Use of clemastine for the preparation of a medicament for the treatment of depression
By using clomastine to promote myelination of oligodendrocytes, the problem of unsatisfactory efficacy of existing depression treatment strategies was solved, and effective relief of depressive symptoms and pathological repair were achieved in mice.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2022-12-30
- Publication Date
- 2026-03-27
AI Technical Summary
Existing treatment strategies for depression are not ideal, with problems such as slow onset of action, serious side effects, and complex and diverse pathological mechanisms, including the possibility of unexplained pathological mechanisms.
Using chlormastine as a drug, the depressive-like phenotype in mice induced by chronic, unpredictable mild stimulation or lipopolysaccharide was alleviated by promoting myelination of oligodendrocytes.
Clomastin can significantly improve depressive-like behavior in mice, restore myelin damage and synaptic structure, and provide a new approach to the prevention and treatment of depression.
Smart Images
Figure CN116139129B_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of mental illness, more particularly, to the technical field of depression, and particularly relates to the use of clemastine in the preparation of a drug for treating depression. BACKGROUND
[0002] Depression is a mental illness characterized by emotional depression, decreased interest and autonomic nervous dysfunction, and has high morbidity, high disability rate, high recurrence rate and high medical burden, which seriously endangers human health and life safety.
[0003] At present, great progress has been made in the pathological study of depression, and the decline of neuronal monoamine neurotransmitter transmission, the overactivation of hypothalamic-pituitary-adrenal (HPA) axis, the abnormal structure and function of neural circuit and neuroinflammatory response are all involved in the disease progression to varying degrees. However, the therapeutic strategies for depression developed based on the above pathological mechanisms have not been very effective, with slow onset, serious side effects and even no effect on many patients. For example, drugs based on monoamine neurotransmitter disorders are ineffective for about 35% of patients; even for those patients who respond to treatment, significant emotional improvement usually occurs only after 3-6 weeks of medication. At the same time, although electroconvulsive therapy (ECT) widely used in clinical treatment has a significant effect, it is accompanied by serious side effects. Therefore, the unsatisfactory status of depression treatment and the lag of drug development strongly suggest that the pathological factors of depression are diverse and complex, and there may be new unexplained pathological mechanisms.
[0004] Imaging studies have shown that there are widespread myelin lesions in the brain tissue of patients with depression and rodent models; at the same time, about 50% of patients with multiple sclerosis, a disease characterized by demyelination, have depressive symptoms. This suggests that demyelination is an important pathological mechanism that promotes the pathological progression of depression, and further exploration of pro-myelination strategies may provide new ideas for the prevention and treatment of depression.
[0005] Clemastine, as the first generation of antihistamines, is often used in clinical practice to improve the symptoms of allergic rhinitis and common cold. Recent studies have also shown that clemastine can effectively delay the pathological progression of various central nervous system diseases. For example, clemastine can reduce brain hemorrhage damage by inhibiting neuronal apoptosis. In a mouse model of amyotrophic lateral sclerosis, clemastine can alleviate symptoms by inhibiting neuroinflammation. In addition, preclinical and clinical trial evidence has shown that clemastine can be used for the treatment of multiple sclerosis by promoting oligodendrocyte myelination. SUMMARY
[0006] The present application mainly aims at the above problems, and provides the use of clemastine in the preparation of a drug for treating depression.
[0007] To achieve the above object, the present application provides a use of clemastine in the preparation of a drug for improving mental illness with depressive symptoms.
[0008] Preferably, the mental illness with depressive symptoms includes depression.
[0009] The present application provides a use of clemastine in the preparation of a drug for treating depression.
[0010] The present application first discovers that clemastine has the efficacy of treating depression, and clemastine can effectively relieve the depressive-like phenotype of mice induced by chronic unpredictable mild stress or lipopolysaccharide by promoting oligodendrocyte myelination. BRIEF DESCRIPTION OF DRAWINGS
[0011] Figure 1 Figures A to H in the drawings show the results of CUMS or LPS-induced depressive-like behavior of mice.
[0012] Figure 2 Figures A and E are the specific flow charts of experiments for CUMS or LPS-induced depressive-like behavior of mice, respectively.
[0013] Figure 2 Figures B to D and F to H show the results of the effect of clemastine on CUMS or LPS-induced depressive-like behavior of mice.
[0014] Figure 3 Figures A to G show the results of the effect of clemastine on myelin lesions in the brain of mice.
[0015] Figure 4 Figures A to D show the results of the effect of clemastine on synaptic structure in the brain of mice. DETAILED DESCRIPTION
[0016] In order to further understand the present application, the preferred embodiments of the present application are described below in conjunction with examples, but it should be understood that these descriptions are only for further illustrating the features and advantages of the present application, and are not limitations to the claims of the present application.
[0017] By taking the mouse depressive-like model induced by chronic unpredictable mild stress (CUMS) and lipopolysaccharide (LPS) as the object, the drug clemastine which has been proved to be effective in promoting myelination in clinical and basic research is used to intervene in CUMS or LPS mice, and the possible improvement of depressive-like behavior of mice by clemastine through promoting myelination is fully and carefully evaluated, and it is found that clemastine can effectively relieve the depressive-like phenotype of mice, thereby providing a new way for the effective prevention and treatment of depression.
[0018] The compounds involved in the following examples can be obtained by alternative but not limited to: chemical separation or synthesis by oneself or purchased from commercial channels.
[0019] Example 1
[0020] Chronic unpredictable mild stress and lipopolysaccharide stimulation can induce mice to present a depressive-like phenotype
[0021] Materials: healthy male SPF C57BL / 6J mice, lipopolysaccharide (LPS, Sigma, L-2280), Topscan behavioral analysis system (CleverSys).
[0022] Methods:
[0023] a) Chronic unpredictable mild stress (CUMS) was used to make a mouse depression research model.
[0024] After the C57BL / 6J mice (7-8 weeks old) arrived, they were adapted to the feeding environment for one week, and then the mice were given mild stimulation for 6 weeks. The specific stimulation factors include: fasting (24 hours), water deprivation (24 hours), feeding cage inclined 45℃ (7 hours), wet bedding (24 hours), circadian rhythm reversal (24 hours), restraint (2 hours), forced swimming (4℃, 5 minutes) and tail clamping (1 cm from the tail tip, 1 minute). These stimulation factors were randomly assigned to CUMS group mice every day. After 6 weeks, the sucrose preference test (SPT), open field test (OFT) and tail suspension test (TST) were used to evaluate the mice's anhedonia, anxiety and despair-like behavior.
[0025] b) Lipopolysaccharide (LPS) intraperitoneal injection was used to make a mouse depression research model.
[0026] After the C57BL / 6J mice (9-10 weeks old) arrived, they were adapted to the feeding environment for one week, and then LPS (0.5 mg / kg) was intraperitoneally injected for 10 consecutive days. Similarly, sucrose preference test (SPT), open field test (OFT) and tail suspension test (TST) were used to evaluate the mice's anhedonia, anxiety and despair-like behavior.
[0027] Results:
[0028] As Figure 1A-H: After CUMS or LPS stimulation, mice showed anhedonia (see A and E in Figure 1 ), anxiety-like (see C and G in Figure 1 ) and despair-like behaviors (see D and H in Figure 1 ). Meanwhile, the total liquid intake of mice during the whole sucrose preference test was calculated, and there was no significant difference between the data of each treatment group and the normal control mice (see B and F in Figure 1 ).
[0029] Example 2
[0030] Clemastine effectively alleviates CUMS or LPS-induced depressive-like behaviors in mice
[0031] Materials: Healthy male SPF C57BL / 6J mice, lipopolysaccharide (LPS, Sigma, L-2280), clemastine (Selleck Chemicals, S1847), Topscan behavioral analysis system (CleverSys).
[0032] Methods:
[0033] a) Chronic unpredictable mild stress (CUMS) was used to make a mouse depression research model.
[0034] After the C57BL / 6J mice (7-8 weeks old) arrived, they were adapted to the feeding environment for a week, and then the mice were given mild stimulation for 6 consecutive weeks. The specific stimulation factors included: fasting (24 hours), water deprivation (24 hours), feeding cage inclined 45℃ (7 hours), wet bedding (24 hours), circadian rhythm reversal (24 hours), restraint (2 hours), forced swimming (4℃, 5 minutes) and tail clamping (1 cm from the tail tip, 1 minute). These stimulation factors were randomly assigned to CUMS group mice every day. After 6 weeks, sucrose preference test (SPT), open field test (OFT) and tail suspension test (TST) were used to evaluate the anhedonia, anxiety and despair-like behaviors of mice.
[0035] b) Lipopolysaccharide (LPS) was injected intraperitoneally to make a mouse depression research model.
[0036] C57BL / 6J mice (9-10 weeks old) were given LPS (0.5 mg / kg) intraperitoneally for 10 consecutive days after they were acclimated in the housing environment for one week. The sucrose preference test (SPT), open field test (OFT) and tail suspension test (TST) were used to evaluate the anhedonia, anxiety and despair-like behaviors of the mice.
[0037] c) Intraperitoneal injection of clemastine to evaluate its antidepressant effect.
[0038] Figure 2 A and E in FIG. 1 are experimental flowcharts. Specifically,
[0039] The mice in the treatment group were given 10 mg / kg clemastine intraperitoneally every day starting from the fifth week of CUMS stimulation, and the effect of clemastine on the depressive behaviors of the mice was evaluated after 14 consecutive injections.
[0040] In the LPS model, the mice were given 10 mg / kg clemastine intraperitoneally for 10 consecutive days after they were given LPS every day. The sucrose preference test (SPT), open field test (OFT) and tail suspension test (TST) were used to evaluate the effect of clemastine on the anhedonia, anxiety and despair-like behaviors of the mice on the 11th day.
[0041] Clemastine was given to some mice in the model group intraperitoneally at the same time as the CUMS or LPS stimulation. Among them, Figure 2 B-D in FIG. 2 show that clemastine treatment can significantly improve the anhedonia (B), anxiety (C) and despair-like behaviors (D) of the mice caused by CUMS. Figure 2 Figure 2 Figure 2 Figure 2 F-H in FIG. 3 show that clemastine treatment can significantly improve the anhedonia (F), anxiety (G) and despair-like behaviors (H) of the mice caused by LPS. Figure 2 Figure 2 Figure 2
[0042] Example 3
[0043] Clemastine treatment can inhibit demyelination in the brain of mice caused by CUMS
[0044] Materials: Healthy male SPF C57BL / 6J mice, lipopolysaccharide (LPS, Sigma, L-2280), clemastine (Selleck Chemicals, S1847), transmission electron microscope (Hitachi, HT7700)
[0045] Western blotting uses antibody information:
[0046] MBP antibody (Servicebio, GB12226);
[0047] α-Tubulin antibody (Bioworld, AP0064).
[0048] Methods:
[0049] a) Chronic unpredictable mild stress (CUMS) was used to make a mouse depression research model.
[0050] After C57BL / 6J mice (7-8 weeks old) arrived, they were adapted to the feeding environment for a week, and then given mild stress for 6 consecutive weeks. The specific stress factors include: fasting (24 hours), water deprivation (24 hours), feeding cage inclined 45℃ (7 hours), wet bedding (24 hours), circadian rhythm reversal (24 hours), restraint (2 hours), forced swimming (4℃, 5 minutes) and tail clamping (1 cm from the tail tip, 1 minute). These stress factors were randomly assigned to CUMS group mice every day. After 6 weeks, the sucrose preference test (SPT), open field test (OFT) and tail suspension test (TST) were used to evaluate the anhedonia, anxiety and despair-like behaviors of mice.
[0051] b) Lipopolysaccharide (LPS) was injected intraperitoneally to make a mouse depression research model.
[0052] After C57BL / 6J mice (9-10 weeks old) arrived, they were adapted to the feeding environment for a week, and then given LPS (0.5 mg / kg) intraperitoneal injection for 10 consecutive days. Similarly, sucrose preference test (SPT), open field test (OFT) and tail suspension test (TST) were used to evaluate the anhedonia, anxiety and despair-like behaviors of mice.
[0053] c) Intraperitoneal injection of clemastine to evaluate its myelin-promoting effect.
[0054] At the beginning of the 5th week of CUMS stimulation, the mice in the treatment group were given 10 mg / kg clemastine intraperitoneally every day for 14 days to evaluate its effect on the depressive-like behavior of mice.
[0055] In the LPS model, mice were given 10 mg / kg clemastine intraperitoneally for 10 days after being given LPS injection every day. On the 11th day, the effects of clemastine on the anhedonia, anxiety-like, and despair-like behaviors of mice were evaluated using behavioral tests such as sucrose preference test (SPT), open field test (OFT), and tail suspension test (TST).
[0056] After the behavioral tests were completed, the mice were perfused to remove their brains, and the degree of myelination in the ventral hippocampal tissue was evaluated by transmission electron microscopy and molecular experiments.
[0057] d) Tissue protein extraction and MBP protein expression detection: After the mice were perfused with physiological saline, their ventral hippocampal tissue was separated and ground to extract total protein for detecting the protein expression level of MBP.
[0058] Results:
[0059] As shown in A-D in Figure 3 , after the mice were given CUMS or LPS stimulation, the key myelin marker MBP was significantly down-regulated; however, after treatment with clemastine, the MBP protein expression level returned to the normal control level. Further, E-G in Figure 3 used transmission electron microscopy to observe the morphology of the ventral hippocampal tissue in detail, and the results showed that the reduction in myelin thickness caused by CUMS could be significantly reversed by clemastine.
[0060] Example 4
[0061] Clemastine treatment can restore synaptic loss in the brain of mice caused by CUMS
[0062] Materials: Healthy male SPF C57BL / 6J mice, lipopolysaccharide (LPS, Sigma, L-2280), clemastine (Selleck Chemicals, S1847), transmission electron microscope (Hitachi, HT7700)
[0063] Methods:
[0064] a) Chronic unpredictable mild stress (CUMS) was used to make the mouse depression model.
[0065] C57BL / 6J mice (7-8 weeks old) were acclimated for one week after arrival, and then subjected to mild stress for 6 consecutive weeks. The stress factors included fasting (24 hours), water deprivation (24 hours), cage tilt (45° for 7 hours), wet bedding (24 hours), reversal of the light-dark cycle (24 hours), restraint (2 hours), forced swimming (4°C for 5 minutes), and tail pinch (1 cm from the tip for 1 minute). These stress factors were randomly assigned to the CUMS group of mice each day. After 6 weeks, the sucrose preference test (SPT), open field test (OFT), and tail suspension test (TST) were used to assess the anhedonia, anxiety, and despair-like behaviors of the mice.
[0066] b) Lipopolysaccharide (LPS) was used to make the mouse depression model.
[0067] C57BL / 6J mice (9-10 weeks old) were acclimated for one week after arrival, and then subjected to LPS (0.5 mg / kg) intraperitoneal injection for 10 consecutive days. The sucrose preference test (SPT), open field test (OFT), and tail suspension test (TST) were used to assess the anhedonia, anxiety, and despair-like behaviors of the mice.
[0068] c) Intraperitoneal injection of clemastine was used to assess its effect on synaptic structure.
[0069] In the CUMS model, the treatment group of mice was given 10 mg / kg clemastine intraperitoneally every day starting at the 5th week of CUMS stimulation, and the effect of clemastine on the depressive-like behavior of mice was evaluated after 14 days of continuous injection.
[0070] In the LPS model, the mice were given 10 mg / kg clemastine intraperitoneally every day after LPS injection for 10 days. On the 11th day, the sucrose preference test (SPT), open field test (OFT), and tail suspension test (TST) were used to assess the effect of clemastine on the anhedonia, anxiety-like, and despair-like behaviors of the mice.
[0071] After the completion of the behavioral experiment, the mouse brain was taken out by perfusion, and the synaptic structure of the ventral hippocampus tissue was evaluated by transmission electron microscopy.
[0072] Results:
[0073] As shown in A-D of Figure 4 , after the mice were given CUMS or LPS stimulation, the number of asymmetric synapses (see B of Figure 4 ) and the thickness of the postsynaptic density (see C-D of Figure 4 ) in the ventral hippocampus tissue of the model group mice were significantly reduced, and after the administration of chlorpromazine treatment, the above indicators were effectively improved.
[0074] By taking the CUMS or LPS-induced mouse depression model as the research object, the applicant determines that 10-day continuous intraperitoneal injection of chlorpromazine (10 mg / kg) can effectively improve the depressive behavior of mice. In vivo animal experiments show that chlorpromazine can inhibit synaptic loss and demyelination, which may be an important reason for its antidepressant effect. Therefore, the present application finds the use of chlorpromazine in the prevention and treatment of depression. Chlorpromazine and various preparations can be made into pharmaceutical compositions for the prevention and treatment of depression.
[0075] In this specification, the present application has been described with reference to its specific embodiments. However, it is obvious that various modifications and changes can be made without departing from the spirit and scope of the present application. Therefore, the specification should be considered as illustrative rather than limiting.
Claims
1. The use of clemastine in the manufacture of a medicament for ameliorating depression.
2. The use of clemastine in the manufacture of a medicament for treating depression.