Application of dimethyl fumarate in preparation of medicine for treating depression

Abstract

The invention discloses application of dimethyl fumarate in preparation of a medicine for treating depression, and relates to the technical field of medicine research and development. Comprising experimental verification and medicine preparation, and the medicine preparation comprises the following steps: raw material preparation: weighing a dimethyl fumarate raw material and a medicinal carrier in proportion; uniformly mixing: fully mixing the dimethyl fumarate and the medicinal carrier by using a three-dimensional mixer or a double-cone mixer; granulating: adding a wetting agent for fluidized bed granulation or wet granulation to form granules with set sizes; granulating and drying: granulating the wet granules, drying, and controlling the water content of the granules; forming is conducted; and packaging: packaging the prepared medicine, and labeling information. The dimethyl fumarate is applied to the field of depression treatment, experiments verify that the dimethyl fumarate has a remarkable improvement effect on depression-like behaviors induced by chronic social contusion stress, and a new direction is provided for development of anti-depression drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical research and development, and in particular to application of dimethyl fumarate in the preparation of a drug for treating depression. Background Art

[0002] Major Depressive Disorder (MDD) is a common mental illness with a global prevalence of approximately 4.4%, affecting more than 300 million people. Depression not only causes patients to suffer from low mood, loss of interest, and cognitive impairment, but also significantly increases the risk of physical diseases such as cardiovascular disease and diabetes. Although traditional antidepressants (such as selective serotonin reuptake inhibitors, SSRIs) have achieved certain clinical efficacy, approximately 30%-50% of patients do not respond well to treatment and are referred to as treatment-resistant depression. In addition, the monoamine neurotransmitter theory cannot fully explain the heterogeneity of depression and its complex relationship with the immune and metabolic systems. These limitations have prompted researchers to explore new pathological mechanisms.

[0003] The inflammation hypothesis stems from observations of the relationship between depression and the immune system. As early as the 1990s, researchers discovered that patients with depression often have abnormal activation of the immune system. For example, Maes et al. (1995) first reported that levels of proinflammatory cytokines (such as IL-6 and TNF-α) in the peripheral blood of patients with depression were significantly elevated. This finding sparked academic attention to the potential role of inflammation in depression. In recent years, the inflammation hypothesis has gradually become an important direction in depression research. Numerous studies have shown that patients with depression often have abnormal activation of the immune system, manifested by elevated levels of proinflammatory cytokines (such as IL-6, TNF-α, and CRP) in the peripheral and central nervous systems. The inflammation hypothesis posits that chronic low-grade inflammation may contribute to the pathogenesis of depression through multiple mechanisms, including abnormal neurotransmitter metabolism, impaired neuroplasticity, and HPA axis dysfunction. Studies have shown that inflammatory factors (such as IL-1β and TNF-α) can activate indoleamine 2,3-dioxygenase (IDO), shifting tryptophan metabolism toward the quinolinic acid pathway, leading to reduced serotonin synthesis and increased production of neurotoxic metabolites. This mechanism partially explains the decreased serotonin levels seen in patients with depression. Furthermore, inflammatory factors can inhibit the expression of brain-derived neurotrophic factor (BDNF), impairing hippocampal neurogenesis and synaptic plasticity. BDNF is a key factor for neuronal survival and function, and its reduced levels are closely associated with cognitive impairment in depression. Inflammatory factors can activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to elevated cortisol levels. Chronic high cortisol levels not only exacerbate neuroinflammation but can also directly damage hippocampal neurons, further exacerbating depressive symptoms. Microglia are the primary immune cells in the central nervous system. Under inflammatory conditions, microglia are activated and release large amounts of proinflammatory cytokines, leading to a vicious cycle of neuroinflammation. Numerous clinical studies support the inflammatory hypothesis. For example, Raison et al. found that CRP levels were significantly elevated in the peripheral blood of patients with treatment-resistant depression, and high CRP levels were associated with a poorer response to antidepressant treatment. Furthermore, anti-inflammatory drugs (such as Celecoxib) combined with antidepressants significantly improved patient symptoms, further confirming the important role of inflammation in depression. Therefore, intervention strategies targeting inflammatory pathways (such as anti-inflammatory drugs) may provide new avenues for the treatment of depression.

[0004] Dimethyl fumarate (DMF) is a small molecule compound with anti-inflammatory and antioxidant properties and has been approved for the treatment of multiple sclerosis (MS). DMF's active metabolite, monomethyl fumarate (MMF), can activate the nuclear factor E2-related factor 2 (Nrf2) pathway. Nrf2 is an important transcription factor that upregulates the expression of multiple antioxidant genes (such as HO-1 and NQO1), thereby alleviating oxidative stress and inflammation. DMF exerts its anti-inflammatory effects by inhibiting the nuclear factor κB (NF-κB) signaling pathway and reducing the production of proinflammatory cytokines (such as TNF-α, IL-6, and IL-1β). DMF promotes the differentiation of anti-inflammatory Th2 cells while inhibiting the activity of pro-inflammatory Th1 and Th17 cells, thereby restoring immune balance. DMF can also promote the expression of brain-derived neurotrophic factor (BDNF) by inhibiting inflammation and oxidative stress, improving neural plasticity and synaptic function. However, whether dimethyl fumarate has a therapeutic effect on depression is unclear, and the specific molecular mechanisms are still unclear. Summary of the Invention

[0005] The purpose of the present invention is to solve the shortcomings of the prior art and to propose the use of dimethyl fumarate in the preparation of drugs for treating depression.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] The use of dimethyl fumarate in preparing a drug for treating depression includes experimental verification and drug preparation, wherein the drug preparation includes the following steps:

[0008] S1: Raw material preparation: weigh dimethyl fumarate raw material and pharmaceutical carrier according to proportion;

[0009] S2: Mixing evenly: Use a three-dimensional mixer or a double cone mixer to fully mix dimethyl fumarate and the pharmaceutical carrier;

[0010] S3: Granulation: Add a wetting agent for fluidized bed granulation or wet granulation to form particles of a set size;

[0011] S4: Granulation and drying: After the wet granules are granulated, drying is performed to control the moisture content of the granules;

[0012] S5: Molding;

[0013] S6: Packaging: Package the prepared medicines and label the information.

[0014] Preferably, in S5, the molding method is: tableting the dried granules, or filling the drug mixture into a capsule shell.

[0015] Preferably, the pharmaceutical carrier is selected from a combination of at least two of diluents, fillers, binders, disintegrants, and lubricants.

[0016] Preferably, the pharmaceutical composition further comprises one or more auxiliary ingredients selected from antioxidants, anti-inflammatory agents, and neurotrophic factor enhancers.

[0017] Preferably, the pharmaceutical composition further comprises one or more pigments and flavors.

[0018] Preferably: the experimental verification method includes:

[0019] Experimental grouping;

[0020] Screening mice as attackers;

[0021] Social frustration stress management;

[0022] Sugar water preference experiment;

[0023] Social interaction experiment.

[0024] Preferably, the experimental groups are specifically:

[0025] After 1 week of acclimatization to a standard environment, 8-week-old mice were subjected to baseline tests of sugar water and body weight. Based on the baseline results, the mice were randomly assigned to various experimental groups, including:

[0026] CON group (normal saline + 0.5% DMSO);

[0027] CSDS group (normal saline + 0.5% DMSO);

[0028] CSDS+DMF (50 mg / kg / d): dimethyl fumarate was administered by oral gavage two hours before stress modeling every day.

[0029] Preferably, the screening criteria for ICR mice as attackers are:

[0030] During the 3-minute screening process for three consecutive days, CD-1 mice showed aggressive behavior towards C57BL / 6J mice for at least two consecutive days, more than 5 times per day, and the latency of the first attack was less than 1 minute. The selected ICR mice were used as qualified attackers in the second stage;

[0031] The social frustration stress treatment is specifically:

[0032] The mice underwent 10 consecutive days of social defeat stress. Every day, the test C57BL / 6J mice were placed in the experimental cage on the same side of the ICR mouse in the CSDS-specific mouse cage. After 5-10 minutes of social defeat, the C57BL / 6J mice were placed on the other side of the perforated isolation baffle of the experimental cage and kept there for 24 hours to allow the mice to receive indirect psychological stress. During this process, each test C57BL / 6J mouse would face a different CD-1 mouse stimulus every day, and the above operation was repeated for 10 consecutive days. The control group mice were placed in pairs on both sides of the CSDS-specific mouse cage without direct physical contact, and rotated every day so that they were neighbors with different C57BL / 6J mice.

[0033] Preferably, the sugar water preference experiment is as follows:

[0034] The sugar water preference test is used to assess the anhedonia of animals. The SPT is mainly divided into two stages: the sugar water adaptation stage and the sugar water test stage. In the adaptation stage, mice are first given two bottles of plain water for 24 hours to avoid the novelty effect. Subsequently, a bottle of plain water and a bottle of 1% sucrose solution are provided at the same time. After 24 hours, the positions of the two water bottles are swapped to avoid position preference. In the test stage, all mice are first abstained from drinking for 12 hours. Then, a bottle of plain water and a bottle of 1% sucrose solution that have been weighed are placed in the cage at the same time. After 12 hours, they are weighed again. Then, the sugar water preference rate is calculated based on the consumption of the two liquids, using the following formula: Sugar water preference rate = sugar water consumption / (sugar water consumption + plain water consumption) × 100%.

[0035] Preferably, the social interaction experiment is as follows:

[0036] After acclimating to the environment for 1 hour, the test C57BL / 6J mice were placed one by one in the social open field, and video recording began. The camera system recorded the trajectory tracking of the C57BL / 6J mice in the open field: first, the trajectory tracking was performed without CD1-1 mice; after a 30-second interval, a new aggressive CD1-1 mouse was placed in the plexiglass cover on the side wall of the open field; and then the trajectory tracking was performed with the CD1-1 mouse.

[0037] The beneficial effects of the present invention are:

[0038] 1. The present invention applies dimethyl fumarate to the field of depression treatment, and experimentally verifies its significant improvement effect on depressive-like behavior induced by chronic social frustration stress, providing a new direction for the development of antidepressant drugs.

[0039] 2. This invention uses the CSDS mouse model to simulate the core symptoms of human depression, such as social withdrawal and loss of interest. The experimental results are highly consistent with clinical depression manifestations, enhancing the translational value of drug development.

[0040] 3. The present invention may produce a synergistic effect with DMF by adding auxiliary ingredients such as anti-inflammatory agents and neurotrophic factor enhancers, further enhancing the antidepressant effect and providing expansion space for drug formulation optimization. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 It is the experimental flow chart of the present invention;

[0042] Figure 2 This is a schematic diagram of the sugar water preference rate of mice in the CSDS group after 10 days of chronic social defeat stress modeling;

[0043] Figure 3 This is a schematic diagram of the SI ratio in the chronic social defeat stress CSDS group of the present invention;

[0044] Figure 4 Schematic diagram of the antidepressant effect of the dimethyl fumarate treatment group of the present invention. DETAILED DESCRIPTION

[0045] The technical solution of the present invention will be further described in detail below in conjunction with specific implementation methods.

[0046] Example 1:

[0047] The use of dimethyl fumarate in preparing a drug for treating depression includes experimental verification and drug preparation, wherein the drug preparation includes the following steps:

[0048] S1: Raw material preparation: weigh dimethyl fumarate raw material and pharmaceutical carrier according to proportion;

[0049] S2: Mixing evenly: Use a three-dimensional mixer or a double cone mixer to fully mix dimethyl fumarate and the pharmaceutical carrier;

[0050] S3: Granulation: Add a wetting agent for fluidized bed granulation or wet granulation to form particles of a set size;

[0051] S4: Granulation and drying: After the wet granules are granulated, drying is performed to control the moisture content of the granules;

[0052] S5: Forming: pressing the dried granules into tablets;

[0053] S6: Packaging: Package the prepared medicines and label the information.

[0054] The pharmaceutical carrier is selected from a combination of at least two of diluents, fillers, binders, disintegrants, and lubricants.

[0055] The pharmaceutical composition further comprises one or more auxiliary ingredients, wherein the auxiliary ingredients are selected from antioxidants, anti-inflammatory agents, and neurotrophic factor enhancers, which further synergistically enhance the antidepressant effect of dimethyl fumarate.

[0056] The ingredients of the pharmaceutical composition further include one or more pigments and flavors.

[0057] Example 2:

[0058] The drug preparation comprises the following steps:

[0059] S1: Raw material preparation: weigh dimethyl fumarate raw material and pharmaceutical carrier according to proportion;

[0060] S2: Mixing evenly: Use a three-dimensional mixer or a double cone mixer to fully mix the dimethyl fumarate and the carrier;

[0061] S3: Granulation: Add a wetting agent for fluidized bed granulation or wet granulation to form particles of a set size;

[0062] S4: Granulation and drying: After the wet granules are granulated, drying is performed to control the moisture content of the granules;

[0063] S5: Molding: Filling the drug mixture into the capsule shell;

[0064] S6: Packaging: Package the prepared medicines and label the information.

[0065] Example 3:

[0066] The use of dimethyl fumarate in the preparation of drugs for treating depression is experimentally verified as follows:

[0067] Research Methodology:

[0068] The present embodiment studies the impact of exogenous dimethyl fumarate intervention on the chronic social frustration stress (CSDS) mouse model. The chronic social frustration stress model (CSDS) induces the depressive-like behavior of animals by simulating human social psychological stress (such as bullying, exclusion and competitive failure). It has a high degree of clinical relevance and can simulate the core symptoms of depression (such as anhedonia, social avoidance and behavioral despair). It is a widely used social stress model simulating depression. By the experiment of the present embodiment, it can be demonstrated that dimethyl fumarate has a preventive and therapeutic effect on depression.

[0069] 1. Experimental Animals

[0070] This experiment used C57BL / 6J mice (8-10 weeks old, weighing 20-25g), 5 mice / cage. The mice were raised under standard environmental conditions: temperature of 22-24°C, humidity of 50±5%, 12-hour light / 12-hour dark cycle, and free access to food and water. All experimental mice were adaptively fed for 1 week before the formal experiment began. The mice were then randomly assigned to various experimental groups based on the baseline test results. All operations throughout the experimental process complied with the specifications and guidelines for animal protection and use and have been approved by the ethics committee.

[0071] 2. Experimental Methods

[0072] 1. Experimental Procedure

[0073] The experimental process is as follows Figure 1 As shown, 8-week-old C57BL / 6J mice were acclimated to a standard environment for one week and then underwent baseline tests on sugar water and body weight. After excluding mice with low weight and low sugar water preference, the mice were randomly assigned to various experimental groups according to the baseline results. They were then subjected to chronic social frustration stimulation for 10 consecutive days, followed by depression-related behavioral tests.

[0074] 2. Experimental Grouping

[0075] Experimental Animals: C57BL / 6J mice were acclimated under standard conditions and randomly divided into three groups (n=8 per group) based on body weight and sugar baseline results:

[0076] CON group (normal saline + 0.5% DMSO),

[0077] CSDS group (normal saline + 0.5% DMSO),

[0078] CSDS+DMF (50 mg / kg / d): dimethyl fumarate was administered by oral gavage two hours before stress modeling every day.

[0079] 3. Construction of CSDS Depression Model

[0080] The specific steps of constructing the model were divided into two stages according to previous reports.

[0081] In the first stage, male ICR mice with sufficient aggressiveness were screened as attackers. The criteria were: during a 3-minute screening session, CD-1 mice must have exhibited aggressive behavior toward C57BL / 6J mice for at least two consecutive days, with a minimum of five attacks per day, and the latency to the first attack must have been less than one minute. These ICR mice were selected as qualified attackers for the second stage.

[0082] The second stage is the social frustration stress stage. The mice experienced social frustration stress for 10 consecutive days. Every day, the test C57BL / 6J mice were placed in the experimental cage on the same side of the ICR mice in the CSDS special mouse cage. After 5-10 minutes of social frustration (direct physical contact stress), the C57BL / 6J mice were placed on the other side of the perforated isolation baffle of the experimental cage and placed for 24 hours to allow the mice to receive indirect psychological stress. In this process, each test C57BL / 6J mouse will face 1 different CD-1 mouse stimulation every day, and the above operation will be repeated for 10 consecutive days. The control group mice were placed in pairs on both sides of the CSDS special mouse cage without direct physical contact, and rotated every day to make them neighbors with different C57BL / 6J mice.

[0083] 4. Sugar Water Preference Experiment

[0084] The sugar water preference experiment is used to assess animals' anhedonia, that is, a decreased interest in rewarding stimuli, which is one of the core symptoms of depression. The SPT is mainly divided into two stages: the sugar water adaptation stage and the sugar water test. During the adaptation stage, mice are first given two bottles of plain water to adapt for 24 hours to avoid the novelty effect. Subsequently, a bottle of plain water and a bottle of 1% sucrose solution are provided at the same time, and the positions of the two water bottles are exchanged after 24 hours to avoid position preference. During the testing phase, all mice are first fasted from drinking for 12 hours, and then a bottle of weighed plain water and a bottle of 1% sucrose solution are placed in the cage at the same time. They are weighed again after 12 hours, and then the sugar water preference rate is calculated based on the consumption of the two liquids. The following formula is used for calculation: Sugar water preference rate = sugar water consumption / (sugar water consumption + white water consumption) × 100%

[0085] 5. Social Interaction Experiment

[0086] The social interaction (SI) test assesses social motivation and social avoidance in animals. This test is based on the animals' natural tendency to explore and interact with their peers. In the CSDS model, animals experiencing chronic social defeat stress often exhibit social avoidance, meaning they decrease their interactions with the target mouse and spend more time in areas without their peers. This behavior is similar to the social withdrawal seen in human depression. After acclimating to the environment for 1 hour, C57BL / 6J mice (control and experimental groups) were individually placed into the social open field and video recorded. The camera system recorded the C57BL / 6J mice tracking tracks in the open field: first, for 2.5 minutes without a CD1-1 mouse; then, after a 30-second interval, a new aggressive CD1-1 mouse (uninvolved in the social defeat phase) was placed in a plexiglass enclosure on the side of the open field; and then, for another 2.5 minutes, with the CD1-1 mouse present. The software recorded and analyzed the following experimental parameters: a. the animal's overall trajectory and total distance traveled; b. the number of times the animal entered different areas (primarily the social area, with corner areas recorded as needed) and the duration of its stay. Based on the software's recorded and analyzed results, the time C57BL / 6J mice spent in the social area during two 2.5-minute periods, defined as T1 and T2, was directly compared between the presence and absence of CD1-1 mice. The SI ratio (T1 / T2) was calculated, with an SI ratio equal to 1 used as the analysis standard. Ideally, due to the animals' exploratory nature, control data would show T1 greater than T2, or an SI ratio greater than 1. However, in experimental groups, due to the initial social frustration experienced by mice, they would avoid the same type of CD1-1 mice, resulting in data with T1 less than T2 or an SI ratio less than 1.

[0087] 3. Experimental results:

[0088] like Figure 2 As shown in the results, after 10 days of chronic social defeat stress, the CSDS group showed a significant decrease in sucrose preference compared to the control group (p<0.001), indicating that the social defeat stress depression model was successfully established. Compared to the model group, the sucrose preference rate in the dimethyl fumarate-treated group increased (p<0.01), returning to levels close to those in the control group, suggesting that dimethyl fumarate treatment effectively alleviated the decrease in sucrose preference caused by the CSDS model.

[0089] like Figure 3As shown, in the chronic social defeat stress (CSDS) group, due to the mice's initial social defeat, they developed social avoidance towards CD1-1 mice of the same type. Most SI ratios were less than 1, significantly lower than the SI value of the control group (p<0.01). However, this phenomenon was alleviated by exogenous administration of dimethyl fumarate. Compared with the model group, the SI value of the treatment group was significantly increased (p<0.01), and was basically at the same level as the control group, indicating that the social avoidance of mice was alleviated and improved after dimethyl fumarate administration.

[0090] like Figure 4 As shown, compared with the CSDS model group, the depression susceptibility (depression incidence) of mice in the dimethyl fumarate treatment group was reduced by more than two times, which shows that exogenous administration of dimethyl fumarate has an antidepressant effect.

[0091] The above examples demonstrate that dimethyl fumarate can increase sucrose preference and improve social avoidance in CSDS mouse models, demonstrating its significant preventive and ameliorative effects on depressive-like behaviors caused by social frustration. Therefore, dimethyl fumarate has great potential and application prospects for the preparation of drugs for the prevention and / or treatment of depression.

[0092] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. The use of dimethyl fumarate in preparing a drug for treating depression, characterized in that: The method includes experimental verification and drug preparation, wherein the drug preparation includes the following steps: S1: Raw material preparation: weigh dimethyl fumarate raw material and pharmaceutical carrier according to proportion; S2: Mixing evenly: Use a three-dimensional mixer or a double cone mixer to fully mix dimethyl fumarate and the pharmaceutical carrier; S3: Granulation: Add a wetting agent for fluidized bed granulation or wet granulation to form particles of a set size; S4: Granulation and drying: After the wet granules are granulated, drying is performed to control the moisture content of the granules; S5: Molding; S6: Packaging: Package the prepared medicines and label the information.

2. The use of dimethyl fumarate according to claim 1 in preparing a drug for treating depression, characterized in that In S5, the forming method is: tableting the dried granules, or filling the drug mixture into a capsule shell.

3. The use of dimethyl fumarate in the preparation of a drug for treating depression according to claim 2, characterized in that: The pharmaceutical carrier is selected from a combination of at least two of diluents, fillers, binders, disintegrants, and lubricants.

4. The use of dimethyl fumarate in the preparation of a drug for treating depression according to claim 3, characterized in that: The pharmaceutical composition further comprises one or more auxiliary ingredients, wherein the auxiliary ingredients are selected from antioxidants, anti-inflammatory agents, and neurotrophic factor enhancers.

5. The use of dimethyl fumarate in the preparation of a drug for treating depression according to claim 4, characterized in that: The ingredients of the pharmaceutical composition further include one or more pigments and flavors.

6. Use of dimethyl fumarate according to any one of claims 1 to 5 in the preparation of a drug for treating depression, characterized in that: The experimental verification method includes: Experimental grouping; Screening mice as attackers; Social frustration stress management; Sugar water preference experiment; Social interaction experiment.

7. The use of dimethyl fumarate in preparing a drug for treating depression according to claim 6, characterized in that: The experimental groups are specifically: After 1 week of acclimatization to a standard environment, 8-week-old mice were subjected to baseline tests of sugar water and body weight. Based on the baseline results, the mice were randomly assigned to various experimental groups, including: CON group; CSDS group; CSDS+DMF: dimethyl fumarate was administered by oral gavage two hours before stress modeling every day.

8. The use of dimethyl fumarate in preparing a drug for treating depression according to claim 7, characterized in that: The screening criteria for ICR mice as attackers are: During the three-day screening process, CD-1 mice showed aggressive behavior towards C57BL / 6J mice for at least two consecutive days, more than 5 times per day, and the latency of the first attack was less than 1 minute. The selected ICR mice were used as qualified attackers in the second stage. The social frustration stress treatment is specifically: The mice underwent 10 consecutive days of social defeat stress. Every day, the test C57BL / 6J mice were placed in the experimental cage on the same side of the ICR mouse in the CSDS-specific mouse cage. After 5-10 minutes of social defeat, the C57BL / 6J mice were placed on the other side of the perforated isolation baffle of the experimental cage and kept there for 24 hours to allow the mice to receive indirect psychological stress. During this process, each test C57BL / 6J mouse would face a different CD-1 mouse stimulus every day, and the above operation was repeated for 10 consecutive days. The control group mice were placed in pairs on both sides of the CSDS-specific mouse cage without direct physical contact, and rotated every day so that they were neighbors with different C57BL / 6J mice.

9. The use of dimethyl fumarate in preparing a drug for treating depression according to claim 8, characterized in that: The sugar water preference experiment is as follows: The sugar water preference test is used to assess the anhedonia of animals. The SPT is mainly divided into two stages: the sugar water adaptation stage and the sugar water test stage. In the adaptation stage, mice are first given two bottles of plain water for 24 hours to avoid the novelty effect. Subsequently, a bottle of plain water and a bottle of 1% sucrose solution are provided at the same time. After 24 hours, the positions of the two water bottles are swapped to avoid position preference. In the test stage, all mice are first abstained from drinking for 12 hours. Then, a bottle of plain water and a bottle of 1% sucrose solution that have been weighed are placed in the cage at the same time. After 12 hours, they are weighed again. Then, the sugar water preference rate is calculated based on the consumption of the two liquids, using the following formula: Sugar water preference rate = sugar water consumption / (sugar water consumption + plain water consumption) × 100%.

10. The use of dimethyl fumarate in preparing a drug for treating depression according to claim 9, characterized in that: The social interaction experiment is as follows: After acclimating to the environment for 1 hour, the test C57BL / 6J mice were placed one by one in the social open field, and video recording began. The camera system recorded the trajectory tracking of the C57BL / 6J mice in the open field: first, the trajectory tracking was performed without CD1-1 mice; after a 30-second interval, a new aggressive CD1-1 mouse was placed in the plexiglass cover on the side wall of the open field; and then the trajectory tracking was performed with the CD1-1 mouse.

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