JP2014193844A - Antidepressant - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an inexpensive antidepressant which is hard to cause problems such as adverse drug reactions, and highly safe for long-term-ingestion.SOLUTION: The antidepressant containing L-ergothioneine expressed by a following formula: the L-ergothioneine is preferred to be contained in a form of mushroom extracts belonging to Flammulina, Leucopaxillus, Phellinus, Tricholoma, Coprinus, Hericiaceae, Lyophyllum, Rozites, Pholiota, Pleurotus, Mycoleptodonoides, Agrocybe, or Grifola.

Description

  The present invention relates to an antidepressant.

  The number of patients with depression is said to be more than 1 million in Japan, which is a serious problem. As for depression, the method to cure it has not been established yet, and symptomatic treatment by administration of an antidepressant is performed. Known antidepressants include tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin / noradrenaline reuptake inhibitors, but thirst, constipation, difficulty urinating, general malaise, weight There is a problem that various side effects such as increase occur.

  The cause of depression has not been clarified, but the lack of monoamines such as serotonin and noradrenaline is thought to be involved due to the monoamine reuptake inhibitory action of tricyclic antidepressants such as imipramine on nerve endings (monoamine). hypothesis).

  On the other hand, in recent years, ergothioneine, which is abundant in the extract powder of Tamogitake, has attracted attention. Tamogitake is a mushroom of the oyster mushroom family that grows naturally in Hokkaido and Tohoku, and is known to biosynthesize ergothioneine. It has been reported that ergothioneine is excellent in an antioxidant action and an anti-inflammatory action (for example, refer nonpatent literatures 1 and 2).

Hartman P. E., Meth. Enzymol., 186, p.310-318, 1990 Ito T. et. Al .: Food Sci. Tech. Res., 17, 103-110, 2011

  It is an object of the present invention to newly provide an inexpensive antidepressant that is unlikely to cause problems such as side effects and that is highly safe even after long-term ingestion.

  As a result of intensive studies to discover a new biological action of L-ergothioneine, the present inventors have unexpectedly found that L-ergothioneine has an antidepressant action, and have completed the present invention. .

  That is, according to the present invention, an antidepressant containing L-ergothioneine is provided. Furthermore, according to the present invention, a prophylactic or inhibitory agent for depression comprising L-ergothioneine as an active ingredient is also provided.

  The present invention can provide an inexpensive antidepressant that is unlikely to cause problems such as side effects and that is highly safe even after long-term ingestion.

FIG. 1 is a graph showing the results of the forced swimming test 1. FIG. 2 is a graph showing the results of the forced swimming test 2. FIG. 3 is a graph showing the ergothioneine concentration in blood. FIG. 4 is a graph showing the concentration of ergothioneine in the brain. FIG. 5 is a graph showing the results of the open field test. FIG. 6 is a graph showing the results of the tail suspension test. FIG. 7 is a graph showing the ergothioneine concentration in blood. FIG. 8 is a graph showing the ergothioneine concentration in the brain.

この構造は結晶状態のエルゴチオネインを示したものであり、溶液中では、チオール構造との互変異性体となることが知られている。 L-ergothioneine is known as an antioxidant substance as is ascorbic acid and cannot be synthesized in vivo, so it must be taken from the outside. L-ergothioneine is a kind of amino acid and has a property of being resistant to heat and acid. L-ergothioneine has the following structure.

This structure represents crystalline ergothioneine, and is known to be a tautomer with a thiol structure in solution.

As L-ergothioneine, a commercially available product by chemical synthesis may be used, but it is preferable to use a product obtained by extracting natural L-ergothioneine from the viewpoint of cost. L-ergothioneine is abundant in mushrooms such as Tamogitake (scientific name: Pleurotus cornucopiae var. Citrinopileatus). Specifically, as mushrooms containing L-ergothioneine, enokitake (Flammulina velutipes) belonging to the genus Enokitake (Flammulina), mushroom (Leucopaxillus giganteus), etc. belonging to the genus Mushroom (Leucopaxillus giganteus) Belonging to (Phellinus), such as Phellinus linteus, such as Tricholoma sp., Belonging to the genus Tricholoma, Coprinus, such as Coprinus comatus, belonging to the genus Hericiaceae Yamabushitake (Hericium erinaceum), etc., Lyophyllum shimeji, Lyophyllum decastes, etc., Rozites belonging to holiota (Rozites caperata), Nameko (Pholiota nameko), etc. Pleurotus (Pleurotus pulmonarius), Oyster mushroom (Pleurotus ostreatus), Elingi (Pleurotus eryngii) and Tamogittake (Pleurotus cornucopiae var. Citrinopileatus), ) Belonging to the genus Agrocybe cylindracea, etc., and Anninko (Grifola gargal) belonging to the genus Grifola.
Preferable mushrooms are particularly preferred because L-ergothioneine is considered to have high safety without worrying about side effects even when used for a long period of time, and as such mushrooms, such as Mushroom (Flammulina velutipes), Miotake mushroom (Leucopaxillus giganteus), Salamander Toyota (Coprinus comatus), Yamabushitake (Hericium erinaceum), Honjimeji (Lyophyllum shimeji), Nameko (Pholiota nameko), Oyster mushroom (Pleurotus ostreatus), Elingi (Pleurotus erytrum) And beech haritake (Mycoleptodonoides aitchisonii).

  Extraction of L-ergothioneine from mushrooms can be carried out by a known method. For example, as described in Japanese Patent Application Laid-Open No. 2012-56914, after a broth obtained by boiling mushrooms such as bamboo shoots is applied to an ion exchange resin, a cationic compound is eluted from the resin, and an eluate is obtained. L-ergothioneine can be extracted by concentrating, separating and purifying it by high performance liquid chromatography, and freeze-drying.

  Since mushrooms containing a large amount of L-ergothioneine such as Tamogitake have been used as food for many years, there is no concern about side effects even when L-ergothioneine is administered over a long period of time, and it is considered highly safe. According to animal experiments by the present inventors, even when a diet containing L-ergothioneine at a concentration of 1.2 mg / g (0.005 mmol / g diet) was administered to mice at 3 g / day for 2 weeks, There was no noticeable change in the amount of behavior, and no behavioral toxicity was observed. For this reason, it is considered that no toxicity is observed at 180 mg / kg body weight / day when the mouse body weight is 20 g. It is known that animals with a small body surface area, such as mice, generally require higher doses compared to humans in order to produce the same effect. In general, a dosage approximately 10 times higher than the human dosage is taken as a standard. Therefore, it is considered that no toxicity is observed in humans even when L-ergothioneine is administered at 18 mg / kg body weight / day.

  The present invention is based on the finding of antidepressant action on L-ergothioneine. In order to obtain the desired effect of the present invention, the daily dose of L-ergothioneine for adults is, for example, 0.005 mg or more, preferably 0.5 to 100 mg, more preferably 3 to 50 mg. The dose of L-ergothioneine can be appropriately adjusted according to sex, weight, age, intake period, severity of symptoms, and the like.

L-ergothioneine can be provided as an antidepressant containing this as an active ingredient. The antidepressant may comprise L-ergothioneine in the form of a purified product or in the form of a mushroom extract, preferably in the form of a bamboo shoot extract. As the mushroom extract of L-ergothioneine, for example, commercially available products such as “Tamogi extract powder” (L Escorporation) and “Coprino extract” (Oryza Oil & Chemicals Co., Ltd.) can be used. The mushroom extract may contain only L-form ergothioneine or may contain a mixture of D-form and L-form ergothioneine.
A mushroom extract such as a bamboo shoot extract contains, for example, 0.1 to 5% by mass of L-ergothioneine. Other components contained in the mushroom extract vary depending on the extraction method, and examples thereof include starch degradation products such as dextran, β-glucan, ergosterol, hexitol, ceramide, triterpenes, and dietary fiber. The antidepressant may contain other components depending on its use.

According to the antidepressant containing L-ergothioneine, as shown in the forced swimming test of FIG. 1 and FIG. 2 and the tail suspension test of FIG. Here, the forced swimming test and the tail suspension test (tail suspension test) are described in the behavioral test on the homepage of the "Mouse Development Laboratory"("TakeshiKoide") of the National Institute of Genetics, for example ( National Institute of Genetics HOME / Organization chart / Mouse development laboratory / Behavioral test, URL: http://www.nig.ac.jp/labs/MGRL/MGRL_behavior%20test.html), to confirm the antidepressant effect This is a generally established test method. Specifically, FIG. 1 shows the results of measuring the immobility time for the normal bait administration group a1, the ascorbic acid administration group b1, and the bait administration group containing bacillus extract powder-containing diet c1 in the forced swimming test. The immobility time of the end-administered group c1 was decreased compared to the normal diet-administered group a1 and the ascorbic acid-containing diet-administered group b1. Furthermore, in FIG. 2, the result of having measured the immobility time about the normal bait administration group a2, the tarogi extract powder containing bait administration group c2, and the ergothioneine containing bait administration group d2 is shown, and the tarogi extract powder containing bait administration group c2 and In the ergothioneine-containing bait administration group d2, a reduction in immobility time was observed compared to the normal bait administration group a2. The shortening of the immobility time indicates that L-ergothionein contained in the tatami extract extract has an antidepressant effect.
Moreover, in FIG. 3 and FIG. 4, the result of having measured the ergothioneine density | concentration in the blood of the normal bait administration group a3, the feed administration group c3 containing a tarogi extract powder, and the ergothioneine containing bait administration group d3, respectively is shown. It was confirmed that the ergothioneine concentration in the blood and the brain of the food administration group c3 containing talgi extract powder and the ergothioneine-containing food administration group d3 were comparable and were very high compared to the normal food administration group a3. From this result, it was found that L-ergothioneine migrates into the blood after oral ingestion of an antidepressant, further passes through the blood-brain barrier, and migrates efficiently to the brain. This confirms that L-ergothioneine has an antidepressant effect.
In FIG. 6, in the tail suspension test, the food administration group c5s containing 1% of tarogi extract powder and the food administration group c5 containing 10% of tarogi extract powder had a shorter immobility time than the normal food administration group a5. The antidepressant effect of L-ergothioneine shown in the swimming test was confirmed.

  Furthermore, ergothioneine has been confirmed in mice in vivo to permeate the cell membrane by the membrane transporter OCTN1 (Kato et al., Pharm Res 27, 832, 2010). OCTN1 is expressed in a wide range of tissues in humans (Tamai et al., FEBS Lett 419, 107, 1997; Sugiura et al., Drug Metab Dispos 38, 1665, 2010) and is also expressed in the brain (Tamai et al. , FEBS Lett 419, 107, 1997; Nishimura and Naito, Drug Metab Pharmacokinet 20, 452, 2005; Taubert et al., Gut 58, 312, 2009). Furthermore, it has been confirmed that human OCTN1 has an activity of incorporating ergothioneine into cells (Grundemann et al., Proc Natl Acad Sci USA 102, 5256, 2005). Considering these findings and the results of FIG. 4 in which L-ergothioneine efficiently migrates to the brain, in humans, L-ergothioneine acts on the brain and improves depressive symptoms by ingestion of an antidepressant. It is considered a thing.

  The antidepressant according to the present invention can also be used in the form of a prophylactic or suppressive for depression. In addition to antidepressants, the prophylactic or inhibitory agents for depression include excipients, bases, disintegrants, lubricants, binders, surfactants, pH adjusters, stabilizers, antioxidants, It may further contain additives commonly used for formulations such as fillers, flavoring agents, preservatives, coloring agents, or coating agents. Formulation of a prophylactic or inhibitory agent for depression can be performed using known pharmaceutical techniques.

  Examples of the prophylactic or suppressive agent for depression are, for example, a solution, a suspension, a powder, or a solid molding, and the dosage form is, for example, a tablet, a capsule, a powder, a granule, a drink, an injection. , Patches, suppositories, and inhalants. The method for administering the prophylactic or therapeutic agent for depression is not particularly limited, but is preferably oral administration. Suitable dosage forms for oral administration include, for example, tablets, capsules, powders, granules, pills, solutions, emulsions, suspensions, solutions, syrups, extracts, and elixirs. It is not limited to these.

  L-ergothioneine can also be provided as a food additive and food for the prevention or suppression of depression. Examples of the food additive include a purified product of L-ergothioneine or a mushroom extract containing L-ergothioneine mixed with a food acceptable carrier, additive, etc., for example, powder, granule, tablet, round Mention may be made of products prepared in the form of solid preparations such as preparations, capsules and dry syrups or liquid preparations such as liquids, drinks and syrups. The food additive is preferably used by being added or mixed in the food during or prior to the production of the food for consumption by those who are depressed or depressed or who are depressed.

  The food is not particularly limited, but for example, solid, semi-solid or liquid food, specifically, confectionery (cookies, rice crackers, jelly, etc.), beverage (milk beverage, lactic acid bacteria beverage, soft drink, vegetable beverage, powder Beverages, sports beverages, supplement beverages, nutritional beverages, etc.), tea beverages (coffee beverages, tea beverages, green tea, blended teas, etc.), breads, soups, processed fish products, processed meat products, noodles, sauces, side dishes, etc. Is mentioned. Foods include health functional foods such as foods for specified health use and functional nutritional foods, supplements (nutritional supplements) used for the purpose of strengthening nutritional components in health foods and foods, and the like. These foods can be produced by blending the food additive into the material in the production process. In addition to the above-mentioned food additives, foods can optionally contain food materials and additives such as seasonings, vegetable juices, gelling agents, or fragrances. The blending amount of the food additive in the food can be appropriately adjusted within a range that does not adversely affect the appearance and taste of the food.

  EXAMPLES Hereinafter, although an Example demonstrates this invention concretely, the antidepressant which concerns on this invention is not restrict | limited by the following Example.

[Forced swimming test using imipramine]
In the forced swimming test, a 7-week-old C57BL / 6 male mouse (Sankyo Laboratories) was placed in a beaker in which water at a temperature of 25 ° C. was poured to such a depth that the tail of the mouse did not reach the bottom. This was done by measuring the time of swimming and moving and the time of immobility. 30 minutes after intraperitoneal administration of imipramine established as an antidepressant, the forced swimming test was performed again. As a result, it was observed that immobility time was actually shortened by administration of imipramine (data not shown). Therefore, it was confirmed that the antidepressant action is shown by the forced swimming test.

[Forced swimming test 1]
Forced swimming test was performed on 5-week-old C57BL / 6 male mice (Sankyo Lab Co., Ltd.), the immobility time was measured within 5 minutes, and the average immobility time was divided into 3 groups. It was. There were 6 mice per group. The forced swimming test was performed according to the same method as the forced swimming test. These three groups of mice were mixed with (a1) normal food, (b1) normal food mixed with 88 mg / 100 g of ascorbic acid (0.5 mmol / 100 g of ascorbic acid) (ascorbic acid-containing food), (c1) normal The feed was fed with a feed (a feed containing a powder of tusks extract) mixed with 10% by weight (10 g / 100 g feed (0.5 mmol / 100 g feed of L-ergothioneine)) of taro extract powder (El Escorporation). The content of L-ergothioneine in this tatami extract is 1.2% by mass as measured by HPLC. Two weeks after the start of administration, a 5-minute forced swimming test was performed again, and the immobility time in 5 minutes was measured. FIG. 1 shows the measurement result of the immobility time.

  As shown in FIG. 1, the immobility time of the cypress extract powder administration group c1 was significantly reduced as compared with the normal bait administration group a1. Therefore, it was shown that Tamogitake extract powder has a depression inhibitory action. On the other hand, the immobility time of the ascorbic acid-containing bait administration group b1 was almost the same as that of the normal bait administration group a1. Thus, ascorbic acid is similar to ergothioneine in that it is a water-soluble antioxidant contained in food, but it has also been found that it has no depression-suppressing effect.

[Forced swimming test 2]
Forced swimming test was performed on 5-week-old C57BL / 6 male mice (Sankyo Lab Co., Ltd.), the immobility time was measured within 5 minutes, and the average immobility time was divided into 3 groups. It was. There were 6 mice per group. The forced swimming test was performed according to the same method as the forced swimming test 1. In these three groups of mice, (a2) normal food, (c2) 10% by mass of litter extract powder (EL Escorporation) (10 g / 100 g food (L-ergothioneine 0.5 mmol / 100 g food)) was mixed with normal food. (D2) ergothioneine (Funakoshi, # FR-111) in the same amount (L-ergothioneine 120 mg (0.5 mmol) / 100 g feed) as contained in the bait extract powder-containing bait in a normal bait , Containing only L form) and fed with ergothioneine-containing food. Two weeks after the start of administration, a 5-minute forced swimming test was performed again, and the immobility time in 5 minutes was measured. FIG. 2 shows the measurement result of the immobility time.

  As shown in FIG. 2, a significant reduction in immobility time was observed in the food administration group c2 containing tarogi extract powder and the food administration group d2 containing ergothioneine compared to the normal food administration group a2. Therefore, it was found that ergothioneine contained in the tatami extract powder has an antidepressant action.

[Measurement of ergothioneine concentration in blood and brain-Comparison between talgi extract powder and ergothioneine]
5-week-old C57BL / 6 male mice (Sankyo Lab Co., Ltd.) were divided into 3 groups, (a3) normal diet, (c3) 10% by mass (10 g / 100 g) of tarogi extract powder (El Escorporation) in the normal diet. Bait (L-ergothioneine 0.5 mmol / 100 g bait)) mixed bait (boiled eggplant powder), (d3) the same amount as that contained in the bait extract powder-containing bait (120 mg (0.5 mmol) L-ergothioneine) / 100 g food) ergothioneine (Funakoshi, # FR-111, containing only L form) was fed (ergothioneine-containing food) and reared for 19 days, and ergothioneine concentrations in blood and brain were measured. There were 6 mice per group. The measurement was performed using HPLC by the method described in Kato et al., Pharm Res 27, 832, 2010. The results are shown in FIG. 3 and FIG.

  As shown in FIG. 3 and FIG. 4, the ergothioneine concentrations in the blood and brain of the food administration group c3 containing talgi extract powder and the food administration group d3 containing ergothioneine are similar and much higher than those in the normal food administration group a3. High concentration. Therefore, it has been found that ergothioneine migrates into the blood after ingestion and crosses the blood brain barrier and migrates efficiently into the brain. From this result and in FIG. 2, almost the same immobility time shortening was observed in the feed administration group c2 containing talg extract powder and the feed administration group d2 containing ergothioneine. It became clear that this was due to ergothioneine.

[Spontaneous motor activity measurement test]
In order to confirm that the decrease in the immobility time observed in the forced swimming test was not due to the increase in the spontaneous exercise amount, the spontaneous exercise amount was measured. The amount of spontaneous exercise was measured as the distance (m) moved in 5 minutes for each group of mice tested in the forced swimming test 1.
As a result, for the mice tested in the forced swimming test 1, there was no significant difference in the amount of spontaneous movement in each group or the route through which the mice passed. Therefore, it was shown that the decrease in the immobility time in the forced swimming test is not due to the increase in the spontaneous exercise amount.

[Open field test]
Each group of mice tested in Forced Swim Test 1 is placed in an open field test device (45 cm long, 45 cm wide, 45 cm high), which is a wide, bright and novel environment for the mice. (Inside, center) Dwell time and number of rises were measured. The behavior of the mouse in the device was actually observed and recorded by an observer, and was also photographed with a video camera to extract data. As a result of the measurement of the compartment stay time, there was no difference in the stay time in each compartment of each group. On the other hand, the number of rises was significantly increased in the food administration group c4 containing talgi extract powder compared to the normal food administration group a4 (FIG. 5), and the search behavior in the novel environment tended to increase. Thus, it was shown that the tatami extract extract may have some effect on the emotion of the mouse. On the other hand, the number of rises of the ascorbic acid-containing diet-administered group b4 was almost the same as that of the normal diet-administered group a4. Thus, ascorbic acid is similar to ergothioneine in that it is a water-soluble antioxidant contained in food, but it has also been found that it does not affect the emotion of mice.

[Tail suspension test]
5-week-old C57BL / 6 male mice (Sankyo Lab Co., Ltd.) were divided into 3 groups of 12 mice each, (a5) normal diet, (c5s) 1% by mass of tarogi extract powder (L ES Corporation) on normal diet ( 1g / 100g bait (L-ergothioneine 0.05mmol / 100g bait) mixed bait (bait containing 1% of tatami extract extract), (c5) 10% by mass of talgi extract powder (El Escorporation) in a normal bait (10g / A 100 g bait (L-ergothioneine 0.5 mmol / 100 g bait)) mixed bait (feed containing 10% tarogi extract powder) was fed and reared. A tail suspension test was conducted 2 weeks after the start of administration. The tail suspension test was performed by attaching a tape to the mouse's tail and suspending this tape on the hook of the tail suspension measuring device and measuring the time during which no movement occurred in 2 minutes. FIG. 6 shows the results of the tail suspension test.

  As shown in FIG. 6, the immobilization time in the tail suspension test is significantly shorter in the diet-administered group c5s containing 1% tarogi extract powder and the diet-administered group c5 containing 10% tarogi extract powder than the normal diet-administered group a5. The value is shown. Therefore, it was also confirmed by the tail suspension test that the moth extract extract has a depression-suppressing effect. Furthermore, it was confirmed that even if the dose of the tatami extract extract is a small amount of 1 g / 100 g diet (L-ergothioneine 0.05 mmol / 100 g diet), the depression-suppressing effect is exhibited.

[Measurement of blood and brain ergothioneine concentrations-Comparison with doses of tarogi extract powder]
5-week-old C57BL / 6 male mice (Sankyo Lab Co., Ltd.) were divided into 3 groups of 4 mice each, (a6) normal diet, (c6s) 1% by mass of tamagi extract powder (L ES Corporation) on normal diet. 1 g / 100 g bait (L-ergothioneine 0.05 mmol / 100 g bait) mixed bait (bait containing 1% cod extract extract), and (c6) 10% by mass (10 g) tamogi extract powder (El Escorporation) in a normal bait / 100 g food (L-ergothioneine 0.5 mmol / 100 g food)) mixed food (food containing 10% tarogi extract powder) and reared for 2 weeks, and the concentration of ergothioneine in the blood and brain of each group of mice was measured. . The measurement was performed by deproteinization by the method described in Kato et al., Pharm Res 27, 832, 2010, and then LC-equipped with HILIC column (phenomenex, 00F-4449-B0, 150 × 2 mm, 3 μm HILIC). Performed using MS / MS. 1 μL of the sample after deproteinization was injected, and 0% was used using a solvent in which 0.1% formic acid / MS distilled water and 0.1% formic acid / acetonitrile were mixed at a ratio of 5: 95-70: 30. Elute at a flow rate of 3 mL / min. First, it was maintained for 0.5 minutes so that the ratio of 0.1% formic acid / acetonitrile was 95%, decreased to 30% over the next 3 minutes, and maintained in that state for another 2 minutes. Subsequently, 0.1% formic acid / acetonitrile was returned to the condition of 95% in 0.1 second, and the state was maintained for another 2.4 minutes. The column temperature was maintained at 50 ° C and the autosampler temperature at 4 ° C. Analysis followed LabSolutions instrument. For the ionization, a cation electrospray method was used. Detection by MS / MS was performed by a multiple reaction monitoring acquisition mode. The parent ion of L-ergothioneine has an m / z value of 230.3, the daughter ion has an m / z value of 127.0, and the parent ion of L-ergothioneine-d9 used as the internal standard has an m / z value of 239. 2. For daughter ions, the m / z value was set to 127.0. Nitrogen gas was used as the nebulizer gas and argon gas was used as the collision gas. The results are shown in FIGS.

  In FIG. 7 and FIG. 8, as observed in FIG. 3 and FIG. 4, the talgi extract powder administration group showed very high blood and brain ergothioneine concentrations compared to the normal diet administration group a3. . In addition, the feed administration group c6 containing 10% tarogi extract powder showed higher ergothioneine concentrations in the blood and brain than the diet administration group c6s containing 1% tarogi extract powder. When combined with the results shown in FIG. 6, the ergothioneine concentration in the blood and brain increases as the dose of the tatoki extract powder increases, but even in small doses, the tail suspension test reduces the same immobility time. It was confirmed that this could be achieved.

a1, a2, a3, a4, a5, a6 Normal diet administration group b1, b4 Ascorbic acid-containing diet administration group c1, c2, c3, c4, c5, c6 10% tarogi extract powder, c5s, c6s tarogi extract powder 1% Containing food administration group d2, d3 Ergothioneine containing food administration group

Claims (6)

  An antidepressant containing L-ergothioneine.   The L-ergothioneine is a genus Flammulina, Leucopaxillus, Phellinus, Tricholoma, Coprinus, Hericiaceae, Lyophyl. Contained in the form of an extract of a mushroom belonging to the genus Rozites, Pholiota, Pleurotus, Mycoleptodonoides, Agrocybe or Grifola, The antidepressant according to claim 1.   The L-ergothioneine is enamel mushroom (Flammulina velutipes), giant mushroom (Leucopaxillus giganteus), moss mushroom (Phellinus linteus), sauber (Tricholoma sp.), Physalis mushroom (Coprinus comatus), L ), Bamboo shoots (Lyophyllum decastes), shochuji (Rozites caperata), sea cucumbers (Pholiota nameko), oyster mushrooms (Pleurotus pulmonarius), oyster mushrooms (Pleurotus ostreatus), eringi (Pleurotus eryngii), citrus tuss The antidepressant according to claim 2, which is contained in the form of an extract of Mycoleptodonoides aitchisonii), Agrocybe cylindracea or Grifola gargal.   A prophylactic or suppressive for depression comprising the antidepressant according to any one of claims 1 to 3.   A food additive for preventing or suppressing depression containing L-ergothioneine.   A food for preventing or suppressing depression comprising the food additive according to claim 5.

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