Composition for preventing mental decline

Abstract

To provide a novel composition effective for prevention of mental function reduction or the like.SOLUTION: A mental function reduction preventing composition includes a hop oxidation reaction product. Mental function reduction includes a state selected from the group consisting of a state related to depression and a state related to anxiety. The composition according to the present invention can be provided in a form of a food composition and can be taken by subjects having reduced mental function or subjects at risk of the mental function reduction. An S-fraction can be used as the hop oxidation reaction product.SELECTED DRAWING: Figure 3

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 routinely exposed to chronic fatigue and stress. Chronic fatigue and stress can affect mental function, resulting in declines in mental function such as loss of motivation and depressive symptoms. In recent years, it has become clear that inflammation in the brain is involved in this mechanism (Non-Patent Document 1).

[0003] Hops, the source of the bitter components in beer, have long been used as a folk medicine and are known to have various health benefits, including sedative and stomach-strengthening effects. Adding a certain amount of an extract obtained from hops to food or beverages can result in a distinctive, intense bitterness, which can diminish palatability. However, it has been reported that oxidizing hops can suppress the characteristic bitterness of hops while maintaining their lipid metabolism-improving function (Patent Document 1). However, there have been no reports to date on the relationship between hop-derived components or their oxidized products and mental function. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2012 / 081675 [Non-patent literature]

[0005] [Non-Patent Document 1] Akira Moji, Journal of Neuroscience (2012) Vol. 114, No. 2, pp. 124-133 Summary of the Invention

[0006] The present inventors have now discovered that hop oxidation products are effective in improving depression and loss of motivation, as well as in alleviating brain inflammation. The present inventors have also discovered that hop oxidation products are effective in improving mood and mental states in humans. The present invention is based on these findings.

[0007] That is, an object of the present invention is to provide a novel composition that is effective in suppressing decline in mental function.

[0008] According to the present invention, the following inventions are provided. [1] A composition for suppressing mental decline and an agent for suppressing mental decline, comprising a hop oxidation reaction product. [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 agent described in [1] above, wherein the decline in mental function is a decline in mood state or a decline in mental state. [4] The composition and agent according to any one of [1] to [3] above, which is administered to a subject with or at risk of having a decline in mental function. [5] The composition and agent according to any one of [1] to [4] above, wherein the decline in mental function is due to stress or chronic fatigue. [6] The composition and agent according to any one of [1] to [5] above, which is a food composition. [7] The composition and agent according to any one of [1] to [6] above, which is in a unit package suitable for single ingestion. [8] The composition and agent according to any one of [1] to [7] above, wherein the hop oxidation reaction product is an S-fraction. [9] The composition and agent according to [8] above, which contains 1 to 500 mg of S-fraction per dose, calculated on a dry mass basis.

[10] A composition for treating, preventing, or ameliorating depression and / or anxiety, and an agent for treating, preventing, or ameliorating depression and / or anxiety, comprising a hop oxidation reaction product.

[0009] The compositions of [1] and

[10] above may be referred to herein as "compositions of the present invention," and the preparations of [1] and

[10] above may be referred to herein as "preparations of the present invention."

[0010] The present invention provides a composition containing a hop oxidation reaction product that can exert functions such as suppressing decline in mental function. Because hop oxidation reaction products utilize components derived from hops, which have been consumed by humans as a food for many years, the present invention is advantageous in that it can be used as a functional material that is safe for mammals, including humans. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 shows the results of HPLC analysis (HPLC chromatogram) of hop oxidation reaction products in Reference Example 1. [Figure 2] FIG. 2 shows an outline of the test in Example 2. [Figure 3] 3 is a graph showing the time of immobility (immobility time) in the control group and test group in the tail suspension test, where * indicates P<0.05, ** indicates P<0.01, and *** indicates P<0.001. [Figure 4] 4 is a graph showing the amount of inflammatory cytokine (IL-1β) in hippocampal tissues collected from the control and test groups. ** indicates P<0.01, and *** indicates P<0.001. [Figure 5] 5 is a graph showing the amount of inflammatory cytokine (IL-1β) in the cerebral cortex collected from the control group and the test group. * indicates P<0.05, *** indicates P<0.001. Specific Description of the Invention

[0012] Hop oxidation products In the present invention, the term "hop oxidation reaction product" refers to a product obtained by oxidizing hops or processed products thereof (hop pellets, hop extract, etc.). The hop oxidation reaction product provided by the present invention can be obtained, for example, by contacting hops with oxygen in the air to oxidize them.

[0013] Hop oxidation products can be produced by oxidizing hops according to the method described in Patent Document 1, for example. The oxidation treatment is preferably carried out by heating hops in air. The heating temperature is not particularly limited, but a preferred upper limit is 100°C, and a more preferred upper limit is 80°C. A heating temperature of 100°C or lower is advantageous in that oxidation proceeds preferentially over isomerization. The preferred lower limit of the heating temperature is 60°C. A heating temperature of 60°C or higher is advantageous in that the oxidation reaction proceeds efficiently. The reaction period is also not particularly limited and can be determined appropriately depending on the hop variety and reaction temperature. For example, a period of 48 to 120 hours is preferred at 60°C, and a period of 8 to 24 hours is preferred at 80°C. The form of hops used in the oxidation reaction is not particularly limited as long as they can be exposed to oxygen in the air. However, powdered hops are preferred to shorten the reaction time.

[0014] In the present invention, hops may be in any form as long as they contain lupulin, and may be harvested and not yet dried, harvested and dried, compressed, crushed, or processed into pellets, but are preferably in the form of hop pellets. Hop pellets may be commercially available, for example, hop cones compressed into pellets (Type 90 pellets), pellets in which the lupulin portion has been selectively concentrated (Type 45 pellets), or isomerized hop pellets (e.g., Isomerized Pellets (HopSteiner)).

[0015] A hop extract oxidation reaction product produced by subjecting a hop extract to oxidation treatment may be provided as the hop oxidation reaction product of the present invention. The hop extract oxidation reaction product can be produced by subjecting a hop extract to oxidation treatment according to the method described in Patent Document 1, for example.

[0016] Hops contain acidic resin components such as α acids (humulones), β acids (lupulones), and iso-α acids (isohumulones). In the present invention, "humulones" is used to include humulone, adhumulone, cohumulone, posthumulone, and prehumulone. In addition, in the present invention, "lupulones" is used to include lupulone, adlupulone, colupulone, postlupulone, and prelupulone. Furthermore, in the present invention, the term "isohumulones" is used to include isohumulone, isoadhumulone, isocohumulone, isoposthumulone, isoprehumulone, Rho-isohumulone, Rho-isoadhumulone, Rho-isocohumulone, Rho-isoposthumulone, Rho-isoprehumulone, tetrahydroisohumulone, tetrahydroisoadhumulone, tetrahydroisocohumulone, tetrahydroisoprehumulone, tetrahydroisoposthumulone, hexahydroisohumulone, hexahydroisoadhumulone, hexahydroisocohumulone, hexahydroisoposthumulone, and hexahydroisoprehumulone. It should be noted that isohumulones exist as cis- and trans-stereoisomers, and unless otherwise specified, the term "isohumulones" includes both cis- and trans-stereoisomers.

[0017] By subjecting hops to oxidation, the content of α acids, β acids, and iso-α acids is reduced, while the content of other components is increased. Examples of such hop oxidation reaction products include those in which, when subjected to HPLC analysis similar to that in Example 1, the ratio of the peak area of ​​α acids, β acids, and iso-α acids to the total HPLC peak area is 20% or less, preferably 10% or less.

[0018] Components other than α acids, β acids, and iso-α acids contained in the oxidation reaction product of the present invention can be easily detected by well-known analytical methods such as HPLC. For example, a hop oxidation reaction product prepared by a procedure similar to that described in Example 1 of Patent Document 1 contains components other than α acids, β acids, and iso-α acids, and the peaks corresponding to these components (also referred to herein as "S-fraction (S-Fr)") may exhibit physiological activity. The peaks in the range indicated by the arrow in Figure 1A of Example 1 of Patent Document 1 (excluding the α acid and β acid peaks) correspond to the S-fraction.

[0019] HPLC analysis of a hop oxidation reaction product prepared under the same conditions as in Patent Document 1 and the resulting HPLC chromatogram are shown in Reference Example 1 and Figure 1. The peaks in the range indicated by arrows A1 and A2 (excluding the α-acid and β-acid peaks) correspond to the S-fraction. In Figure 1, the peak area in the range fractionated by arrows A1 and A2 is the sum of the peak area for A1 from 3 to 25 minutes in retention time and the peak area for A2 from 32 to 39 minutes in retention time (excluding the α-acid and β-acid peaks). Here, "up to 25 minutes in retention time" in A1 refers to the time until the appearance of a peak identified as trans-isocohumulone. Furthermore, characteristic peaks were observed at retention times of approximately 9.7 minutes, 11.8 minutes, and 12.3 minutes in the range fractionated by A1 in Figure 1. In addition, a shoulder peak was observed in the range fractionated by A2 in Figure 1, with its start point at a retention time of approximately 32 minutes, its top point (excluding the α acid and β acid peaks) at a retention time of approximately 35 to 36 minutes, and its end point at a retention time of approximately 39 minutes.

[0020] Hop oxidation reaction products preferably contain α-acid oxides, iso-α-acid oxides, and β-acid oxides, and examples of such oxides include "tricyclooxyisohumulones." Here, "tricyclooxyisohumulones" include tricyclooxyisocohumulone A (TCOIcoH A: see Formula 1 below, IUPAC name: (3aS,5aS,7S,8aS)-3,3a-dihydroxy-7-(1-hydroxy-1-methylethyl)-6,6-dimethyl-2-(2-methylpropanoyl)-5a,6,7,8-tetrahydro-3aH,5H-cyclopenta[c]pentalene-1,4-dione), tricyclooxyisohumulone A (TCOIcoH A: See formula 2 below, IUPAC name: (3aS,5aS,7S,8aS)-3,3a-dihydroxy-7-(1-hydroxy-1-methylethyl)-6,6-dimethyl-2-(3-methylbutyryl)-5a,6,7,8-tetrahydro-3aH,5H-cyclopenta[c]pentalene-1,4-dione), a group of compounds including tricyclooxyisoadhumulone A (TCOIadH A: See formula 3 below, IUPAC name: (3aS,5aS,7S,8aS)-3,3a-dihydroxy-7-(1-hydroxy-1-methylethyl)-6,6-dimethyl-2-(2-methylbutanoyl)-5a,6,7,8-tetrahydro-3aH,5H-cyclopenta[c]pentalene-1,4-dione). In the present specification, TCOIcoH A, TCOIH A, and TCOIadH A may hereinafter be collectively referred to as TCOIHsA. The TCOIHsA content is measured by the method described in Example 1 below.

[0021] [ka]

[0022] [ka]

[0023] [ka]

[0024] Examples of oxidation products other than "tricyclooxyisohumulones" contained in hop oxidation products (preferably S-fraction) include scorpiofumulinol A and scorpiocohumulinol A.

[0025] In the present invention, the hop oxidation reaction product may be provided as an aqueous medium extract. The aqueous medium is not particularly limited as long as it is one commonly used in food production, but is preferably water or ethanol, and more preferably water. The extraction temperature is not particularly limited, but is preferably 60°C or less, and in consideration of extraction efficiency, 50 to 60°C is more preferable.

[0026] The hop oxidation reaction product (preferably, an aqueous medium extract of a hop oxidation reaction product) used in the present invention can be characterized by the ratio (on a dry mass basis) of the total amount of tricyclooxyisohumulone A and tricyclooxyisocohumulone A to the total amount of scorpiofumulinol A and scorpiocohumulinol A. For example, an aqueous medium extract of a hop oxidation reaction product in which this ratio is in the range of 1 to 30, preferably an aqueous medium extract of a hop oxidation reaction product in which this ratio is in the range of 2 to 20, can be used.

[0027] The hop oxidation reaction product used in the present invention can be characterized by the content (in dry mass terms) of TCOIHs in the S-fraction. For example, a hop oxidation reaction product (preferably, an aqueous medium extract of a hop oxidation reaction product) having a TCOIH content of 5 to 15% by mass, preferably 5 to 12% by mass, can be used. When the S-fraction of the hop oxidation reaction product is primarily composed of the components of the fraction indicated by the arrow A1 in Figure 1, the content can be measured using a method similar to that for measuring mature hop bitter acids, as described in Biosci., Biotechnol., Biochem., 2015 (79): 1684-1694.

[0028] The Brix value of the aqueous medium extract of the hop oxidation reaction product is not particularly limited, but is, for example, 3 or less, and preferably 1.5 to 3. Insoluble components may be removed from the aqueous medium extract of the hop oxidation reaction product by decantation or filter paper, etc. The aqueous medium extract of the hop oxidation reaction product may also be treated with activated carbon.

[0029] In addition to hop oxidation reaction products, the compositions and preparations of the present invention may contain one or more other ingredients intended to suppress mental decline, such as tryptophan.

[0030] Purpose As shown in the Examples below, hop oxidation products (preferably S-fraction) have the effect of improving depression and loss of motivation, as well as improving mood and mental state, and further alleviating intracerebral inflammation. Depression, loss of motivation, decreased mood, and decreased mental state are typical examples of mental decline, and it has been shown that intracerebral inflammation is involved in depression and loss of motivation (Non-Patent Document 1). Therefore, hop oxidation products can be used as an active ingredient in compositions for suppressing mental decline and agents for suppressing mental decline.

[0031] In the present invention, "mental function" is used to include emotional function (emotional and willful functions) and mental vitality. "Deterioration of mental function" is used to include deterioration of mental function due to stress or chronic fatigue, and deterioration of mental function due to brain inflammation. Examples of "deterioration of mental function" include depression-related states and anxiety-related states. Depression-related states include, for example, depressed state, loss of motivation, loss of energy, loss of vitality, feelings of sadness, loneliness, depression, hopelessness, and loss of curiosity. Anxiety-related states include, for example, anxiety, mental fatigue, feelings of loneliness, restlessness, confusion, fear, and worries. Examples of "deterioration of mental function" also include depressed state, loss of motivation, decreased mood state, and decreased mental state. Deterioration of mood state and decreased mental state include, for example, decreased overall mood state, and "overall mood state" refers to mood states such as anger-hostility, confusion-bewilderment, depression-depression, fatigue-lethality, tension-anxiety, vitality-energy, and friendliness.

[0032] 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.

[0033] As described above, hop oxidation reaction products 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, hop oxidation reaction products can be used as an active ingredient 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 hop oxidation reaction products, and agents for treating, preventing, or ameliorating depression and / or anxiety, which comprise hop oxidation reaction products.

[0034] The compositions and agents of the present invention can be provided in the form of pharmaceuticals (e.g., pharmaceutical compositions), quasi-drugs, foods, feeds (including pet foods), etc., and can be administered according to the following description.

[0035] The hop oxidation reaction product, which is the active ingredient 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 methods commonly used in the art. Pharmaceutically acceptable carriers include excipients, binders, diluents, additives, flavorings, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, etc.

[0036] When the hop oxidation reaction product, which is the active ingredient of the present invention, is provided as a food product, it can be provided as is or can be incorporated into a food product. The food product provided in this manner contains an effective amount of the hop oxidation reaction product. As used herein, "containing an effective amount of the hop oxidation reaction product" refers to a content such that the hop oxidation reaction product (preferably the S-fraction) is ingested within the range described below when ingested in a typical amount for that particular food product. The term "food" is used to encompass health foods, functional foods, dietary supplements, supplements, health-claimed foods (e.g., foods for specified health uses, foods with nutrient functions, foods with functional claims), and foods for special dietary uses (e.g., foods for infants, foods for pregnant women, foods for sick people). When the hop oxidation reaction product, which is the active ingredient of the present invention, is ingested by animals other than humans, the food referred to in the present invention is, of course, used as feed.

[0037] Because the compositions, agents, and hop oxidation reaction products of the present invention have the effect of suppressing mental decline, they can be provided by being incorporated into foods consumed daily or as supplements. In this case, the compositions, agents, and hop oxidation reaction products of the present invention can be provided in unit packaging forms in which the amount to be ingested per meal is predetermined. Examples of unit packaging 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, agents, and hop oxidation reaction products of the present invention, the intake amount per meal can be determined according to the intake amount per serving of hop oxidation reaction products, as described below. The foods of the present invention may be provided with instructions regarding the intake amount displayed on the packaging, or may be provided together with a document or the like containing such instructions.

[0038] As described above, the food of the present invention can be provided by incorporating the hop oxidation reaction product into foods consumed daily or as supplements, but the hop oxidation reaction product can also be incorporated into health foods or functional foods, preferably foods containing one or more other ingredients intended to suppress mental decline. Alternatively, the food of the present invention containing the hop oxidation reaction product may further contain one or more other ingredients intended to suppress mental decline. Examples of other ingredients intended to suppress mental decline include those similar to those described above.

[0039] The form of the "food" is not particularly limited, and may be, for example, a beverage, a semi-liquid, or a gel. Examples of supplements include tablets or tablets produced by kneading a dry powder of a hop oxidation reaction product with an excipient, a binder, etc., and then compressing the mixture, as well as capsules or other forms.

[0040] The foods provided by the present invention are not particularly limited as long as they contain the hop oxidation reaction product, which is the active ingredient of the present invention. Examples of such foods include non-alcoholic beverages such as soft drinks, carbonated drinks, fruit juice drinks, vegetable juice drinks, fruit and vegetable juice drinks, milk, soy milk, dairy drinks, drink-type yogurt, drink-type jelly, 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; cookies, cakes, and the like. Examples of such beverages include, but are not limited to, Western confectioneries such as jelly and chocolate, Japanese confectioneries such as manju and yokan, candies, chewing gum, frozen desserts and ice creams such as yogurt, jelly, and pudding, and 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 using eggs, processed seafood and meat (including liver and other offal) products (including delicacies), processed foods such as soups, and liquid foods such as concentrated liquid foods. Mineral water includes both sparkling and non-sparkling mineral water.

[0041] 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).

[0042] 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.

[0043] The hop oxidation reaction products, which are the active ingredients of the present invention, are derived from hops, which have been consumed by humans as a food for many years. Therefore, they are low in toxicity and can be safely used in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, etc.) that require them. The intake or administration amount of the hop oxidation reaction products can be determined depending on the recipient's sex, age, and weight, symptoms, administration time, dosage form, administration route, and other factors, as well as other drugs to be combined. The intake or administration amount (in dry mass terms) of the hop oxidation reaction products of the present invention per adult is, for example, 0.5 to 16,000 mg (preferably 0.5 to 8,000 mg, more preferably 0.5 to 4,000 mg), and the intake or administration amount (in dry mass terms) of the S-fraction per adult is, for example, 0.1 to 2,000 mg (preferably 0.1 to 1,000 mg, more preferably 0.1 to 500 mg, and particularly preferably 0.2 to 100 mg). The above-mentioned intake amount of the hop oxidation reaction product, which is the active ingredient of the present invention, and the following intake timing and intake period are applicable whether the hop oxidation reaction product is used for non-therapeutic purposes or therapeutic purposes, and in the case of therapeutic purposes, "intake" can be read as "administration."

[0044] Depending on the subject, the hop oxidation reaction product may be ingested or administered in several divided doses. If a medium- to long-term effect is expected, the above-mentioned amount may be ingested or administered at least once a week (preferably at least once every three days, more preferably continuously every day) for one month (preferably three months, more preferably six months).

[0045] The hop oxidation reaction product can also be ingested or administered to a subject before and / or after an event that causes a decline in mental function. The number of ingestion or administration can be one or more times before and after the event, and preferably three or more, four or more, five or more, or six or more times. Examples of events that cause a decline in mental function include stress and chronic fatigue.

[0046] 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

[0047] The present invention provides a method for suppressing a decline in mental function, comprising ingesting or administering to a subject in need thereof an effective amount of a hop oxidation reaction product or a composition containing the same. The subject for administration is a mammal, including a human, and preferably a human. The method for suppressing a decline in mental function of the present invention can be carried out according to the descriptions of the compositions and agents of the present invention and the active ingredients of the present invention.

[0048] The present invention provides a method for treating, preventing, or ameliorating depression and / or anxiety, comprising ingesting or administering to a subject in need thereof an effective amount of a hop oxidation reaction product or a composition containing the same. The subject for administration is a mammal, including a human, and preferably a human. The treatment, prevention, or amelioration method of the present invention can be carried out in accordance with the descriptions of the compositions and agents of the present invention and the active ingredients of the present invention.

[0049] The present invention provides use of a hop oxidation reaction product or a composition containing the same for producing a composition for inhibiting mental decline or for producing an agent for inhibiting mental decline. The present invention also provides use of a hop oxidation reaction product or a composition containing the same for inhibiting mental decline or as an agent for inhibiting mental decline. The present invention also provides a hop oxidation reaction product for use in inhibiting mental decline. The use of the present invention and the hop oxidation reaction product of the present invention can be carried out in accordance with the descriptions of the compositions and agents of the present invention and the active ingredients of the present invention.

[0050] The present invention provides use of a hop oxidation reaction product or a composition containing the same for the manufacture of a composition for the treatment, prevention, or amelioration of depression and / or anxiety, or for the manufacture of an agent for the treatment, prevention, or amelioration of depression and / or anxiety. The present invention also provides use of a hop oxidation reaction product or a composition containing the same for the treatment, prevention, or amelioration of depression and / or anxiety, or as an agent for the treatment, prevention, or amelioration of depression and / or anxiety. The present invention also provides a hop oxidation reaction product for use in the treatment, prevention, or amelioration of depression and / or anxiety. The use of the present invention and the hop oxidation reaction product of the present invention can be carried out in accordance with the descriptions of the compositions and agents of the present invention and the active ingredients of the present invention.

[0051] The methods and uses of the present invention may be used in mammals, including humans, and are intended to be both therapeutic and non-therapeutic. As used herein, "non-therapeutic" does not include 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]

[0052] The present invention will be described in more detail based on the following examples, but the present invention is not limited to these examples.

[0053] Reference Example 1: Preparation of hop pellet oxidation reaction product Pellets of Hallertauperle (HPE) hops were used. The hops were ground in a mill and heated at 80°C for up to 24 hours. The resulting product was pretreated as follows and then subjected to HPLC analysis.

[0054] [Pretreatment for reactant analysis] The collected product was added to ethanol to a concentration of 10% w / v, and extraction was carried out for 1 hour at 50° C. The obtained extract was diluted 10 times with ethanol. [HPLC configuration equipment] Pump: LC-10ADvp x 3 (SHIMADZU) Degasser: DGU-20A5 (SHIMADZU) System controller: CBM-20A (SHIMADZU) Autosampler: SIL-20ACHT (SHIMADZU) Column oven: CTO-20AC (SHIMADZU) Photodiode array detector: SPD-M20A (SHIMADZU) Waveform analysis software: LCSolution (SHIMADZU)

[0055] [HPLC conditions] Column: Alltima C18 2.1mm ID x 100mm, particle size 3μm Flow rate: 0.6mL / min Dissolution medium A: Water / phosphoric acid, 1000 / 0.2, (v / v) + EDTA (free) 0.02% (w / v) Elution solvent B: Acetonitrile Elution solvent C: Water Injection volume: 3μL Column temperature: 40℃ Detection wavelength: 270 nm (oxidation reaction products, iso-α acids, α acids, β acids) Gradient program:

[0056] [Table 1]

[0057] Under the above analytical conditions, the ratio (%) of the area values ​​of the α-acid, β-acid, and iso-α-acid peaks to the total area value (mAU·min) of all peaks detected at a detection wavelength of 270 nm was calculated. For waveform analysis, regions containing solvent peaks and negative peaks due to injection shock were excluded from the analysis. The HPLC chromatogram obtained during analysis of the above product is shown in Figure 1.

[0058] Example 1: Preparation of hop oxidation reaction products (1) Hop oxidation process Hallertauperle (HPE) hops were ground in a pellet mill, and the resulting ground hops were heated at 60°C for approximately 120 hours while stirring in the atmosphere. Water was added to the resulting heated hops (matured hop pellets) to a solids concentration of 5 w / v%, and an extraction treatment was carried out at 50°C for 30 minutes. The resulting extract was subjected to solid-liquid separation by decantation, yielding a solid-liquid separated liquid (Brix approximately 2).

[0059] (2) Activated carbon treatment process Activated carbon (Y180C, manufactured by Ajinomoto Fine Chemicals Co., Ltd.; 0.5 w / v% relative to the solid-liquid separated liquid) and polyvinyl polypyrrolidone (Polyclar 10, manufactured by ISP Japan Co., Ltd.; 0.4 w / v% relative to the solid-liquid separated liquid) were added to the solid-liquid separated liquid obtained in (1) above, and the mixture was allowed to stand for 2 hours. A filter aid (diatomaceous earth) was added to the resulting mixture, and the mixture was filtered to obtain a filtrate (Brix value: approximately 1.5). The resulting filtrate was used in the following examples as the aqueous extract of hop oxidation products.

[0060] (3) Analysis of Hop Oxidation Products The filtrate obtained in (2) above (aqueous extract of hop oxidation products) was analyzed by HPLC-MSMS under the following conditions to measure the contents of various components contained in the hop oxidation products. Hop oxidation products are known to contain scorpiofumulinol A, scorpiocohumulinol A, tricyclooxyisohumulone A, and tricyclooxyisocohumulone A as α-acid oxides, iso-α-acid oxides, and β-acid oxides (Biosci., Biotechnol., Biochem., 2015 (79):1684-1694; J., Agric., Food Chem., 2015:63:10181-10191). In addition, the standards used in the analysis were prepared according to the methods described in J., Agric., Food Chem., 2015:63:10181-10191 and J. Nat. Prod. 2014, 77, 1252-1261.

[0061] [HPLC conditions] Column: Unison UK-C18 100 x 2 mm id, particle size 3 μm Flow rate: 0.25mL / min Column temperature: 40℃ Mobile phase A: 1% formic acid in water Mobile phase B: acetonitrile containing 1% formic acid Injection volume: 3μL Gradient: 0 → 30 min, 15 → 31% B 30→40 minutes, 31→80%B 40→43 minutes, 80%B The subsequent washing and equilibration steps

[0062] [MSMS conditions] Mass spectrometer: AB SCIEX 4000Q Trap Ion source: ESI - negative ion mode Ion spray voltage: -4500V Analysis parameters:

[0063] [Table 2]

[0064] The above steps (1) and (2) were carried out three times to obtain a filtrate, and the contents of scorpiofumulinol A, scorpiocohumulinol A, tricyclooxyisohumulone A, and tricyclooxyisocohumulone A were measured. As a result, the ratio of the total amount of tricyclooxyisohumulone A and tricyclooxyisocohumulone A to the total amount of scorpiofumulinol A and scorpiocohumulinol A ((tricyclooxyisohumulone A + tricyclooxyisocohumulone A) / (scorpiofumulinol A + scorpiocohumulinol A)) was as follows: Lot 1:3.2 Lot 2: 6.8 Lot 3: 12.1

[0065] From the above results, it was found that in the hop oxidation reaction products, the ratio of the total amount of tricyclooxyisohumulone and tricyclooxyisocohumulone to the total amount of scorpiofumulinol and scorpiocohumulinol was approximately 2-20.

[0066] Example 2: Effects of hop oxidation products on depression and hypoactivity (1) Overview of the test The test substance was the dried product (containing S-Fr) of the aqueous extract of hop oxidation products obtained in Example 1(2). Mice were administered the test substance, and then lipopolysaccharide (LPS) was administered to induce intracerebral inflammation. After administration of the test substance, the mice were again administered the test substance, and a tail suspension test was performed to evaluate the effect of the test substance on depression and loss of motivation. After the test, brain tissue was collected from the mice, and intracerebral inflammation was evaluated by quantifying inflammatory cytokines in the brain tissue. A summary of the test is shown in Figure 2.

[0067] (2) Administration of hop oxidation reaction products (S-Fr) (I) Five-week-old ICR (CD-1) male mice (Charles River Japan) were divided into five groups with equal mean body weights, as shown in Table 3. After one week of acclimation, the "S-Fr 1 mg group," "S-Fr 10 mg group," and "S-Fr 50 mg group" were orally administered hop oxidation products via gavage into the stomach at S-Fr dry weight equivalents of 1, 10, and 50 mg / kg body weight. The administered hop oxidation products containing S-Fr were prepared by adding distilled water to the dried water extract of hop oxidation products obtained in Example 1(2) immediately before administration. Specifically, an aqueous solution of S-Fr prepared with distilled water to a volume of 10 mL / kg body weight was orally administered into the stomach via gavage once daily for six consecutive days. In addition, the "control group" (non-inflammation group) and the "non-S-Fr-treated group" were given dilution solvent (distilled water) by oral gavage once daily for 6 consecutive days at a volume of 10 mL / kg body weight. According to the 2005 FDA guidelines, the S-Fr doses of 1, 10, and 50 mg / kg body weight for mice are equivalent to 5, 49, and 243 mg, respectively, in human doses (60 kg body weight) based on body surface area (Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, URL: https: / / www.fda.gov / downloads / drugs / guidances / ucm078932.pdf).

[0068] [Table 3]

[0069] (3) Induction of intracerebral inflammation LPS (Sigma-Aldrich) was dissolved in distilled water to prepare a 1.5 mg / mL LPS solution. The test groups (non-S-Fr administration group and S-Fr administration group) received 0.5 mg of LPS intracerebroventricularly at 1 hour after S-Fr or distilled water administration on day 6 of S-Fr administration. The control group (non-inflammatory group) received 10 μL of distilled water intracerebroventricularly at 1 hour after S-Fr or distilled water administration.

[0070] (4) Administration of hop oxidation reaction products (S-Fr) (II) 23 hours after the administration of LPS or distilled water described in (3) above, mice in each group were forced to receive intragastrically the amount of S-Fr or distilled water shown in Table 3.

[0071] (5) Weight measurement The day before the tail suspension test (at approximately 7 weeks of age), the weights of each group were measured. The results (mean ± standard deviation) were 35.0 ± 0.7 g for the control group (non-inflammation-induced group), 34.4 ± 0.5 g for the non-S-Fr administration group, 35.9 ± 0.7 g for the S-Fr 1 mg administration group, 35.0 ± 0.6 g for the S-Fr 10 mg administration group, and 34.5 ± 0.5 g for the S-Fr 50 mg administration group, with no significant difference in weight between the groups.

[0072] (6) Tail suspension test The tail suspension test was performed 1 hour after the administration of S-Fr or distilled water as described in (4) 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.

[0073] 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 given period is used to assess 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 therefore also an index of motivation. In fact, existing antidepressants with clinical efficacy are known to suppress LPS-induced immobility (Park et al. Journal of Neuroinflammation 2011, 8:12).

[0074] (7) Evaluation of brain inflammation Three hours after the tail suspension test, mice from each group were euthanized, and the hippocampus and cerebral cortex were collected. The levels of inflammatory cytokines in the hippocampus and cerebral cortex were then measured. Specifically, the collected hippocampus and cerebral cortex were bead-disrupted in RIPA buffer (Wako Pure Chemical Industries, Ltd.), and the inflammatory cytokine interleukin-1β (IL-1β) was quantified using a Mouse IL-1β ELISA Ready-SET-Go! ELISA kit (eBioscience). The IL-1β quantification value was divided by the total protein concentration in the homogenate, which was determined by the bicinchoninic acid (BCA) method using a BCA Protein Assay kit (Thermo Fisher Science), to evaluate the IL-1β content per unit protein mass in the hippocampus or cerebral cortex.

[0075] (8) Results The results of the tail suspension test and the evaluation of intracerebral inflammation are shown in Figures 3 to 5. All tests were performed by Dunnett's test using a group not administered S-Fr as a control.

[0076] As shown in Figure 3, the immobility time in the tail suspension test was significantly increased in the S-Fr-treated group, which had been induced with inflammation, compared with the control group (non-inflammation group). On the other hand, the S-Fr-treated group tended to show a decrease in immobility time compared with the non-S-Fr-treated group, and the immobility time was significantly reduced in the S-Fr 10 mg and S-Fr 50 mg groups in particular. These results confirmed that S-Fr administration improved depression and loss of motivation and reduced immobility time.

[0077] Furthermore, as shown in Figures 4 and 5, IL-1β levels in the hippocampus and cerebral cortex were significantly increased in the S-Fr-untreated group after induction of inflammation compared with the control group (non-inflammation group). On the other hand, a tendency for IL-1β levels to decrease in the S-Fr-treated group compared with the non-S-Fr-treated group was confirmed. IL-1β levels were significantly decreased in the hippocampus in the S-Fr 1 mg and 10 mg groups (Figure 4) and in the cerebral cortex in the S-Fr 50 mg group (Figure 5). These results indicate that S-Fr administration can alleviate brain inflammation, thereby improving depression and reduced motivation.

[0078] Example 3: Effects of Hop Oxidation Products on Mood and Mental Status (1) Overview of the test A human study was conducted to verify the effects of hop oxidation products on mental function (particularly mood and mental state). The study was a placebo-controlled, randomized, double-blind, parallel-group comparative study. The study period was 12 weeks, during which participants ingested either a test food or a control food. Specifically, healthy men and women aged 45 to 64 years ingested capsules containing hop oxidation products as the test food and capsules not containing hop oxidation products as the control food, and the effects of hop oxidation products (particularly S-Fr) on mood and mental state were examined.

[0079] (2) Subjects Subjects who were deemed healthy by a doctor in a preliminary examination were randomly assigned to a test food group (30 people) and a control food group (30 people). The subjects analyzed were 27 people (13 men, 14 women) in the test food group and 30 people (14 men, 16 women) in the control food group, and the ages (mean ± standard deviation) of the subjects analyzed were 54.6 ± 5.4 years in the test food group and 55.4 ± 5.3 years in the control food group. The subjects were instructed to continue living the same lifestyle as before the test period during the study.

[0080] (3) Test food During the study period (12 weeks), the test food group was instructed to ingest three capsules of the test food, and the control food group was instructed to ingest three capsules of the control food once daily with water or lukewarm water. The test food was a "capsule containing hop oxidation products" (each capsule contained 35 mg of S-Fr, calculated as dry mass). The control food was a "capsule not containing hop oxidation products," manufactured in the same manner except that dextrin (Pinex #100: Matsutani Chemical Industry Co., Ltd.) was added instead of S-Fr. The formulation of the test food per capsule is shown in Table 4.

[0081] [Table 4]

[0082] (4) Measurement A. Measurement items The following tests were performed as measurement items. Profile of Mood States 2nd Edition (short version) (sometimes referred to as the "POMS2 test" in this specification)

[0083] B. Measurement period The POMS2 test was conducted once when the subjects visited the clinic before starting the test food intake, and once 6 and 12 weeks after starting the intake. At 6 and 12 weeks, the test food was taken approximately 30 minutes before the measurement.

[0084] C. Measurement method The POMS2 test was conducted as follows: subjects answered a total of 35 questions about their mood state over the past week. Responses were calculated for each item on seven scales: "Anger-Hostility," "Confusion-Bewilderment," "Depression-Depression," "Fatigue-Lethargy," "Tension-Anxiety," "Vibrancy-Energy," and "Friendliness," as well as an "Overall Mood State," to evaluate their mood state over the past week. Scores on each scale were evaluated using T-scores (values ​​transformed to approximate a normal distribution with a mean of 50 and a standard deviation of 10).

[0085] (5) Evaluation and analysis For each index evaluated by the POMS2 test, a score (actual value) was obtained at each measurement point, and the corresponding score before intake was subtracted from that score to determine the change. The actual values ​​and changes for both groups were tested using a two-sample t-test.

[0086] (6) Results The results are shown in Table 5. [Table 5]

[0087] Regarding the "tension-anxiety" category, only in the test food group, the actual measured values ​​and the change in the amount of change tended to improve at both 6 and 12 weeks after the start of intake, and a significant difference was observed in the actual measured values ​​between the two groups at 12 weeks after the start of intake (P<0.05).

[0088] For each of the categories of "confusion-bewilderment," "depression-depression," "fatigue-lethargy," and "general mood state," only the test food group showed a tendency for the actual measured values ​​and the amount of change to improve at both 6 and 12 weeks after the start of intake. Furthermore, for each of these categories except for "depression-depression," the amount of change at 6 weeks after the start of intake in the test food group tended to be significantly improved compared to the control food group (P<0.1).

[0089] In the POMS2 test, smaller actual measured values ​​for "anger-hostility," "confusion-bewilderment," "depression-depression," "fatigue-lethargy," "tension-anxiety," and "overall mood state" indicate a better state, while larger actual measured values ​​for "vigor-vitality" and "friendship" indicate a better state. Therefore, in this test, smaller changes in "anger-hostility," "confusion-bewilderment," "depression-depression," "fatigue-lethargy," "tension-anxiety," and "overall mood state" indicate a greater improvement in the state compared to before the start of intake, and larger changes in "vigor-vitality" and "friendship" indicate a greater improvement in the state compared to before the start of intake.

[0090] The above results show that when subjects took capsules containing hop oxidation products, the "tension-anxiety" category of the POMS2 test, which evaluates mood and mental state, improved (significant difference), and the "confusion-bewilderment," "fatigue-lethargy," and "overall mood state" categories also improved (significant trend).This indicates that hop oxidation products (especially S-Fr) have the effect of improving mood and mental state.

Claims

1. A composition for suppressing a decline in mental function, comprising a hop oxidation reaction product, wherein the decline in mental function is an anxiety-related condition, and the anxiety-related condition is a sense of anxiety that can be evaluated by the POMS2 test, and the hop oxidation reaction product is an aqueous medium extract of hops obtained by oxidizing hops at a temperature of 60°C or higher and 100°C or lower, and the aqueous medium extract is an extract obtained by subjecting oxidized hops to water extraction at a temperature of 50°C to 60°C, and the composition contains tricyclooxyisocohumulone A, tricyclooxyisohumulone A, scorpiofumulinol A, and scorpiocohumulinol A.

2. 2. The composition according to claim 1, wherein the ratio (on a dry mass basis) of the total amount of tricyclooxyisohumulone A and tricyclooxyisocohumulone A to the total amount of scorpiofumulinol A and scorpiocohumulinol A is in the range of 2 to 20.

3. 3. The composition of claim 1 or 2, which is administered to a subject with or at risk of having a decline in mental function, wherein the decline in mental function is an anxiety-related condition, and the anxiety-related condition is a feeling of anxiety that can be assessed by the POMS2 test.

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.

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