselection rate decreased with each reversal, reaching a low level of approximately 5-10% after 3 or 4 reversals. This indicates that the younger group learned the rules well, showed high adaptability, and had low persistence.

[0102] In the middle-aged group, the re-selection rate did not decrease as much with repeated administrations compared to the younger group. In the middle-aged group, the GLP-1RA administration group showed a slightly lower re-selection rate compared to the NC administration group.

[0103] In the NC-administered group of elderly patients, the re-selection rate did not decrease even after 3 or 4 reversals, remaining at around 10%-20%. In contrast, the GLP-1RA-administered group of elderly patients showed a significantly lower re-selection rate compared to the NC-administered group, as can be seen particularly from Figure 8, especially from 3-5 reversals.

[0104] Based on the above, the composition containing GLP-1RA of the present invention is effective in reducing age-related persistence. Example 2: Effect of GLP-1RA administration on obesity-induced obesity In this example, we investigated the effects of administering GLP-1RA to obese mice in a young age group, as described in "4. Administration of GLP-1 receptor agonist (GLP-1RA)" above.

[0105] Figure 9 shows the reselection rates when NC was administered to normal mice (WT) and obese mice (LepR-KO). Obese mice (LepR-KO) showed a higher reselection rate from session 6 onwards compared to normal mice (WT). This is consistent with the common technical understanding that obesity can be a contributing factor to persistence.

[0106] Figure 10 shows the reselection rates when GLP-1RA was administered to normal mice (WT) and obese mice (LepR-KO). In Figure 9, the NC-administered group of obese mice consistently showed high reselection rates from session 6 onwards in inversion 1. In Figure 10, administration of GLP-1RA significantly reduced the reselection rate of obese mice (LepR-KO), bringing it to a level where there was no significant difference compared to the GLP-1RA-administered group of normal mice (WT).

[0107] Figure 11 compares the reselection rate of obese mice (LepR-KO) administered with that of the same mice administered with NC. In obese mice (LepR-KO), GLP-1RA administration significantly reduced the reselection rate. In the NC-administered group, as also shown in Figure 9, there was no decrease in reselection rate.

[0108] Based on the above, the composition containing GLP-1RA of the present invention is effective in reducing obesity-related insatiable appetite. Example 3: Effect of GLP-1 secretion-promoting agent administration on persistent dysplasia (1) In this example, the effects of administering a GLP-1 secretion promoter to normal mice in the middle-aged group described in "5. Administration of GLP-1 secretion promoter" above were investigated. The comparative example was the group administered physiological saline.

[0109] The results are shown in Figure 12. In the middle-aged group, the allulose-administered group showed a significantly lower re-selection rate than the saline-administered group, particularly in reversal 2. Based on the above, the composition containing the GLP-1 secretion promoter of the present invention is effective in reducing age-related persistence.

[0110] Materials and Methods II Unless otherwise specified, Examples 4-6 of this specification were carried out using the following materials and methods.

[0111] 1. Laboratory animals (1) Normal mouse Male C57BL / 6JmsSlc mice were used for behavioral studies. For the juvenile group, 8-week-old male mice were purchased from Sankyo Labo Service (Tokyo, Japan).

[0112] The solutions for each reagent were administered starting one week after the reagents were purchased. The mice were housed individually in cages in a room with controlled light exposure (8am-8pm) for 17-19 weeks, including obsessive behavior tests.

[0113] The mice were fed CE-2 (CLEA Japan, Tokyo, Japan) and restricted feeding was implemented starting one week before the start of the obsessive behavior test. The restricted feeding was carried out to reduce each mouse's weight to approximately 80% of its weight before the restriction. Two days before the start of the obsessive behavior test, the mice were given 10 tablets of Purified Rodent Diet 5TUL 10mg (TestDiet, St. Louis, MO, USA) daily. Once the obsessive behavior test began, Purified Rodent Diet was given as a reward for completing tasks during the test, and more than one hour after the completion of a task, additional food necessary for weight maintenance was given using CE-2.

[0114] Body weight and food intake were measured five days a week after the first administration of each reagent. The diet consisted of CE-2. (2) Afferent vagus nerve-specific GLP-1 receptor-deficient mice B6(SJL)-Glp1r<tm1.1Stof> / J and B6.129S6(FVB)-Slc17a6<tm2(cre)Lowl> We purchased / MwarJ from Oriental Yeast Co., Ltd., performed self-pollination, and obtained 8-week-old Glp1r flox / flox ; Slc17a-Cre + / - Male mice were used in the behavioral tests. These mice were in which the receptor for GLP-1, a peptide hormone that plays a role in suppressing appetite and promoting insulin secretion, was specifically knocked out in the afferent vagus nerve (afferent vagus nerve-specific Glp1R-KO mice).

[0115] 3. Reagents The following reagents were used. Tilzepatide (trade name: Manjaro) (HY-P1731, MedChemExpress, USA) was administered once a week as a GLP-1 and GIP receptor agonist (hereinafter referred to as "GLP-1RA / GIPRA"), and letatorutide (HY-P3506B, MedChemExpress, USA) was administered once a week as a GLP-1, GIP receptor, and glucagon receptor agonist (hereinafter referred to as "GLP-1RA / GIPRA / GCGRA").

[0116] Tilsepotide: CAS No. 2023788-19-2, trade name Zepbound (subcutaneous injection), Manjaro (subcutaneous injection); Retatrutide: CAS No. 2381089-83-2 4. Administration of allulose to afferent vagus nerve-specific GLP-1 receptor-deficient mice (Glp1R-KO) Glp1r flox / flox ; Slc17a-Cre + / - For male mice (afferent vagus nerve-specific Glp1R-KO mice), at 9 weeks of age as the young age group, they were used as the allulose administration group (N = 3). Also, C57BL / 6JmsSlc male mice (normal mice) were used as the allulose administration group (N = 7) with 9 weeks of age as the young age group. D-allulose (3 g / kg body weight) (3 g per 1 kg of body weight) was dissolved in physiological saline to make an allulose solution. For each mouse, the allulose solution or physiological saline solution was administered to the stomach using a probe from 8 am to 9 am every day so that it was 3 g / kg body weight until the end of the perseverative behavior test.

[0117] 5. Administration of GLP-1 and GIP receptor agonists (GLP-1RA / GIPRA) For C57BL / 6JmsSlc male mice (normal mice), at 9 weeks of age as the young age group, they were randomly divided into a GLP-1RA / GIPRA administration group (N = 4) and a vehicle administration group (N = 5).

[0118] GLP-1RA / GIPRA (36 μg / ml) was dissolved in a formulation solution at pH 8 (50 mM sodium phosphate, 70 mM sodium chloride, 0.007% polysorbate 20, 1.2% DMSO) and used as the GLP-1RA / GIPRA solution. The formulation solution was used as the control vehicle solution.

[0119] Using an insulin subcutaneous injection syringe with a needle (BD Lodose® 3 / 10mL 29G, needle length 12.7mm, Becton Dickinson Japan, Tokyo, Japan), each mouse was subcutaneously administered either GLP-1RA / GIPRA solution at a dose of 144 μg / kg body weight or Vehicle solution. For mice used in the obsessive behavior test, administration was performed every Monday from 4 PM to 7 PM before the start of restricted feeding. After the start of restricted feeding, administration was performed every Friday from 4 PM to 7 PM. On days when the obsessive behavior test was performed, administration was performed at least one hour after the end of the test.

[0120] 6. Administration of GLP-1, GIP receptor, and glucagon receptor agonists (GLP-1RA / GIPRA / GCGRA) C57BL / 6JmsSlc male mice (normal mice) were randomly divided at 9 weeks of age into a young age group and either a GLP-1RA / GIPRA / GCGRA administration group (N=6) or a vehicle administration group (N=7).

[0121] GLP-1RA / GIPRA / GCGRA (12 μg / ml) was dissolved in a pH 8 formulation solution (50 mM sodium phosphate, 70 mM sodium chloride, 0.007% polysorbate 20, 0.4% DMSO) and used as the GLP-1RA / GIPRA / GCGRA solution. The formulation solution was used as the control vehicle solution.

[0122] Using an insulin subcutaneous injection syringe with a needle (BD Lodose® 3 / 10mL 29G, needle length 12.7mm, Becton Dickinson Japan, Tokyo, Japan), each mouse was subcutaneously administered either GLP-1RA / GIPRA / GCGRA solution or Vehicle solution to a dose of 48 μg / kg body weight. For mice used in the obsessive behavior test, administration was performed every Monday from 4 PM to 7 PM before the start of restricted feeding. After the start of restricted feeding, administration was performed every Friday from 4 PM to 7 PM. On days when the obsessive behavior test was performed, administration was performed at least one hour after the end of the test.

[0123] Example 4: Effect of GLP-1 secretion-promoting agent administration on persistent dysplasia (2) In this example, we investigated the effects of administering a GLP-1 secretagogue (allulose) to young afferent vagus nerve-specific GLP-1 receptor knockout mice (afferent vagus nerve-specific Glp1R-KO) (prepared in "1. Experimental Animals (2) Afferent Vagus Nerve-Specific GLP-1 Receptor Deficient Mice" above).

[0124] The comparative example is a group of normal mice (WT) administered allulose. C57BL / 6JmsSlc male mice (normal mice) The results are shown in Figure 13. In the young afferent vagus nerve-specific Glp1R-KO group, the reselection rate in inversion 1 was significantly higher than in normal mice (WT). Therefore, the composition containing the GLP-1 secretion promoter of the present invention controls the reduction of persistence by activating GLP-1 receptors expressed in afferent vagus nerves.

[0125] Example 5: Effects of GLP-1 and GIP receptor agonist administration on persistence In this example, the effects of administering GLP-1RA / GIPRA to a group of normal mice in the juvenile stage, as described in "5. Administration of GLP-1 and GIP receptor agonist (GLP-1RA / GIPRA)" above, were investigated. The comparative example was the vehicle-administered group.

[0126] C57BL / 6JmsSlc Male Mouse (Normal Mouse) Younger group: GLP-1RA / GIPRA administration group (N=4) and vehicle administration group (N=5) The results are shown in Figure 14. In the younger group, in both the GLP-1RA / GIPRA administration group and the vehicle administration group, the reselection rate decreased with each subsequent inversion, reaching a low level of approximately 5-10% after 3 or 4 inversions. This indicates that the younger group learned the rules well, showed high adaptability, and exhibited low persistence. Nevertheless, the GLP-1RA / GIPRA administration group showed a significantly lower reselection rate than normal mice (WT) from the very beginning of the obsessive behavior test, i.e., from inversion 1. Therefore, compositions containing GLP-1RA / GIPRA are effective in reducing persistence.

[0127] Example 6: Effects of GLP-1, GIP receptor, and glucagon receptor agonist administration on persistence. In this example, the effects of administering GLP-1RA / GIPRA / GCGRA to a group of normal mice in the juvenile stage, as described in "6. Administration of GLP-1, GIP receptor, and glucagon receptor agonists (GLP-1RA / GIPRA / GCGRA)" above, were investigated. The comparative example was the vehicle-administered group.

[0128] C57BL / 6JmsSlc Male Mouse (Normal Mouse) Younger group: GLP-1RA / GIPRA / GCGRA administration group (N=6) and vehicle administration group (N=7) The results are shown in Figure 15. In the younger group, in both the GLP-1RA / GIPRA / GCGRA administration group and the vehicle administration group, the reselection rate decreased with each subsequent inversion, reaching a low level of approximately 5-10% after 3 or 4 inversions. This indicates that the younger group learned the rules well, showed high adaptability, and exhibited low persistence. Nevertheless, from the beginning of the obsessive behavior test, i.e., the GLP-1RA / GIPRA / GCGRA administration group showed a significantly lower reselection rate than normal mice (WT) at inversion 1. Therefore, compositions containing GLP-1RA / GIPRA / GCGRA are effective in reducing persistence. [Industrial applicability]

[0129] The compositions of the present invention, including those for food, beverages, supplements, and pharmaceuticals, can reduce obsessive behavior. Improvements are expected in cases where obsessive behavior causes difficulties in the individual's life or negative impacts on those around them. Furthermore, in cases involving diseases or symptoms that may lead to obsessive behavior, such as dementia, administering the compositions of the present invention can prevent the onset of obsessive behavior.

Claims

1. A composition for reducing persistence, comprising at least one GLP-1 receptor agonist, a GLP-1 secretagogue, or GLP-1.

2. The composition according to claim 1, wherein the GLP-1 receptor agonist is selected from the group consisting of semaglutide, exenatide, liraglutide, lixisenatide, dulaglutide, tilzepatide, and letatoltide.

3. The GLP-1 secretion-promoting agents include allulose, propionic acid, butyric acid, valeric acid, pantothenic acid, cholic acid, 3-aminoisobutyric acid, γ-aminobutyric acid, 2-aminobutyric acid, pipecolic acid, ornithine, citrulline, tyrosine methyl ester, piperidine, taurine, pyridoxal, pyridoxamine, pyridoxine, sarcosine, N,N-dimethylglycine, cytosine, 1,3-diaminopropane, nicotinic acid, indole-3-acetamide, and D-alamine. Nin, 5-hydroxylysine, 1-methylnicotinamide, thiamine, carnitine, gluconic acid, prostaglandin E2, methionine sulfoxide, spermidine and spermine, folic acid, caproic acid, lauric acid, pentadecanoic acid, oleic acid, vaccenic acid, linolenic acid, myristoleic acid, palmitoleic acid, arachidic acid, eicosenoic acid, eicosadienoic acid, dihomo-γ-linolenic acid, arachidonic acid, rumenic acid, 10-trans-12-cis Conjugated linoleic acid, antheisopentadecanoic acid, isopalmitic acid, antheisoheptadecanoic acid, isoheptadecanoic acid, palmitic acid amide, myristic acid amide, linoleic acid, 10-hydroxy-12-octadecenoic acid, docosahexaenoic acid, eicosapentaenoic acid, phenylalanine, tryptophan, proline, arginine, glutamine, metformin, deoxycholic acid, oxytocin, vasopressin, GPR40 receptor agonist, GPR120 receptor agonist, GPR40 receptor / GPR120 receptor dual agonist, WY The composition according to claim 1, comprising: a dipeptide which is FY, GW, KA, KF, NI, QL, QY, PM, WF, or WN; a peptide which is VAWRRRCKGTD, WRNRRCKGTD, WIRGCRL, RYLGYLE, SRYPS, or LIVTQTM; a microorganism belonging to the genera Bifidobacterium, Citrobacter, or Lactobacillus that produces geraniol, citronellal, tryptophan-bound cholic acid, bile acid, and / or indolepropionic acid; and one or more substances selected from the group consisting of tryptophan-bound cholic acid, bile acid, indolepropionic acid, isoquercitrin, delphinidin 3-rutinoside, curcumin, berberine, [6]-Gingerol, quercetin, cinnamaldehyde, and capsaicin.

4. The composition according to any one of claims 1 to 3, wherein the persistence is based on one or more diseases or conditions selected from the group consisting of dementia, autism spectrum disorder, schizophrenia, depression, attention deficit hyperactivity disorder, obesity, diabetes, and aging.

5. The composition according to any one of claims 1 to 3, which is a pharmaceutical composition, a food, a beverage, or a supplement.

6. Use for the manufacture of GLP-1 receptor agonists, GLP-1 secretagogues, or compositions for reducing the persistence of GLP-1.

7. A screening method for GLP-1 secretagogues or GLP-1 receptor agonists, using the reduction of persistence as an indicator.

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