Composition for preventing, treating and / or alleviating depressive symptoms and composition for increasing physical activity

Abstract

To provide a compound having therapeutic or preventive effect on a disease indicating a depressive symptom.SOLUTION: It has been discovered that tomatidine or tomatine has antidepressive action, and tomatine further has the action of increasing momentum.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a composition for preventing, treating and / or alleviating depressive symptoms and a composition for increasing physical activity. [Background technology]

[0002] Depression is a condition in which mental and physical stress causes brain dysfunction, and symptoms include insomnia, loss of appetite, feeling depressed all day, and a reluctance to move. The number of patients worldwide is over 264 million (Non-Patent Document 1), and 1.276 million in Japan (including bipolar disorder; Non-Patent Document 2).

[0003] Existing antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), noradrenergic-specific serotonergic antidepressants (NaSSAs), tricyclic antidepressants, and tetracyclic antidepressants.

[0004] Both drugs increase the extracellular concentration of serotonin and noradrenaline, and are slow acting, requiring several weeks to several months for the antidepressant effect to appear. In addition, there are patients with treatment-resistant depression, and these drugs are ineffective in approximately 30% of patients.

[0005] Clinical studies in the 2000s found that ketamine exhibits rapid (within a few hours of administration) and sustained (lasting for about a week) antidepressant effects when administered intravenously once. These effects are also effective in patients with depression for whom existing medications are ineffective. In March 2019, esketamine nasal spray was approved in the United States as a treatment for treatment-resistant depression (to be used in combination with existing antidepressants). However, ketamine and esketamine have serious side effects, including concerns about drug dependency and the induction of schizophrenia-like symptoms.

[0006] The muscle atrophy-inhibiting effect of tomatidine has been reported (Non-Patent Document 3), and Patent Document 1 describes a method for inhibiting muscle atrophy, which includes administering tomatidine. It has also been reported that administration of tomatidine reduces the size of atherosclerotic lesions (Non-Patent Document 4), and Patent Document 2 describes an agent for preventing and treating arteriosclerosis that contains tomatidine as an active ingredient. In tomato production, approximately 20% of the fruit weight is discarded, so there is hope for effective use of discarded tomatoes (unripe tomatoes). However, the effect of tomatidine on central nervous system diseases is unknown. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Patent Publication No. 2017-226670 [Patent Document 2] Patent Publication 2009-209099 [Non-patent literature]

[0008] [Non-Patent Document 1] WHO, "Depression", [online], January 30, 2020, [Retrieved July 21, 2020], Internet<URL:https: / / japan-who.or.jp / factsheets / factsheets_type / depression / > [Non-Patent Document 2] Ministry of Health, Labor and Welfare, "Overview of Patient Survey in 2017", [online], March 1, 2019, [Retrieved July 21, 2020], Internet<URL:https: / / www.mhlw.go.jp / toukei / saikin / hw / kanja / 17 / dl / kanja.pdf> [Non-Patent Document 3] DYLE, Michael C., et al.Journal of Biological Chemistry, 2014, 289.21: 14913-14924. [Non-Patent Document 4] NPO Japan Food Function Research Association, "Tomatidine in tomatoes has muscle atrophy suppression effect ~ Cabinet Office Strategic Innovation Promotion Program (SIP) Public Symposium", [online], November 30, 2017, [Retrieved July 21, 2020], Internet<URL:http: / / www.jafra.gr.jp / f402.html> Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present invention is to provide a compound having a therapeutic or preventive effect on diseases exhibiting depressive symptoms. [Means for solving the problem]

[0010] As a result of intensive research aimed at solving the above problems, the present inventors discovered that tomatidine and tomatine exhibit antidepressant effects, and further discovered that tomatine has the effect of increasing locomotion, thereby completing the present invention.

[0011] That is, the present invention is as follows. 1. A composition for the prevention, treatment and / or alleviation of depression symptoms, anxiety symptoms and / or obsessive-compulsive disorder, comprising a tomato extract as an active ingredient, or comprising tomatine or a pharmacologically acceptable salt thereof as an active ingredient. 2. A composition for preventing, treating and / or alleviating depressive symptoms, comprising a tomato extract as an active ingredient, or comprising tomatidine or a pharmacologically acceptable salt thereof as an active ingredient. 3. The composition described in the preceding paragraph 1, which is a preventive food. 4. The composition described in the preceding paragraph 3, wherein the composition contains tomatine or a pharmacologically acceptable salt thereof. 5. The composition described in the preceding paragraph 2, which is a preventive food. 6. The composition described in the preceding item 5, wherein the composition contains tomatidine or a pharmacologically acceptable salt thereof. 7. The composition described in the preceding item 1, which is a preventive therapeutic agent. 8. The composition described in the preceding paragraph 7, wherein the composition contains tomatine or a pharmacologically acceptable salt thereof. 9. The composition described in the preceding item 2, which is a preventive therapeutic agent. 10. The composition according to item 9 above, wherein the composition comprises tomatidine or a pharmacologically acceptable salt thereof. 11. A composition for increasing activity, comprising a tomato extract as an active ingredient, or comprising tomatine or a pharmacologically acceptable salt thereof as an active ingredient. Effect of the Invention

[0012] Tomatidine or tomatine is effective for preventing and / or treating a mental disorder exhibiting a depressive symptom. Therefore, a composition containing tomatidine or tomatine, or a pharmacologically acceptable salt thereof, is a composition for preventing and / or treating a depressive symptom. In addition, tomatine is effective in increasing locomotion, and therefore a composition containing tomatine or a pharmacologically acceptable salt thereof is a composition for increasing locomotion. [Brief description of the drawings]

[0013] [Figure 1] Evaluation of lipopolysaccharide (LPS)-induced depression-like behavior by prophylactic administration of tomatidine. (A) Experimental schedule, (B) Body weight change rate (%) from before LPS administration to 23 hours after administration, (C) LMA 24 hours after LPS administration, (D) TST 26 hours after LPS administration, (E) FST 28 hours after LPS administration. *P<0.05, **P<0.01, ***P<0.001 (Tukey's post hoc test). The vehicle for tomatidine was 2% DMSO / saline. The bar graphs in Figures B, C, D, and E show the vehicle-administered group and the tomatidine-administered group, from the left. [Diagram 2]Evaluation of LPS-induced depression-like behavior by administration of the mTORC1 inhibitor rapamycin in the medial prefrontal cortex (mPFC) before prophylactic administration of tomatidine. (A) Experimental schedule, (B) LMA 24 hours after LPS administration, (C) TST 26 hours after LPS administration, (D) FST 28 hours after LPS administration, (E) Schematic diagram of the administration site in the mPFC. *P<0.05, **P<0.01, ***P<0.001 (Tukey's post hoc test). The vehicle for rapamycin is 10% DMSO / PBS, and the vehicle for tomatidine is 2% DMSO / saline. The bar graphs in Figures B, C, and D show, from left to right, the Vehicle+Vehicle administration group, the Vehicle+Tomatidine administration group, the Rapamycin+Vehicle administration group, and the Rapamycin+Tomatidine administration group. [Diagram 3] Evaluation results of LPS-induced depression-like behavior by therapeutic administration of tomatidine. (A) Experimental schedule, (B) Body weight change rate (%) from before LPS administration to 22 hours and 15 minutes after administration, (C) LMA 24 hours after LPS administration, (D) TST 26 hours after LPS administration, (E) FST 28 hours after LPS administration. *P<0.05, **P<0.01, ***P<0.001 (Tukey's post hoc test). The vehicle for tomatidine is 2% DMSO / saline. The bar graphs in Figures B, C, D, and E show the vehicle-administered group and the tomatidine-administered group, from the left. [Figure 4]Evaluation of LPS-induced depression-like behavior by administration of the mTORC1 inhibitor rapamycin in the medial prefrontal cortex (mPFC) before therapeutic administration of tomatidine. (A) Experimental schedule, (B) LMA 24 hours after LPS administration, (C) TST 26 hours after LPS administration, (D) FST 28 hours after LPS administration, (E) Schematic diagram of the administration site in the mPFC. *P<0.05, **P<0.01 (Tukey's post hoc test). The vehicle for rapamycin is 10% DMSO / PBS, and the vehicle for tomatidine is 2% DMSO / saline. The bar graphs in Figures B, C, and D show, from left to right, the Vehicle+Vehicle administration group, the Vehicle+Tomatidine administration group, the Rapamycin+Vehicle administration group, and the Rapamycin+Tomatidine administration group. [Diagram 5] Evaluation of lipopolysaccharide (LPS)-induced depression-like behavior by prophylactic administration of tomatine. (A) Experimental schedule, (B) Body weight change rate (%) from before LPS administration to 23 hours after administration, (C) LMA 24 hours after LPS administration, (D) TST 26 hours after LPS administration, (E) FST 28 hours after LPS administration. *P<0.05, **P<0.01, ***P<0.001 (Tukey's post hoc test). The vehicle for tomatine was 2% DMSO / saline. The bar graphs in Figures B, C, D, and E show the vehicle-administered group, the tomatidine-administered group, and the tomatine-administered group, respectively, from the left. [Figure 6] Evaluation results of LPS-induced depression-like behavior by therapeutic administration of tomatine. (A) Experimental schedule, (B) Body weight change rate (%) from before LPS administration to 22 hours and 15 minutes after administration, (C) LMA 24 hours after LPS administration, (D) TST 26 hours after LPS administration, (E) FST 28 hours after LPS administration. *P<0.05,***P<0.001 (Tukey's post hoc test). The vehicle for tomatine is 2% DMSO / saline. The bar graphs in Figures B, C, D, and E show the vehicle-administered group, the tomatidine-administered group, and the tomatine-administered group, respectively, from the left. [Figure 7] Evaluation results of LPS-induced depression-like behavior by administration of mTORC1 inhibitor rapamycin in the medial prefrontal cortex (mPFC) before prophylactic administration of tomatine. (A) Experimental schedule, (B) LMA 24 hours after LPS administration, (C) TST 26 hours after LPS administration, (D) FST results 28 hours after LPS administration, (E) Schematic diagram of administration site in mPFC. *P<0.05, **P<0.01 (Tukey's posthoc test). The vehicle for rapamycin is 10% DMSO / PBS, and the vehicle for tomatine is 2% DMSO / saline. The bar graphs in Figures B, C, and D show, from left to right, the Vehicle + Vehicle administration group, the Vehicle + Tomatine administration group, the Rapamycin + Vehicle administration group, and the Rapamycin + Tomatine administration group. [Figure 8] Evaluation of LPS-induced depression-like behavior by administration of the mTORC1 inhibitor rapamycin in the medial prefrontal cortex (mPFC) before therapeutic administration of tomatine. (A) Experimental schedule, (B) LMA 24 hours after LPS administration, (C) TST 26 hours after LPS administration, (D) FST results 28 hours after LPS administration, (E) Schematic diagram of the administration site in the mPFC. *P<0.05, **P<0.01 (Tukey's posthoc test). The vehicle for rapamycin is 10% DMSO / PBS, and the vehicle for tomatine is 2% DMSO / saline. The bar graphs in Figures B, C, and D show, from left to right, the Vehicle + Vehicle administration group, the Vehicle + Tomatine administration group, the Rapamycin + Vehicle administration group, and the Rapamycin + Tomatine administration group. [Figure 9] Evaluation results of the anti-anxiety and anti-obsessive-compulsive disorder effects of tomatine and tomatidine. The vehicle for tomatidine and tomatine was 2% DMSO / saline. *P<0.05 (Dunnett's posthoc test). The bar graphs in the figure show, from the left, the vehicle administration group, the tomatidine administration group, and the tomatine administration group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] (Subject of the present invention) The present invention relates to a composition for preventing, treating and / or alleviating depression, anxiety and / or obsessive-compulsive disorder, and a composition for increasing physical activity.

[0015] (Tomatidine) Tomatidine is a compound represented by the following formula (1) and can be used in the form of either a free base or a pharmacologically acceptable salt thereof. As the pharmacologically acceptable salt, a pharmacologically acceptable acid addition salt is preferred, and the hydrochloride is more preferred. A single dose of tomatidine demonstrated preventive (see Example 1) and therapeutic (see Example 3) effects in depression model mice induced by LPS administration.

[0016] [ka]

[0017] (Tomatine) Tomatine (α-tomatine) is a compound represented by the following formula (2) and can be used in the form of either a free base or a pharmacologically acceptable salt thereof. As the pharmacologically acceptable salt, a pharmacologically acceptable acid addition salt is preferred, and a hydrochloride is more preferred. A single dose of tomatine demonstrated preventive (see Example 5) and therapeutic (see Example 6) effects in depression model mice induced by LPS administration.

[0018] [ka]

[0019] (Composition for preventing and / or treating depression, anxiety and / or obsessive-compulsive disorder) The preventive or therapeutic composition (prophylactic or therapeutic agent) of the present invention has effects such as preventing the onset of symptoms, improving or alleviating symptoms, suppressing the aggravation of symptoms, and preventing the recurrence of symptoms regarding depressive symptoms, anxiety symptoms, and / or obsessive-compulsive disorder.

[0020] Depressive symptoms refer to depressed mood, sleep disorders, loss of interest and pleasure, appetite disorders, impaired thinking, concentration and decision-making abilities, feelings of worthlessness and self-blame, fatigue and loss of energy, etc. Depression or depressive states in the present invention also include depressive states with relatively mild symptoms that are not diagnosed as depression according to diagnostic criteria, and depressive states associated with other diseases (e.g., depression associated with anxiety disorders, depression associated with cancer), etc.

[0021] The preventive or therapeutic agent of the present invention can be administered orally or parenterally. For oral administration, known dosage forms for administration such as tablets, capsules, coated tablets, troches, and liquids such as solutions or suspensions can be used. In addition, parenteral administration can include intravenous, intramuscular, or subcutaneous administration by injection, transmucosal administration such as nasal or oral administration using sprays or aerosols, rectal administration using suppositories, and transdermal administration using patches, liniments, gels, and the like. Preferred are oral administration and nasal administration.

[0022] The preventive or therapeutic agent of the present invention may contain, in addition to tomatidine or tomatine or a pharmacologically acceptable salt thereof, other medicinal ingredients that are effective against depression, anxiety, and obsessive-compulsive disorder. In addition to these medicinal ingredients, the agent may contain a suitable pharmacologically acceptable carrier well known to those skilled in the art depending on the administration form, etc. Examples of pharmacologically acceptable carriers include antioxidants, stabilizers, preservatives, flavoring agents, colorants, dissolving agents, solubilizing agents, surfactants, emulsifiers, antifoaming agents, viscosity adjusting agents, gelling agents, absorption promoters, dispersants, excipients, and pH adjusting agents.

[0023] When the preventive or therapeutic agent of the present invention is prepared as an injectable preparation, it is preferably in the form of a solution or suspension, and when it is intended for transmucosal administration such as nasal or oral cavity, it is preferably in the form of a powder, drops, or aerosol. When it is intended for rectal administration, it is preferably in the form of a semisolid preparation such as a cream or suppository. All of these preparations can be prepared by any method known to those skilled in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences (Mack Publishing Company, Easton, PA, 1970). The injectable preparation can contain, as a carrier, for example, plasma-derived proteins such as albumin, amino acids such as glycine, and sugars such as mannitol, and can further contain buffers, solubilizers, and isotonic agents. When it is used as a water-soluble preparation or a lyophilized preparation, Tween can be used to prevent aggregation. (登録商標) 80, Tween (登録商標) It is preferable to add a surfactant such as 20. Furthermore, parenteral administration forms other than injection preparations may contain distilled water or physiological saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, and hydrogenated naphthalene. For example, preparations for rectal administration such as suppositories contain, as common excipients, for example, polyalkylene glycols, petrolatum, and cacao oil. Vaginal preparations may contain absorption enhancers such as bile salts, ethylenediamine salts, and citrate salts. Preparations for inhalation may be solid and may contain, for example, lactose as an excipient, and nasal drops may be water or oil solutions.

[0024] The dosage and administration schedule of the preventive or therapeutic agent of the present invention can be adjusted depending on the required amount, treatment method, disease or degree of need, etc. of each individual subject to be treated. The dosage can be specifically determined according to the age, body weight, general health condition, sex, diet, administration time, administration method, excretion rate, drug combination, and patient's condition, and may be determined in consideration of other factors. When the preventive or therapeutic agent of the present invention is administered to a disease showing depression, anxiety symptoms, or obsessive-compulsive disorder, it is preferable that the active ingredient contained in the agent contains an amount effective for reducing the symptoms of depression, anxiety symptoms, and obsessive-compulsive disorder. Tomatidine or tomatine or a pharmacologically acceptable salt thereof can be used safely, and the daily dosage varies depending on the condition and body weight of the patient, the type of compound, the administration route, etc. For example, the amount of the active ingredient is preferably about 0.01 to 1000 mg / kg / day, preferably 0.1 to 500 mg / kg / day, 0.1 to 100 mg / kg / day, 1.0 to 100 mg / kg / day, 10 to 100 mg / kg / day, 100 to 200 mg / kg / day, 200 to 300 mg / kg / day, 300 to 400 mg / kg / day, or 400 to 500 mg / kg / day in the case of parenteral administration, and is preferably about 0.01 to 500 mg / kg / day, preferably 0.1 to 100 mg / kg / day, 0.1 to 1.0 mg / kg / day, 1.0 to 20 mg / kg / day, 20 to 40 mg / kg / day, 40 to 60 mg / kg / day, or 80 to 100 mg / kg / day in the case of oral administration. The frequency of administration may be once or multiple times per day, or once every few days, for example, 1 to 3 times, 1 to 2 times, or once per day.

[0025] Furthermore, the present invention relates to a method comprising administering the prophylactic or therapeutic agent of the present invention to a patient in need of prevention and / or treatment of depressive symptoms. The subject of administration may be a human or non-human animal diagnosed with a depressive symptom, or a human or non-human animal in need of relief from a depressive symptom. Preferred non-human animals include pets and livestock.

[0026] (Composition for preventing and / or alleviating depression, anxiety and / or obsessive-compulsive disorder) The prophylactic or alleviating composition (food (including beverage)) of the present invention has effects such as preventing the onset of symptoms, improving or alleviating symptoms, suppressing the aggravation of symptoms, and preventing the recurrence of symptoms regarding depressive symptoms, anxiety symptoms, and / or obsessive-compulsive disorder.

[0027] Preferred examples of the food or beverage of the present invention include health foods, functional foods, and foods for specified health uses. There is no limitation on the form of the food or beverage. For example, the food or beverage may be in the form of a mixture mixed with an existing food or beverage, or in the form of a formulation. For example, the food or beverage may be in the form of a tablet, capsule, powder, granule, jelly, and the like. The food of the present invention can be administered orally. For oral administration, known dosage forms such as tablets, capsules, coated tablets, lozenges, and liquids such as solutions or suspensions can be used. The active ingredient tomatidine or tomatine or a pharmacologically acceptable salt thereof contained in the food of the present invention can be safely ingested. The daily intake amount varies depending on the condition and body weight of the person taking it, the type of compound, and the like. For example, it is desirable to administer the active ingredient amount of about 0.01 to 500 mg / kg / day, preferably 0.1 to 100 mg / kg / day, 0.1 to 1.0 mg / kg / day, 1.0 to 20 mg / kg / day, 20 to 40 mg / kg / day, 40 to 60 mg / kg / day, or 80 to 100 mg / kg / day. The frequency of intake may be once or multiple times per day, or once every few days. For example, it may be 1 to 3 times, 1 to 2 times, or once per day.

[0028] (Motivation-increasing composition) The composition for increasing physical activity of the present invention (therapeutic agent for increasing physical activity, food for increasing physical activity) provides the effect of increasing the physical activity of the ingestor or recipient of the composition (reducing fatigue in an exerciser and extending the exercise time, increasing speed during exercise, and increasing distance traveled during exercise). For the active ingredient of the composition for increasing locomotion of the present invention and its content, dosage, intake amount, administration route, etc., please refer to the description of the composition for preventing, treating and / or alleviating depressive symptoms, anxiety symptoms and / or obsessive-compulsive disorder. EXAMPLES

[0029] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[0030] (Long-Term Activity Assessment (LMA)) Mice were placed in a test chamber (38 cm long x 26 cm wide x 24 cm high) and allowed to explore freely within the chamber for 10 minutes. The distance traveled (m) during the 10 minutes was automatically measured using Smart software (Panlab Harvard Apparatus) and used as the amount of spontaneous locomotion.

[0031] (Tail suspension test: TST) Mice were hung upside down for six minutes and the time they remained immobile was measured. The longer the time they remained immobile, the stronger the depressive symptoms were. Mice administered antidepressants had a shorter time remaining immobile.

[0032] (Forced swim test: FST) Mice were forced to swim in a cylinder for six minutes, and the time they remained immobile between two and six minutes was measured. The longer the time they remained immobile, the stronger the depressive symptoms were. Mice administered antidepressants reduced the time they remained immobile.

[0033] (Glass Marble Burying Test) This test evaluates the anxiety level based on the behavior of the mouse burying glass marbles placed on the bedding in the bedding. In addition, since the behavior of trying to cover harmless glass marbles with the bedding appears to be similar to the compulsive behavior of obsessive-compulsive disorder patients who repeat the behavior while recognizing it as irrational, this test can evaluate some of the symptoms of anxiety and obsessive-compulsive disorder (Reference: Taku Yamaguchi, Mitsuhiro Yoshioka. Evaluation method for anxiety-related behavior, Practical Behavioral Pharmacology (Editor: Japanese Pharmacological Society, Chief Editor: Hiroshi Takeda, Minoru Tsuji, Akinori Akaike) p.43-52, Kinpodo (2010)). In this example, the more glass marbles buried in the bedding, the stronger the symptoms of anxiety and obsessive-compulsive disorder were considered to be. EXAMPLES

[0034] We examined whether prophylactic administration of tomatidine (purchased from Cayman Chemical) could suppress lipopolysaccharide (LPS)-induced depression-like behavior. Tomatidine (0.1 mg / kg, ip) was administered 30 min before LPS (0.8 mg / kg, ip). Locomotor activity measurements (LMA) were performed 24 h after LPS administration, tail suspension test (TST) 26 h after LPS administration, and forced swimming test (FST) 28 h after LPS administration. The experimental schedule is shown in Figure 1A. Body weight was measured from before LPS administration to 23 hours after administration. LPS administration significantly reduced body weight, and tomatidine administration tended to suppress LPS-induced weight loss (Figure 1B). In the LMA, LPS and tomatidine had no significant effect on locomotor activity (FIG. 1C). In the TST (FIG. 1D) and FST (FIG. 1E), LPS increased the immobility time (depression-like behavior), but this increase was significantly inhibited by tomatidine. These results confirmed that prophylactic administration of tomatidine suppressed LPS-induced depression-like behavior, and that tomatidine has an antidepressant effect (depression prevention effect). EXAMPLES

[0035] We examined whether the antidepressant effect of prophylactic administration of tomatidine was suppressed by administration of the mTORC1 inhibitor rapamycin in the medial prefrontal cortex (mPFC). Tomatidine (0.1 mg / kg, ip) was administered 30 min before LPS (0.8 mg / kg, ip), followed by rapamycin (0.01 nmol / side, mPFC) 15 min before that. LMA was performed 24 h after LPS administration, TST 26 h after, and FST 28 h after. The experimental schedule is shown in Figure 2A. In the LMA, rapamycin and tomatidine had no significant effect on locomotor activity (FIG. 2B). In the TST ( Fig. 2C ) and FST ( Fig. 2D ), the antidepressant effect of tomatidine was significantly suppressed by intra-mPFC administration of rapamycin. These results confirm that the antidepressant effect of prophylactic administration of tomatidine was suppressed by the mTORC1 inhibitor rapamycin in the mPFC, and that the preventive effect of tomatidine on depression is mediated by mTORC1 in the mPFC. EXAMPLES

[0036] We examined whether therapeutic administration of tomatidine could suppress LPS-induced depression-like behavior. Tomatidine (0.1 mg / kg, ip) was administered 22 hours and 45 minutes after LPS (0.8 mg / kg, ip). LMA was performed 24 hours after LPS administration, TST was performed 26 hours after LPS administration, and FST was performed 28 hours after LPS administration. The experimental schedule is shown in Figure 3A. Body weight was measured from before LPS administration to 22 hours and 15 minutes after administration. LPS administration significantly reduced body weight (Figure 3B). In the LMA, LPS and tomatidine had no significant effect on locomotor activity (FIG. 3C). In the TST (FIG. 3D) and FST (FIG. 3E), LPS increased the immobility time (depression-like behavior), but this increase was significantly suppressed by tomatidine (antidepressant effect). These results confirmed that therapeutic administration of tomatidine suppressed LPS-induced depression-like behavior, and that tomatidine has an antidepressant effect (treatment effect for depression). EXAMPLES

[0037] We examined whether the antidepressant effect of therapeutic tomatidine was suppressed by administration of the mTORC1 inhibitor rapamycin into the mPFC. 22 hours and 30 minutes after LPS (0.8 mg / kg, ip), rapamycin (0.01 nmol / side, mPFC) was administered, followed by tomatidine (0.1 mg / kg, ip) 15 minutes later. LMA was performed 24 hours after LPS administration, TST 26 hours after LPS administration, and FST 28 hours after LPS administration. The experimental schedule is shown in Figure 4A. In the LMA, rapamycin and tomatidine had no significant effect on locomotor activity (FIG. 4B). In the TST ( Fig. 4C ) and FST ( Fig. 4D ), the antidepressant effect of tomatidine was significantly suppressed by intra-mPFC administration of rapamycin. These results confirm that the antidepressant effect of therapeutic tomatidine was suppressed by administration of the mTORC1 inhibitor rapamycin in the mPFC, and that the therapeutic effect of tomatidine on depression is mediated by mTORC1 in the mPFC. EXAMPLES

[0038] We examined whether prophylactic administration of tomatine (purchased from Tokyo Chemical Industry Co., Ltd.) could suppress lipopolysaccharide (LPS)-induced depression-like behavior. Tomatine (0.3 mg / kg, ip) was administered 30 min before LPS (0.8 mg / kg, ip). Locomotor activity measurements (LMA) were performed 24 h after LPS administration, tail suspension test (TST) 26 h after LPS administration, and forced swimming test (FST) 28 h after LPS administration. The experimental schedule is shown in Figure 5A. Body weight was measured from before LPS administration to 23 hours after administration. LPS administration significantly reduced body weight, and tomatine administration tended to suppress the LPS-induced weight loss (Figure 5B). In the TST (FIG. 5D) and FST (FIG. 5E), LPS increased the immobility time (depression-like behavior), but this increase was significantly suppressed by tomatine. These results suggest that prophylactic administration of tomatine suppressed LPS-induced depression-like behavior, confirming the antidepressant effect of tomatine (preventive effect against depression). In addition, the results in FIG. 5C confirmed that tomatine has the effect of increasing locomotion. EXAMPLES

[0039] We examined whether therapeutic administration of tomatine could suppress LPS-induced depression-like behavior. Tomatine (0.3 mg / kg, ip) was administered 22 hours and 45 minutes after LPS (0.8 mg / kg, ip). LMA was performed 24 hours after LPS administration, TST was performed 26 hours after LPS administration, and FST was performed 28 hours after LPS administration. The experimental schedule is shown in Figure 6A. Body weight was measured from before LPS administration to 22 hours and 15 minutes after administration. LPS administration resulted in a significant decrease in body weight (Figure 6B). In the LMA, LPS and tomatine had no significant effect on locomotor activity (FIG. 6C). In the TST (FIG. 6D) and FST (FIG. 6E), LPS increased the immobility time (depression-like behavior), but this increase was significantly suppressed by tomatine (antidepressant effect). These results confirmed that therapeutic administration of tomatine suppressed LPS-induced depression-like behavior, and that tomatine has an antidepressant effect (treatment effect for depression). EXAMPLES

[0040] We examined whether the antidepressant effect of prophylactic administration of tomatine is suppressed by administration of the mTORC1 inhibitor rapamycin in the medial prefrontal cortex (mPFC). Tomatine (0.3 mg / kg, ip) was administered 30 min before LPS (0.8 mg / kg, ip), followed by rapamycin (0.01 nmol / side, mPFC) 15 min before that. LMA was performed 24 h after LPS administration, TST 26 h after, and FST 28 h after. The experimental schedule is shown in Figure 7A. In the LMA, rapamycin and tomatine had no significant effect on locomotor activity (FIG. 7B). In the TST (FIG. 7C) and FST (FIG. 7D), the antidepressant effects of tomatine were significantly suppressed by intra-mPFC administration of rapamycin. These results confirmed that the antidepressant effect of prophylactic administration of tomatine was suppressed by the mPFC mTORC1 inhibitor rapamycin, and that the preventive effect of tomatine on depression is mediated by mTORC1 in the mPFC. EXAMPLES

[0041] We examined whether the antidepressant effect of therapeutic tomatine administration was suppressed by administration of the mTORC1 inhibitor rapamycin into the mPFC. 22 hours and 30 minutes after LPS (0.8 mg / kg, ip), rapamycin (0.01 nmol / side, mPFC) was administered, followed by tomatine (0.3 mg / kg, ip) 15 minutes later. LMA was performed 24 hours after LPS administration, TST 26 hours after, and FST 28 hours after. The experimental schedule is shown in Figure 8A. In the LMA, rapamycin and tomatine had no significant effect on locomotor activity (FIG. 8B). In the TST (FIG. 8C) and FST (FIG. 8D), the antidepressant effects of tomatine were significantly suppressed by intra-mPFC administration of rapamycin. These results confirmed that the antidepressant effect of therapeutic tomatine was suppressed by administration of the mTORC1 inhibitor rapamycin in the mPFC, and that the therapeutic effect of tomatine in treating depression is mediated by mTORC1 in the mPFC. EXAMPLES

[0042] We investigated whether tomatine and tomatidine have anti-anxiety and anti-obsessive-compulsive disorder effects. The marble-burying test was performed 2 hours after intraperitoneal administration of vehicle (2% DMSO / saline), tomatidine (0.1 mg / kg), or tomatine (0.3 mg / kg). As shown in Figure 9, the marble-burying behavior was significantly suppressed in the tomatine-treated group. On the other hand, tomatidine did not suppress the marble-burying behavior. These results confirmed that tomatine has anti-anxiety and anti-obsessive-compulsive disorder effects. [Industrial Applicability]

[0043] According to the present invention, it is possible to provide a composition for preventing, treating and / or alleviating depressive symptoms and a composition for increasing physical activity.

Claims

1. A composition for preventing, treating and / or alleviating depression symptoms, anxiety symptoms and / or obsessive-compulsive disorder, comprising tomatine or a pharmacologically acceptable salt thereof as an active ingredient.

2. A composition for preventing, treating and / or alleviating depressive symptoms, comprising tomatidine or a pharmacologically acceptable salt thereof as an active ingredient.

3. The composition of claim 1 , wherein the composition is a prophylactic food.

4. The composition of claim 2 , wherein the composition is a prophylactic food.

5. The composition of claim 1 , wherein the composition is a prophylactic treatment.

6. The composition of claim 2 , wherein the composition is a prophylactic treatment.

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