Composition for preventing mental decline

Abstract

To provide novel materials that can suppress the decline of mental function, and to provide compositions containing the same.SOLUTION: According to the present invention, there is provided a composition for suppressing the decline of mental function, which comprises a peptide having the amino acid sequence of GTWY (SEQ ID NO: 1) or a pharmaceutically acceptable salt or solvate thereof. The composition of the present invention can be ingested by a subject with declined mental function or a subject having a risk of declined mental function. The decline of mental function can be selected from depression-related conditions and anxiety-related conditions.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a composition for suppressing decline in mental function, etc. [Background technology]

[0002] In modern society, people of all ages, from young to old, are experiencing declines in mental function, such as loss of motivation and depression due to fatigue, stress, etc. This decline in mental function is a major social problem, as it directly leads to a decline in work productivity and a decline in the quality of daily life.

[0003] Whey protein hydrolysates have been suggested as a food ingredient that can improve mental decline (Patent Document 1), but there are currently few food ingredients that are effective in suppressing mental decline and can be easily ingested in daily life. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Special Publication No. 2006-510367 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a novel material capable of suppressing the decline of mental function and a composition containing the same. [Means for solving the problem]

[0006] The present inventors have now found that the tetrapeptide GTWY ameliorates depression and loss of motivation in the tail suspension test, and the present invention is based on this finding.

[0007] That is, the present invention provides the following inventions. [1] A composition for suppressing mental decline and an agent for suppressing mental decline, comprising, as an active ingredient, a peptide having the amino acid sequence of GTWY (SEQ ID NO: 1) or a pharmaceutically acceptable salt or solvate thereof. [2] The composition and agent described in [1] above, wherein the decline in mental function is one or more conditions selected from the group consisting of depression-related conditions and anxiety-related conditions. [3] The composition and preparation described in [1] or [2] above, which is administered to a subject with impaired mental function or a subject at risk of impaired mental function. [4] The composition and agent according to any one of [1] to [3] above, in which a peptide having the amino acid sequence of GTWY (SEQ ID NO: 1) or a pharmaceutically acceptable salt or solvate thereof is administered to a subject in an amount of 0.01 to 100 mg (converted to dry mass) per human per day. [5] The composition and agent according to any one of [1] to [4] above, which is a food composition. [6] The composition and agent according to any one of [1] to [5] above, which is in a unit package suitable for single ingestion. [7] A composition for treating, preventing, or ameliorating depression and / or anxiety, and an agent for treating, preventing, or ameliorating depression and / or anxiety, comprising as an active ingredient a peptide having the amino acid sequence of GTWY (sequence number 1) or a pharmaceutically acceptable salt or solvate thereof.

[0008] The compositions of [1] and [7] above may be referred to herein as "compositions of the present invention," and the preparations of [1] and [7] above may be referred to herein as "preparations of the present invention."

[0009] The tetrapeptide GTWY (SEQ ID NO: 1), which is the active ingredient of the compositions and preparations of the present invention, is advantageous in that it can be used as a functional material that exhibits the function of suppressing the decline of mental function, and can also be used as a functional material that is safe for mammals, including humans. [Brief explanation of the drawings]

[0010] [Figure 1]1 is a graph showing the mean ± standard error of the time of immobility (immobility time) in the GTWY peptide non-administered group (control group) (0 mg / kg) and the GTWY peptide-administered groups (0.3 mg / kg, 1 mg / kg) in the tail suspension test (Example 1). * indicates p<0.05 vs. the control group (Dunnett's test). [Figure 2] 2 is a graph showing the mean ± standard error of the time of immobility (immobility time) in the GTWY peptide non-administered group (control group) (0 mg / kg) and the GTWY peptide-administered groups (0.1 mg / kg, 0.3 mg / kg) in the tail suspension test (Example 1). * indicates p<0.05 vs. the control group (Dunnett's test). Specific Description of the Invention

[0011] The compositions and agents of the present invention contain a peptide having the amino acid sequence of GTWY (SEQ ID NO: 1) (hereinafter, sometimes referred to as the "peptide of the present invention") as an active ingredient. Here, "a peptide having an amino acid sequence" refers to a peptide whose sequence is specified by the amino acid sequence. The peptide of the present invention is also referred to as β-lactolin (Nutrients 2019, 11, 348; doi:10.3390 / nu11020348).

[0012] The peptides of the present invention may be obtained by chemical synthesis or by chemical or enzymatic degradation of proteins or polypeptides derived from milk, soybeans, wheat, eggs, livestock meat, fish, seafood, etc. Specifically, the peptide sequences of the present invention are contained in at least milk whey and casein, bovine serum albumin (BSA), soybean glycinin, wheat glutenin, egg yolk ribovitellin, egg white ovalbumin, ovotransferrin, lysozyme, and chicken protein collagen. Therefore, these foods or food ingredients can be subjected to acid hydrolysis, protease enzyme treatment, or microbial fermentation to produce the peptides. The compositions and preparations of the present invention may be prepared from the above-mentioned foods or food ingredients as they are, or may be used as concentrates or as dried powders prepared by spray drying, freeze-drying, or other methods. Furthermore, they may be purified to any degree, such as by removing impurities, salts, enzymes, etc., as needed.

[0013] The amino acids constituting the peptides of the present invention may be composed of only L-amino acids, only D-amino acids, or a mixture of both. Furthermore, the peptides may be composed of only naturally occurring amino acids, or only modified amino acids in which an arbitrary functional group, such as phosphorylated or glycosylated amino acids, is bound to amino acids, or a mixture of both. Furthermore, when the peptide contains two or more asymmetric carbon atoms, it may be an enantiomer, a diastereomer, or a mixture of both.

[0014] Furthermore, the peptides of the present invention may be in the form of a free base, a pharmaceutically acceptable salt, or a solvate thereof, and the compositions and pharmaceutical preparations of the present invention may contain any of these, or a mixture of all or part of these. Pharmaceutically acceptable salts include acid addition salts, metal salts, ammonium salts, and organic amine addition salts. Pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloride, sulfate, and phosphate, and organic acid salts such as acetate, maleate, fumarate, citrate, and methanesulfonate. Pharmaceutically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt. Pharmaceutically acceptable ammonium salts include ammonium and tetramethylammonium salts. Pharmaceutically acceptable organic amine addition salts include addition salts of morpholine, piperidine, and the like.

[0015] The compositions and pharmaceutical preparations of the present invention can be provided as the peptide of the present invention alone, or as a material (e.g., a food ingredient) containing the peptide of the present invention. The compositions and pharmaceutical preparations of the present invention can also be provided by mixing the peptide of the present invention or a material containing the peptide of the present invention with other ingredients (e.g., a food ingredient, a food additive, or a pharmaceutical additive). The content of the peptide of the present invention in the compositions and pharmaceutical preparations of the present invention can be determined arbitrarily depending on the purpose, use, form, dosage form, symptoms, body weight, etc., and the present invention is not limited thereto. However, the content can be 0.00001 to 50% by mass (solid content equivalent) of the total amount, more preferably 0.0001 to 10% by mass (solid content equivalent). In the present invention, the pharmaceutical preparations of the present invention can consist of the peptide of the present invention, and the compositions of the present invention can comprise the peptide of the present invention and other ingredients.

[0016] The content of the peptide of the present invention can be measured by liquid chromatography tandem mass spectrometry (LC / MS / MS). Those skilled in the art can easily set the conditions for this measurement, and it goes without saying that a standard peptide of a purity suitable for LC / MS / MS measurement should be used during the measurement. For example, AQUA peptide manufactured by SIGMA ALDRICH can be used.

[0017] Food materials containing the peptides of the present invention include enzymatic hydrolysates of proteins, preferably enzymatic hydrolysates of whey proteins (hereinafter sometimes referred to as "whey hydrolysates"). Methods for producing whey hydrolysates containing the peptides of the present invention are known, and can be produced, for example, according to the description in International Publication No. 2017 / 086303. Alternatively, commercially available whey enzymatic hydrolysates containing the peptides of the present invention may be used; for example, LE80GF-US (manufactured by DMV) or HW-3 (manufactured by Megmilk Snow Brand) may be used as the peptides of the present invention.

[0018] When the peptide of the present invention is contained in the composition and preparation of the present invention as a whey protein hydrolysate, the peptide of the present invention can be contained in a proportion of 0.001 to 10% by mass (solid content equivalent) of the whey protein hydrolysate, more preferably 0.01 to 5% by mass (solid content equivalent). Furthermore, the whey protein hydrolysate can be contained in the composition and preparation of the present invention in a proportion of 0.001 to 95% by mass (solid content equivalent), preferably 0.01 to 50% by mass (solid content equivalent).

[0019] As shown in the Examples below, the peptide of the present invention has an effect of improving depressive states and loss of motivation. Since depressive states and loss of motivation are typical examples of mental decline, the peptide of the present invention can be used as an active ingredient of a composition for suppressing mental decline and an agent for suppressing mental decline.

[0020] In the present invention, "mental function" is used to mean emotional function (emotional and willful functions) and mental vitality. Examples of "deteriorated mental function" include depression-related states and anxiety-related states. Depression-related states include, for example, depressed state, loss of willpower, loss of motivation, loss of energy, loss of vitality, feelings of sadness, loneliness, depression, despair, and loss of curiosity. Anxiety-related states include, for example, feelings of anxiety, mental fatigue, loneliness, restlessness, confusion, fear, and worry.

[0021] In the present invention, "suppressing mental function decline" is used to mean not only improving mental function in a subject with mental decline, but also reducing the risk in a subject at risk of mental decline. That is, the compositions and agents of the present invention can be ingested or administered to a subject with mental decline or a subject at risk of mental decline. Here, "a subject at risk of mental decline" means a subject who does not have mental decline but is at risk of mental decline in the future. Furthermore, "reducing the risk" includes alleviating the decline in mental function. Note that the subjects to be ingested or administered are mammals, including humans, as described below.

[0022] As described above, the peptides of the present invention can be used to suppress decline in mental function. Because decline in mental function is involved in the onset and progression of depressive and anxious states, the peptides of the present invention can be used as active ingredients in compositions for treating, preventing, or ameliorating depression and anxiety, and in agents for treating, preventing, or ameliorating depression and anxiety. That is, the present invention provides compositions for treating, preventing, or ameliorating depression and / or anxiety, which comprise the peptides of the present invention, and agents for treating, preventing, or ameliorating depression and / or anxiety, which comprise the peptides of the present invention.

[0023] The compositions and agents of the present invention can be provided in the form of pharmaceuticals (e.g., pharmaceutical compositions), quasi-drugs, foods (e.g., food compositions), feeds (including pet foods), etc., and can be implemented as described below.

[0024] The peptides of the present invention can be orally administered to humans and non-human animals. Oral preparations include granules, powders, tablets (including sugar-coated tablets), pills, capsules, syrups, emulsions, and suspensions. These preparations can be formulated using pharmaceutically acceptable carriers by techniques commonly used in the art. Pharmaceutically acceptable carriers include excipients, binders, diluents, additives, flavorings, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, etc.

[0025] When providing the peptides of the present invention as food, they can be provided as such or can be incorporated into food. For example, when providing the peptides of the present invention as food, enzymatic hydrolysates of proteins, such as whey hydrolysates, containing the peptides of the present invention can be provided as such or can be incorporated into food. Foods provided in this manner contain an effective amount of the peptides of the present invention. As used herein, "containing an effective amount" of the peptides of the present invention refers to a content such that the peptides of the present invention are ingested in the range described below when ingested in the amount normally consumed for each food. Furthermore, the term "food" is used to encompass health foods, functional foods, nutritional supplements, health-promoting foods (e.g., foods for specified health uses, foods with nutrient functions, foods with functional claims), foods for special dietary uses (e.g., foods for infants, foods for pregnant women, foods for the sick), and supplements. It goes without saying that when the peptides of the present invention are ingested by animals other than humans, the foods referred to in the present invention are used as feed.

[0026] Because the peptides of the present invention have the effect of suppressing the decline of mental function as described above, they can be incorporated into foods consumed daily or provided as supplements. That is, the compositions and agents of the present invention can be provided in the form of food. In this case, the compositions and agents of the present invention can be provided in a unit package form in which the amount to be ingested per meal is predetermined. Examples of unit package forms per meal include packs, wrappings, cans, bottles, etc., in which a fixed amount is specified. To better exert the various effects of the compositions and agents of the present invention, the intake amount per meal can be determined according to the intake amount of the peptides of the present invention per serving, as described below. The foods of the present invention may be provided with instructions regarding the intake amount displayed on the packaging or with a document or the like containing such instructions.

[0027] The predetermined intake amount per serving in the unit package form may be the effective daily intake amount, or the effective daily intake amount divided into two or more (preferably two or three) intake amounts. Thus, the unit package form of the composition and agent of the present invention may contain the peptide of the present invention at the daily human intake amount described below, or may contain the peptide of the present invention in an amount of one-half to one-sixth of the daily human intake amount described below. For convenience of intake, the composition and agent of the present invention are preferably provided in a "unit package form per serving," in which the intake amount per serving is the effective daily intake amount.

[0028] The form of the "food" is not particularly limited, and may be, for example, a drink, a semi-liquid or gel form, or a solid or powder form. Examples of "supplements" include tablets produced by adding an excipient, a binder, etc. to the peptide of the present invention, kneading the mixture, and then tableting, and capsules enclosed in capsules.

[0029] The foods provided by the present invention are not particularly limited as long as they contain the peptide of the present invention, and examples thereof include non-alcoholic beverages such as soft drinks, carbonated drinks, fruit juice drinks, vegetable juice drinks, fruit and vegetable juice drinks, livestock milk such as cow's milk, soy milk, dairy drinks, drink-type yogurt, drink-type or stick-type jellies, coffee, cocoa, tea drinks, nutritional drinks, energy drinks, sports drinks, mineral water, near-water, and non-alcoholic beer-flavored drinks; carbohydrate-containing foods and beverages such as rice, noodles, bread, and pasta; cheeses, hard or soft yogurt, fresh cream made from livestock milk or other fats and oils, and ice cream. Examples of such products include dairy products; Western confectioneries such as cookies, cakes, and chocolates; Japanese confectioneries such as manju and yokan; tablet confectioneries (refreshing confectioneries) such as ramune (sweet soybeans); candies, gums, frozen desserts and iced desserts such as jellies and puddings; and various confectioneries such as snacks; alcoholic beverages such as whiskey, bourbon, spirits, liqueurs, wine, fruit wine, sake, Chinese alcohol, shochu, beer, non-alcoholic beer with an alcohol content of 1% or less, happoshu (low-malt beer), other miscellaneous alcoholic beverages, and chuhai; processed foods such as egg products, processed seafood and meat products (including liver and other offal) (including delicacies), processed foods such as miso soup and other soups; condiments such as miso, soy sauce, furikake (rice seasoning), and other seasonings; and liquid foods such as concentrated liquid foods. Mineral water includes both sparkling and non-sparkling mineral water. The foods provided by the present invention also include both food manufacturing ingredients and food additives.

[0030] Tea beverages include all types of fermented tea, semi-fermented tea, and non-fermented tea, such as black tea, green tea, barley tea, brown rice tea, sencha, gyokuro tea, roasted green tea, oolong tea, turmeric tea, pu-erh tea, rooibos tea, rose tea, chrysanthemum tea, ginkgo leaf tea, and herbal teas (e.g., mint tea and jasmine tea).

[0031] Examples of fruits used in fruit juice beverages and fruit and vegetable juice beverages include apples, mandarin oranges, grapes, bananas, pears, peaches, mangoes, acai, blueberries, and plums, while examples of vegetables used in vegetable juice beverages and fruit and vegetable juice beverages include tomatoes, carrots, celery, pumpkins, cucumbers, and watermelons.

[0032] The intake amount of the peptide of the present invention can be determined depending on the recipient's sex, age, and weight, symptoms, administration time, dosage form, administration route, and other combined drugs. The daily intake (dry mass equivalent) of the peptide of the present invention for an adult intended to suppress decline in mental function is, for example, 0.01 to 100 mg (preferably 0.1 to 10 mg). The above-mentioned intake amount of the peptide of the present invention and the timing and duration of intake described below apply to both non-therapeutic and therapeutic uses of the peptide of the present invention; in the case of therapeutic uses, "intake" can be interpreted as "administration." The peptide of the present invention can also be administered to mammals other than humans (e.g., mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, dolphins, sea lions, etc.), and the intake amount, timing, and duration can be determined with reference to the descriptions for humans.

[0033] It is preferable to continue taking the peptide of the present invention for the period during which the inhibitory effect on mental decline is expected. That is, the peptide of the present invention can be taken or administered in the above amount for at least one day (preferably 3 days, more preferably 5 days, and particularly preferably 10 days), and can be taken or administered in the above amount once a day (preferably twice or three times a day). It is also desirable to start taking the peptide of the present invention before the date and time at which the inhibitory effect on mental decline is expected, so the start time can be on the day of the expected time (preferably 1 hour before that day) or one day before the expected date (preferably 3 days before, more preferably 5 days before). Examples of taking the peptide before the date and time at which the inhibitory effect on mental decline is expected include before stress or fatigue, which may cause mental decline.

[0034] The compositions, preparations, and foods of the present invention may be labeled to indicate that they have the effect of suppressing decline in mental function. In this case, to make the labeling easier for consumers to understand, the compositions, preparations, and foods of the present invention may be labeled with some or all of the following labels. It goes without saying that in the present invention, "suppression of decline in mental function" is used in a sense that includes the following labels. For those who are worried about various things For those who lose motivation easily - For those who are concerned about a decline in motivation or drive For those who tend to get depressed For those who want to stay positive For those who become anxious when irritated For those who get anxious when nervous - For those who get anxious under pressure

[0035] Another aspect of the present invention provides a method for suppressing decline in mental function, comprising administering to a subject in need thereof an effective amount of a peptide of the present invention, or a pharmaceutically acceptable salt or solvate thereof, or a composition comprising the same. The present invention also provides a method for treating, preventing, or ameliorating depression and / or anxiety, comprising administering to a subject in need thereof an effective amount of a peptide of the present invention, or a pharmaceutically acceptable salt or solvate thereof, or a composition comprising the same. The methods of the present invention can be carried out according to the descriptions for the compositions and agents of the present invention.

[0036] According to yet another aspect of the present invention, there is provided use of the peptide of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of an agent for suppressing mental decline, as an agent for suppressing mental decline, or in the method of the present invention. According to another aspect of the present invention, there is also provided use of the peptide of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of an agent for treating, preventing, or ameliorating depression and / or anxiety, as an agent for treating, preventing, or ameliorating depression and / or anxiety, or in the method of the present invention. The use of the present invention can be carried out according to the description for the composition and agent of the present invention.

[0037] According to yet another aspect of the present invention, there is provided a peptide having the amino acid sequence of GTWY (SEQ ID NO: 1), or a pharmaceutically acceptable salt or solvate thereof, for use in suppressing decline in mental function. The present invention also provides a peptide having the amino acid sequence of GTWY (SEQ ID NO: 1), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment, prevention, or amelioration of depression and / or anxiety. The present invention also provides a peptide having the amino acid sequence of GTWY (SEQ ID NO: 1), or a pharmaceutically acceptable salt or solvate thereof, for use in the method of the present invention. The above-mentioned peptide having the amino acid sequence of GTWY (SEQ ID NO: 1) and its pharmaceutically acceptable salt and solvate can be used in accordance with the description of the compositions and agents of the present invention.

[0038] The methods and uses of the present invention may be used in mammals, including humans, and both therapeutic and non-therapeutic uses are intended. As used herein, "non-therapeutic" means not including surgical, therapeutic, or diagnostic procedures for humans (i.e., medical procedures for humans), and specifically does not include methods of surgical, therapeutic, or diagnostic procedures for humans performed by a physician or a person under the supervision of a physician. [Example]

[0039] The present invention will be described in more detail based on the following examples, but the present invention is not limited to these examples.

[0040] Example 1: Effect of tetrapeptides on depression and hypoactivity (1) Overview of the test GTWY peptide (Bachem) was dissolved in distilled water and orally administered to mice. One hour later, the tail suspension test was performed to evaluate the effect of the test substance on depression and loss of motivation.

[0041] (2) Administration of GTWY peptide After one week of acclimation, 5-week-old ICR (CD-1) male mice (Charles River Japan) were orally administered GTWY peptide at 0, 0.3, or 1.0 mg / kg body weight (dry weight equivalent) via intragastric gavage. The administered GTWY peptide was prepared by adding distilled water immediately before administration. Specifically, an aqueous solution of GTWY peptide prepared with distilled water to a volume of 10 mL / kg body weight was orally administered via intragastric gavage. In addition, the 0 mg / kg group received dilution solvent (distilled water) via intragastric gavage to a volume of 10 mL / kg body weight. All studies were conducted with eight mice per group.

[0042] (3) Tail suspension test A tail suspension test was performed 1 hour after administration of the GTWY peptide or distilled water described in (2) above. Specifically, the mice were placed in an inverted position in individual cages at 60 lux and 23.5 ± 1°C. One end of a tape (1 cm wide, 15 cm long) was fixed to the top of the cage so that the mouse's head was 45–50 cm above the cage bottom, and the other 2 cm of the tape was wrapped around the tail (1 cm from the tip of the tail) to secure the tape to the tail. The mice were then suspended for 6 minutes (tail suspension). The tail-suspended mice were visually observed from a separate room using a video camera and monitor, and the time spent immobile (immobility time) (seconds) during the 6 minutes was measured. Immobility was defined as a state in which the mouse's limbs had stopped moving and there was no strain.

[0043] The tail suspension test was developed as a method for assessing depressive-like behavior (Cryan JF, et al. Neurosci Biobehav Rev. 2005; 29: 571-625). When mice are suspended upside down with their tails fixed, they exhibit escape behavior followed by immobility (hanging motionless). The duration of immobility observed within a certain period of time is evaluated as depressive-like behavior. The immobility observed in the tail suspension test is thought to represent a state of despair in which the experimental animal has given up on escaping from the exposed environment, i.e., a loss of motivation to escape, and is also an index of motivation.

[0044] (5) Results The results of the tail suspension test are shown in Figures 1 and 2. All tests were performed by Dunnett's test using a non-administered group as a control.

[0045] As shown in Figure 1, the immobility time in the tail suspension test was significantly reduced in the 0.3 mg / kg and 1.0 mg / kg GTWY peptide-administered groups compared to the non-GTWY peptide-administered group. This confirmed that GTWY peptide administration improved the depressed state and decreased motivation and reduced the immobility time.

[0046] As shown in Figure 2, the immobility time in the tail suspension test was significantly reduced in the 0.1 mg / kg and 0.3 mg / kg GTWY peptide-administered groups compared to the control group. This confirmed that GTWY peptide administration improved the depressed state and decreased motivation and reduced the immobility time.

Claims

1. A composition for suppressing decline in mental function, comprising as an active ingredient a tetrapeptide consisting of the amino acid sequence of GTWY (SEQ ID NO: 1) or a pharmaceutically acceptable salt or solvate thereof, wherein the suppression of decline in mental function is achieved by alleviating anxiety and / or improving mental vitality, the composition is to be ingested by a human in an amount of 0.01 to 10 mg (converted to dry mass) per day, and the human is a healthy individual.

2. The composition of claim 1, which is administered to a person with or at risk of mental decline.

3. The composition according to claim 1 or 2, wherein the tetrapeptide consisting of the amino acid sequence of GTWY (SEQ ID NO: 1), or a pharmaceutically acceptable salt or solvate thereof, is administered to a human in an amount of 0.01 to 5 mg (in dry mass terms) per day.

4. The composition according to any one of claims 1 to 3, which is a food composition.

5. The composition according to any one of claims 1 to 4, which is in a unit package form suitable for single ingestion.

Images