Use of 4-TMAP to treat or alleviate depression

Abstract

The present invention discloses a new use for 4-(trimethylammonium) valeric acid (4-TMAP), specifically the use of 4-(trimethylammonium) valeric acid in the manufacture of a drug for treating depression. The present invention also proposes a pharmaceutical composition containing 4-(trimethylammonium) valeric acid and the use of the pharmaceutical composition in the manufacture of a drug for treating depression. The present invention not only enriches the prior art of antidepressant drugs, but also develops new indications for 4-(trimethylammonium) valeric acid (4-TMAP), and has potential economic and social value.

Description

[Technical Field]

[0001] The present invention relates to the field of medicinal chemistry, and in particular to the use of 4-TMAP in the manufacture of drugs for treating or alleviating depression. [Background technology]

[0002] Depression is a common mental disorder, clinically manifested by low mood, insomnia, loss of appetite, and difficulty concentrating. Severe depression increases the risk of suicide and has a serious impact on the patient's life and safety. According to data from the World Health Organization, more than 320 million people worldwide suffer from depression. Research and analysis predicts that depression will become a major disease burden in middle- and high-income countries by 2030. Therefore, it is urgent to explore the pathogenesis of depression and find treatment methods.

[0003] Currently, commonly used antidepressant drugs in clinical practice include monoamine oxidase inhibitors (MAOIs), norepinephrine and dopamine reuptake inhibitors (NDRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), serotonin antagonists and reuptake inhibitors (SARIs), and tricyclic antidepressants (TCAs) and tetracyclic antidepressants. These drugs exert their antidepressant effects by enhancing the functions of serotonin, dopamine, and norepinephrine. Although these drugs play an important role in the treatment of depression, they are prone to causing severe side effects, including headache, dizziness, gastrointestinal upset, sexual dysfunction, and blood pressure / weight abnormalities. Furthermore, they commonly suffer from drawbacks such as a long onset time, poor drug sensitivity, high cost, and strong drug resistance. Analysis of the reasons for this may be due to factors such as relatively poor drug target specificity and a lack of understanding of their mechanisms of action.

[0004] With the increasing number of patients with depression, current antidepressant drugs are unable to meet clinical needs. Therefore, it is extremely important to explore new antidepressant drugs with significant antidepressant effects, minimal side effects, and clear mechanisms of action.

[0005] 4-(trimethylammonium) pentanoate (4-TMAP) is a bacterial metabolite discovered in mice and is a structural analogue of carnitine. Its structure is shown in formula (I). [ka] 4-TMAP, an analog of mildronate, is present in the intestine and brain of specific pathogen-free mice. Mildronate is a potent inhibitor of human GBB hydroxylase (BBOX1) and carnitine acetyltransferase (CrAT), enzymes involved in the synthesis of carnitine and the transport of large amounts of fatty acids into mitochondria, respectively. 4-TMAP binds to the human BBOX1 active site in a conformation similar to that of mildronate and has a lower dissociation constant. Exploring other biological activities of known compounds in the prior art and exploring their medicinal value is an important topic in the field of drug discovery. Summary of the Invention

[0006] The main objective of the present invention is to provide a use of 4-TMAP in the manufacture of a drug for treating or alleviating depression, which, on the one hand, increases new indications for the compound, and, on the other hand, provides a clinical method for treating or alleviating depression to meet market demand.

[0007] To achieve the above objectives, the technical solutions adopted by the present invention are as follows: Provided is the use of 4-(trimethylammonium) valeric acid (4-TMAP) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or alleviating depression.

[0008] The present invention further provides the use of 4-(trimethylammonium) valeric acid (4-TMAP) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or alleviating depression in a mammal, wherein the mammals preferably include primates and rodents, and more preferably include humans, monkeys, or mice.

[0009] The present invention further provides a pharmaceutical composition comprising 4-(trimethylammonium) valeric acid (4-TMAP) or a pharmaceutically acceptable salt thereof, said pharmaceutical composition comprising a therapeutically effective amount of 4-(trimethylammonium) valeric acid (4-TMAP) or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is preferably ≥ 0.1 mg of the active ingredient per kg of mammal in a single dose.

[0010] In addition, the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle.

[0011] Examples of excipients, carriers, adjuvants, and vehicles include, but are not limited to, anti-adherents, binders, coatings, compression aids, disintegrants, dyes, lubricants, emulsifiers, fillers (diluents), film formers or coatings, flavorings, fragrances, glidants (flow enhancers), lubricants, adsorbents, suspending or dispersing agents, or sweeteners. Exemplary excipients, carriers, adjuvants, and vehicles include, but are not limited to: Butylated hydroxytoluene (BHT), calcium carbonate, calcium monohydrogen phosphate, calcium stearate, cross-linked carboxymethylcellulose, cross-linked polyvinylpyrrolidone, citric acid, cross-linked povidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, propylparaben, retinol palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0012] The pharmaceutical composition is prepared in the form of an injection preparation or an oral preparation. The injection preparations are classified into liquid injections, injection powders, and injection tablets according to their physical form. The injection preparations are classified into intradermal injections, subcutaneous injections, intramuscular injections, intravenous injections, and spinal injections according to their injection part. The preferred solvent for the injection preparations is water for injection or physiological saline.

[0013] Formulations for internal use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients. These excipients are, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate), granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starch including potato starch, cross-linked sodium carboxymethylcellulose, alginates, or alginic acid), binders (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol), lubricants, glidants, and anti-adherents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc). Preparations for oral use may also be in the form of chewable tablets or hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, kaolin), or in the form of soft gelatin capsules, in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil). Powders, granules, and pills can be prepared using the ingredients listed above under tablets or capsules in a conventional manner, for example, using a mixer, fluidized bed equipment, or spray-drying equipment.

[0014] Other pharmaceutically acceptable excipients used in oral formulations include, but are not limited to, colorants, flavoring agents, plasticizers, humectants, and buffers. Formulations for oral use may also be in the form of chewable tablets or hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin), or in the form of soft gelatin capsules, in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil). Powders, granules, and pills can be prepared using the ingredients listed above under tablets or capsules in a conventional manner, for example, using a mixer, fluidized bed equipment, or spray-drying equipment.

[0015] In some embodiments, application includes administering a composition described herein intramuscularly, intravenously (e.g., in the form of a sterile solution, in a solvent system suitable for intravenous use), intradermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, transsuperficially, intratumorally, transperitoneally, subcutaneously, subconjunctivally, intracapsularly, transmucosally, intrapericardially, intraumbilically, intraocularly, orally (e.g., in the form of a tablet, capsule, capsule, or syrup), topically (e.g., in a cream, gel, lotion, ointment), topically, by inhalation, injection, or infusion (e.g., continuous infusion in the form of a cream or lipid composition, direct immersion of target cells, local perfusion, catheterization, lavage).

[0016] Compared with the prior art, the present invention has the following beneficial effects: 1. The small molecule drug disclosed in the present invention for treating or alleviating depression can significantly improve depressive state in different mouse models of depression, shortening immobility time during forced swimming and tail suspension experiments, and improving preference for sugar water in mice. At the same time, compared to the positive control brexpiprazole, it has the characteristics of lower dosage, stronger therapeutic effect, and longer duration of action. 2. The present invention enriches the existing novel methods for treating or alleviating depression and has potential commercial value. Through preliminary screening, the present invention has discovered a new use for 4-(trimethylammonium) valeric acid (4-TMAP), providing a new solution concept for the search for better antidepressant drugs. [Brief explanation of the drawings]

[0017] [Figure 1] 1 shows the changes in the content of 4-TMAP in cerebral tissue at different times after intraperitoneal injection of 4-TMAP in Example 1. [Figure 2] 1 shows the effect of 4-TMAP administration on forced swimming in mice in a CUMS-induced depression model in Example 2, and the numbers between groups in the figure represent the P values ​​between the groups. [Figure 3] This shows the effect of 4-TMAP administration on tail suspension in mice in the CUMS-induced depression model in Example 2, and the numbers between groups in the figure represent the P values ​​between the groups. [Figure 4] This shows the effect of 4-TMAP administration on the preference for sugar water in mice in the CUMS-induced depression model in Example 2, and the numbers between groups in the figure represent the P values ​​between the two. [Figure 5] This shows the effect of 4-TMAP administration on forced swimming in mice in the Cort-induced depression model in Example 3, and the numbers between groups in the figure represent the P values ​​between the groups. [Figure 6] This shows the effect of 4-TMAP administration on tail suspension in mice in a Cort-induced depression model in Example 3, and the numbers between groups in the figure represent the P values ​​between the two. [Figure 7] This shows the effect of 4-TMAP administration on the preference for sugar water in mice in a Cort-induced depression model in Example 3, and the numbers between groups in the figure represent the P value between the two. [Figure 8] This shows the effect of 4-TMAP administration on forced swimming in mice in the AAD-induced depression model in Example 4, and the numbers between groups in the figure represent the P values ​​between the two. [Figure 9] This shows the effect of 4-TMAP administration on tail suspension in mice in an AAD-induced depression model in Example 4, and the numbers between groups in the figure represent the P values ​​between the two. [Figure 10] This shows the effect of 4-TMAP administration on the preference for sugar water in mice in an AAD-induced depression model in Example 4, and the numbers between groups in the figure represent the P values ​​between the two. [Figure 11] This is the minimum dose of 4-TMAP that alleviates the depressive-like behavior of mice detected by the forced swimming test in Example 5, and the numbers between groups in the figure represent the P values ​​between the two groups. [Figure 12] This is the minimum dose of 4-TMAP that alleviates the depressive-like behavior of mice detected by the tail suspension experiment in Example 5, and the numbers between groups in the figure represent the P values ​​between the two. [Figure 13] This is the minimum dose of 4-TMAP that alleviates the depressive-like behavior of mice detected by the sugar water preference experiment in Example 5, and the numbers between groups in the figure represent the P value between the two. [Figure 14] 1 shows the results of monitoring the duration of depressive-like behavior in mice following a single administration of 4-TMAP in the forced swimming experiment in Example 6, and the numbers between groups in the figure represent the P values ​​between the two groups. [Figure 15] This shows the results of monitoring the duration of depressive-like behavior in mice following a single administration of 4-TMAP in the tail suspension experiment in Example 6, and the numbers between groups in the figure represent the P values ​​between the two groups. [Figure 16] The antidepressant effects of 4-TMAP and brexpiprazole were compared in the forced swimming experiment of Example 7, and the numbers between the groups in the figure represent the P values ​​between the two. [Figure 17] The antidepressant effects of 4-TMAP and brexpiprazole were compared in the tail suspension experiment of Example 7, and the numbers between the groups in the figure represent the P values ​​between the two. [Figure 18]The antidepressant effects of 4-TMAP and brexpiprazole were compared in the sugar water preference experiment of Example 7, and the numbers between the groups in the figure represent the P values ​​between the two. DETAILED DESCRIPTION OF THE INVENTION

[0018] In order to make the technical means, creative features, objectives and effects achieved by the present invention easily understandable, the present invention will be further described below in conjunction with specific embodiments.

[0019] This invention discloses a new type of antidepressant drug. Three different depression models were established in mice, namely, chronic unpredictable depression and sexual mildness Stress depression model ( CUMS ), corticosterone-induced depression model ( Cort The mouse models are the amino acid food-induced depression model (AAD). The antidepressant effects of small molecule drugs in these mouse models are evaluated using behavioral tests including the forced swimming test (FST), tail suspension test (TST), and sugar-water preference test (SPT). The antidepressant effects and duration of antidepressant effects are also compared with those of brexpiprazole, a third-generation antipsychotic commonly used in clinical trials.

[0020] Example 1: 4-TMAP can enter the blood-brain barrier via blood circulation and exert its antidepressant effect 4-TMAP was administered intraperitoneally to mice (relative dose 10 mg / kg). Serum and brain tissue were collected at 10 time points after administration: 0 h, 0.5 h, 1 h, 1.5 h, 2.0 h, 2.5 h, 3.0 h, 4.0 h, 6 h, and 12 h. Small molecular weight substances in the serum were extracted using a polar substance extraction method. The freshly collected brain tissue was immediately frozen in liquid nitrogen and frozen sections (10 μm) were prepared. The time course of 4-TMAP was detected using IMS imaging mass spectrometry. As shown in Figure 1, it was demonstrated that 4-TMAP circulates throughout the body, crosses the blood-brain barrier, and directly enters the cerebral tissue to exert its effects.

[0021] Example 2: Chronic Unpredictability sexual mildness stress( CUMSEffects of 4-TMAP in a mouse model of depression Twenty-four 6-8 week-old SPF C57 / B6j male mice (purchased from Ji Sui Yaokang) were randomly divided into four groups: one group was normal mice + saline group (6 mice), one group was normal mice + 4-TMAP group (6 mice), and one group was CUMS Mice + saline group (6 mice), one group CUMS The mice were grouped into a group of 6 mice + 4-TMAP. After adapting to the environment, from day 0, CUMS Mice were exposed to chronic, unpredictable mild stimuli for 21 days, simulating the chronic low-intensity stress experienced in human daily life. Each day, one stimulus was selected from daytime and nighttime and administered to the mice. The order was random and not repeated consecutively, so that the mice could not predict the appearance of the stimulus (Table 1). After creating the depression model for 21 days, we confirmed its success through forced swimming, tail suspension, and sugar water preference tests (significant differences were observed between the model and normal mice). [Table 1] JPEG2025530455000023.jpg92170

[0022] Mice in the 4-TMAP group were given 200 μL of 4-TMAP (0.1 mg / kg) via retro-orbital vein injection, and mice in the saline group were given 200 μL of saline. Two hours after administration, the mice were subjected to forced swimming and tail suspension tests, and the time the mice in each group remained motionless during the forced swimming and tail suspension tests was compared. The specific experimental method was as follows: The forced swimming experiment apparatus was a transparent, 20 x 30 cm circular tank filled with pure water, 20 cm in diameter and 15 cm deep. The temperature of the pure water was 23-25°C. A video camera was installed directly in front of the apparatus, level with the water surface. After placing the mouse in the water, a 6-minute video recording of its activity in the water was collected. The final 4 minutes of the video were analyzed for the amount of immobility the mouse experienced. Immobility was defined as the behavior of the mouse remaining immobile while floating, without struggling, or by occasional shaking. The longer the immobility time, the more severe the depression. In the tail suspension experiment, the mice's tails were suspended with adhesive tape in a position where they could not escape or grab nearby surfaces, and a video camera was attached directly in front of them to record the mice's activity for 6 minutes while suspended. The mice's immobility time within the last 4 minutes after the video was recorded was analyzed. This test is based on the fact that animals develop an immobile posture when subjected to short-term unavoidable stress, and the more severe the depression phenotype, the less time they spend trying to escape. The results are shown in Figures 2 and 3. CUMS The resting time of the mice +4-TMAP group was CUMS The levels were significantly lower than those in the mouse + saline group, and were almost the same as those in the normal mouse group. CUMS showed that it could clearly alleviate depression-like behavior in mice.

[0023] The sugar water preference test was used to evaluate the preference for sugar water in mice and could reflect the degree of anhedonia in mice. A total of two sugar water preference tests were conducted throughout the entire animal experiment. Before creating the model, the sucrose preference index of all mice was measured through the sugar water preference test to ensure that the conditions of the mice in the experiment were consistent. After the experiment was completed, a formal sugar water preference test was conducted, including an adaptation training section and a test section. During training, the mice were given two bottles of 1% (w / v) sucrose solution per cage for the first 24 hours, and then one bottle was replaced with pure water over the next 24 hours. After adaptation was complete and 24 hours of fasting and water deprivation, the sugar water preference index was measured. During the test, the mice were only allowed to choose between two pre-weighed bottles: one containing 1% (w / v) sucrose solution and the other pure water. After 24 hours of fasting, the two bottles were removed and weighed, and the mice's total fluid consumption, sugar water consumption, and pure water consumption were recorded. The sugar water preference coefficient is calculated as follows: Sugar water preference coefficient (%) = sugar water consumption / (sugar water consumption + pure water consumption) × 100%. As shown in Figure 4, the experimental results show that the sugar water preference of the CUMS mice + 4-TMAP group was: CUMS The values ​​were significantly higher than those in the mouse + saline group (P<0.01) and were almost the same as those in the normal mice. CUMS We demonstrated that it can clearly reverse anhedonia-like depressive behavior in mice.

[0024] Example 3: Effects of 4-TMAP in a corticosterone-induced (Cort) mouse model of chronic depression Twenty-four 6-8-week-old SPF C57 / B6j male mice (purchased from Ji Sui Yao Kang) were randomly divided into four groups: one group consisting of normal mice and saline (6 mice), one group consisting of normal mice and 4-TMAP (6 mice), one group consisting of Cort mice and saline (6 mice), and one group consisting of Cort mice and 4-TMAP (6 mice). After adaptation to the environment, starting on day 0, the Cort mice (MCE, HY-B1618) received a corticosterone solution at a final concentration of 25 μg / mL (pH 7.0-7.4) in their drinking water, while the normal mice received regular drinking water, which was changed every two days. The model was established for 21 consecutive days. Following model establishment, forced swimming, tail suspension, and sugar water preference tests were performed to confirm the success of the model (significant differences were observed between the normal mice and the Cort mice).

[0025] Mice in the 4-TMAP group received 200 μL of 4-TMAP (0.1 mg / kg) intravenously, while mice in the saline group received 200 μL of saline. Two hours after administration, the mice underwent forced swimming and tail suspension tests. The immobility time of mice in each group during these tests was compared. As shown in Figures 5 and 6, the immobility time of the Cort mice + 4-TMAP group was significantly lower than that of the Cort mice + saline group and similar to that of the control mice, indicating that 4-TMAP can significantly alleviate corticosterone-induced depression-like behavior in mice. As shown in Figure 7, the sugar water preference test results for the Cort mice + 4-TMAP group showed significantly higher sugar water preference than that of the Cort mice + saline group (P<0.01) and similar to that of the control mice, indicating that 4-TMAP can significantly alleviate Cort-induced anhedonia-like depression-like behavior in mice.

[0026] Example 4: Effects of 4-TMAP in an amino acid diet-induced (AAD) mouse model of chronic depression Twenty-four 6-8 week-old SPF C57 / B6j male mice (purchased from Ji Sui Yaokang) were randomly divided into four groups: one group consisting of normal mice + saline (6 mice), one group consisting of normal mice + 4-TMAP (6 mice), one group consisting of AAD mice + saline (6 mice), and one group consisting of AAD mice + 4-TMAP (6 mice). After adaptation to the environment, the normal mice group were fed regular mouse chow, and the AAD mice group were fed an amino acid diet (Medicience, MD12062) from day 0. After four consecutive weeks of feeding, forced swimming, tail suspension, and sugar water preference tests confirmed the successful creation of depression models (significant differences were observed between the normal mice and the AAD mice).

[0027] Mice in the 4-TMAP group received 200 μL of 4-TMAP (0.1 mg / kg) intravenously, while mice in the saline group received 200 μL of saline. Two hours after administration, the mice underwent forced swimming and tail suspension tests. The immobility time of mice in each group was compared. As shown in Figures 8 and 9, the immobility time of the AAD mice + 4-TMAP group was significantly lower than that of the AAD mice + saline group and similar to that of the control mice, indicating that 4-TMAP can significantly alleviate the depressive behavior induced by amino acid diet in mice. The sugar water preference test results, shown in Figure 10, showed that the preference for sugar water in the AAD mice + 4-TMAP group was significantly higher than that of the AAD mice + saline group (P<0.01) and similar to that of the control mice, indicating that 4-TMAP can significantly alleviate the anhedonia-like depressive behavior induced by AAD in mice.

[0028] Example 5: Minimal dose of 4-TMAP to alleviate depressive-like behavior in mice In a mouse model of chronic depression induced by AAD, 4-TMAP was administered intravenously at doses of 10 μg / kg, 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, and 10 mg / kg. Two hours after administration, forced swimming, tail suspension, and sugar water preference tests were performed to determine the minimum dose at which 4-TMAP exerted its antidepressant effect. As shown in Figures 11, 12, and 13, 4-TMAP significantly reduced immobility time in mice at concentrations of 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, and 10 mg / kg, demonstrating its antidepressant effect at 0.1 mg / kg, indicating that 0.1 mg / kg is the minimum therapeutic dose for 4-TMAP. At the same time, significant antidepressant effects were still observed at concentrations of 0.3 mg / kg, 1 mg / kg, and 10 mg / kg.

[0029] Example 6: Duration of a single treatment of depression-like behavior in mice with 4-TMAP In a mouse model of chronic depression induced by AAD, 4-TMAP (0.1 mg / kg) was intravenously administered to mice. Forced swimming and tail suspension tests were performed at 2, 24, 36, 48, and 72 hours after administration to monitor the duration of the antidepressant effect of a single dose of 4-TMAP. As shown in Figures 14 and 15, 4-TMAP significantly reduced the immobility time of mice at 2 and 24 hours after administration, tending to reduce immobility time at 36 hours. The effect disappeared at 48 and 72 hours. This suggests that the antidepressant effect of a single dose of 4-TMAP in mice is maintained for 24-36 hours.

[0030] Example 7: Comparison of the antidepressant effects of 4-TMAP and brexpiprazole In a mouse model of chronic AAD-induced depression, mice were intravenously administered 4-TMAP (0.1 mg / kg) or brexpiprazole (0.1 mg / kg or 3 mg / kg). Two hours after administration, the antidepressant effects of 4-TMAP and brexpiprazole were compared using forced swimming, suspension, and sugar-water preference tests. The experimental results, shown in Figures 16, 17, and 18, demonstrate that brexpiprazole failed to alter depressive-like behavior in mice at a dose of 0.1 mg / kg. However, at a dose of 3 mg / kg, it significantly reduced immobility time in mice, similar to that of 0.1 mg / kg of 4-TMAP, suggesting that 4-TMAP has a lower onset of action than brexpiprazole.

[0031] The basic principles, main features, and advantages of the present invention have been shown and described above. The present invention is not limited to the above embodiments. The above embodiments and the description of the specification merely illustrate the principles of the present invention. Those skilled in the art should understand that various changes and modifications can be made to the present invention without departing from the spirit and scope of the present invention, and all of these changes and modifications are included within the scope of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. Use of 4-(trimethylammonium) valeric acid (4-TMAP) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or alleviating depression.

2. Use of 4-(trimethylammonium) valeric acid (4-TMAP) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or alleviating depression in a mammal.

3. 3. The use according to claim 2, wherein the mammal comprises a primate or a rodent.

4. The use according to any one of claims 2 to 3, characterized in that the mammal comprises a human, a monkey or a mouse.

5. A pharmaceutical composition comprising 4-(trimethylammonium) valeric acid (4-TMAP) or a pharmaceutically acceptable salt thereof as an active ingredient.

6. 6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition comprises a therapeutically effective amount of 4-(trimethylammonium) valeric acid (4-TMAP) or a pharmaceutically acceptable salt thereof.

7. 7. The pharmaceutical composition of claim 6, wherein the therapeutically effective amount is ≧0.1 mg of active ingredient per kg of mammal in a single dose.

8. The pharmaceutical composition according to any one of claims 5 to 7, further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, or vehicle.

9. The pharmaceutical composition according to any one of claims 5 to 8, characterized in that the pharmaceutical composition is selected from an injection formulation or an oral formulation.

10. Use of the pharmaceutical composition according to any one of claims 5 to 9 in the manufacture of a medicament for treating or alleviating depression.

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