Application of 3, 5-dimethoxy-4 '-hydroxystilbene in preparation of rapid antidepressant drug
By preparing a pharmaceutical preparation containing 3,5-dimethoxy-4'-hydroxystilbene and applying it to a mouse depression model, the problems of slow onset and multiple side effects of existing antidepressant drugs were solved, and a rapid and significant antidepressant effect was achieved.
Patent Information
- Application Number
- CN202510940163.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-08
- Publication Date
- 2025-09-16
AI Technical Summary
Existing antidepressants have slow onset, high inefficiency and many side effects. There is a lack of fast, effective and safe antidepressants in clinical practice. The use of 3,5-dimethoxy-4'-hydroxystilbene in the treatment of depression has not been reported.
3,5-Dimethoxy-4'-hydroxystilbene was used in the preparation of a fast-acting antidepressant drug. Experiments were conducted in social defeat stress and chronic restraint stress mouse models by oral administration. Pharmaceutically approved formulations such as tablets, capsules, and sustained-release tablets were used. The antidepressant effect was evaluated through social interaction, forced swimming, and tail suspension tests.
3,5-Dimethoxy-4'-hydroxystilbene exhibits rapid and significant antidepressant effects in mouse models, improving social avoidance and despair behaviors, reducing immobility time, and significantly improving depressive-like behaviors.
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Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of biomedicine, and in particular to application of 3,5-dimethoxy-4'-hydroxystilbene in the preparation of rapid antidepressant drugs. Background Art
[0002] 3,5-dimethoxy-4'-hydroxystilbene (CNS name: Pterostilbene, PTE), commonly known as pterostilbene, chemical formula: C 16 H 16 O3, molecular weight: 256.3, alias 3,5-dimethoxy-4'-hydroxystyrene, (E)-3,5-dimethoxy-4'-hydroxystyrene, (E)-4-[2-(3,5-dimethoxyphenyl)-vinyl]-phenol and 4-[(1E)-2-(3,5-dimethoxyphenyl)-vinyl]-phenol, its structural formula is:
[0003]
[0004] PTE is an active ingredient derived from plants such as rosewood, blueberry, grape and palm tree. Its structure is similar to resveratrol and it is a compound with a polyphenolic acid structure. Literature records that PTE has good anti-inflammatory, antioxidant, anti-tumor, neuroprotective, lipid-lowering and blood sugar-lowering activities.
[0005] Depression affects a significant number of patients. However, among the first-line antidepressants currently available, those developed based on monoaminergic theory are primarily monoamine reuptake inhibitors (MARIs), including MAOIs, tricyclic and tetracyclic antidepressants, selective serotonin reuptake inhibitors (SRIs), and neurexin reuptake inhibitors (NEs); and atypical antidepressants, including citalopram, venlafaxine, and sertraline. However, these antidepressants generally suffer from slow onset of action (2-4 weeks to take effect), high inefficacy rates (approximately 30%), and numerous adverse reactions. Furthermore, NMDA receptor inhibitors currently under development, such as ketamine at subanesthetic doses, offer rapid antidepressant effects. However, their psychotropic properties are susceptible to psychoneurological side effects and addiction, significantly limiting their clinical application. There is a critical lack of rapidly effective, highly effective, and safe antidepressants. Although literature has reported that 3,5-dimethoxy-4'-hydroxystilbene has certain pharmacological effects on the anti-inflammatory immune, nervous, endocrine, and digestive systems, there are no published reports demonstrating its use in the treatment of depression. Summary of the Invention
[0006] The purpose of the present invention is to address the above-mentioned defects of the prior art and provide the use of 3,5-dimethoxy-4'-hydroxystilbene in the preparation of rapid antidepressant drugs.
[0007] The purpose of the present invention can be achieved through the following technical solutions:
[0008] Application of 3,5-dimethoxy-4'-hydroxystilbene in the preparation of rapid antidepressant drugs.
[0009] Application of a composition containing 3,5-dimethoxy-4'-hydroxystilbene in the preparation of a rapid antidepressant drug.
[0010] As a preferred embodiment of the present invention, the composition containing 3,5-dimethoxy-4'-hydroxystilbene further contains pharmaceutical excipients for preparing 3,5-dimethoxy-4'-hydroxystilbene into a pharmaceutically acceptable preparation.
[0011] As a further preference of the present invention, the pharmaceutically acceptable preparation is selected from tablets, enteric-coated tablets, sustained-release tablets, capsules, enteric-coated capsules, powders, dispersible tablets, oral liquids, syrups, granules, dripping pills, oral patches, inhalation sprays, suppositories, micropills, microcapsules, injections, freeze-dried preparations, liposomes, microspheres or other sustained-release or controlled-release preparations.
[0012] The experimental study of the present invention found that 3,5-dimethoxy-4'-hydroxystilbene has a very significant and rapid therapeutic effect on the depressive-like behavior of mice in the social defeat stress model and chronic restraint stress model. First, it was found that: using the social defeat stress depression model (CSDS), mice were gavaged with 3,5-dimethoxy-4'-hydroxystilbene (120mg / kg) for 2 days and 5 days. Through the social interaction test (SI), forced swim test (FST) and tail suspension test (TST), it was found that 3,5-dimethoxy-4'-hydroxystilbene can significantly improve the social avoidance behavior and behavioral despair behavior of mice;
[0013] The chronic restraint stress model (CRS) was used to evaluate the rapid antidepressant effect of 3,5-dimethoxy-4'-hydroxystilbene. It was found that after oral administration of 3,5-dimethoxy-4'-hydroxystilbene solution (120 mg / kg) for 2 days and 5 days, 3,5-dimethoxy-4'-hydroxystilbene could significantly improve the behavioral despair and anxiety behaviors of mice through examination of the forced swimming test (FST), tail suspension test (TST) and open field test (OFT).
[0014] The above two typical depression model studies both clearly suggest that 3,5-dimethoxy-4'-hydroxystilbene has a rapid and significant effect in treating depression, and its mechanism of action needs further study.
[0015] The key technical point of the present invention is that the antidepressant effect of 3,5-dimethoxy-4'-hydroxystilbene is evaluated using the chronic social defeat stress (CSDS) model and the chronic restraint stress (CRS) model under the oral administration mode with core indicators such as social interaction, forced swimming, tail suspension test, and open field test, and significant pharmacological efficacy is achieved. BRIEF DESCRIPTION OF THE DRAWINGS
[0016] Figure 1 Experimental design and drug administration schedule for the chronic social defeat stress model in mice.
[0017] Figure 2 This figure shows the rapid antidepressant effect of oral administration of 3,5-dimethoxy-4'-hydroxystilbene (120 mg / kg) in mice induced by a chronic social defeat stress model. A, D: Sociability test for mice 2 and 5 days after oral administration of 3,5-dimethoxy-4'-hydroxystilbene; B, E: Forced swim test for mice 2 and 5 days after oral administration of 3,5-dimethoxy-4'-hydroxystilbene; C, F: Tail suspension test for mice 2 and 5 days after oral administration of 3,5-dimethoxy-4'-hydroxystilbene. CSDS denotes social defeat stress group, and PTE denotes 3,5-dimethoxy-4'-hydroxystilbene administration group. Statistical analysis was performed using one-way ANOVA. *p < 0.05, **p < 0.01, ***p < 0.001 indicate statistical significance; ns indicates no statistical significance.
[0018] Figure 3 Design of experimental model and schedule of drug administration for chronic restraint stress model in mice.
[0019] Figure 4 The rapid antidepressant effect of oral administration in a chronic restraint stress model mouse model. A: Open field test; B, E: Forced swim test in each group 2 and 5 days after oral administration of 3,5-dimethoxy-4'-hydroxystilbene (120 mg / kg); C, F: Tail suspension test in each group 2 and 5 days after oral administration of 3,5-dimethoxy-4'-hydroxystilbene; D: Body weight change of the experimental mice 5 days later. The results showed that 5 consecutive days of pterostilbene administration significantly improved the immobility time in the tail suspension test and forced swim test in CRS model mice, indicating that pterostilbene can significantly improve the depressive-like behavior of CRS mice.
[0020] Figure 5Figure 1 shows the trajectory of an open-field behavioral test. CRS denotes the chronic restraint stress model, and PTE denotes the 3,5-dimethoxy-4'-hydroxystilbene treatment group. Statistical analysis was performed using one-way ANOVA. *p<0.05, **p<0.01, ***p<0.001 indicate statistically significant differences; ns indicates no statistical significance. The results showed that pterostilbene significantly increased the time CRS mice spent in the center of the open field. DETAILED DESCRIPTION
[0021] The present invention will be further described below by way of specific examples, but this should not be construed as limiting the present invention. A person of ordinary skill in the art may also make various adjustments, modifications, replacements, changes, and improvements based on the above technical solutions. Any adjustments, modifications, replacements, changes, and improvements based on the above technical concepts fall within the scope of the present invention.
[0022] The present invention is explained in detail by the following examples, but it is not intended that the present invention is limited thereto.
[0023] Example 13, Rapid antidepressant effect of oral administration of 5-dimethoxy-4'-hydroxystilbene on chronic social defeat stress model mice
[0024] The social defeat stress model used CD-1 mice (retired mice, male, 4-6 months old, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., weighing 48±5g) and C57BL / 6J mice (male, 7-8 weeks old, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., weighing 21±3g) and was adaptively raised for one week under a standard breeding environment (free access to food and water, alternating day and night, each 12 hours).
[0025] Establishment of animal model: CD-1 mice were screened for 3 consecutive days, and aggressive CD-1 mice were selected for modeling. CD-1 mice and C57 mice were separated by a transparent plastic partition with holes, and C57 mice were placed on the same side of CD-1 mice every day to accept the attack, each time for 5-10 minutes, and accepted the attack of a new CD-1 mouse every day. After the end, the C57 mice were placed next door and continued to accept the visual and taste stress of CD-1 mice for the remaining 24 hours. The model was established for 10 consecutive days. On the 11th day, mice with a social coefficient <1 (i.e., depression-sensitive mice) were screened based on social avoidance behavior and were evenly divided into CSDS model group and 3,5-dimethoxy-4'-hydroxystilbene gavage administration group for experiments. Social behavior evaluation, tail suspension test, forced swimming test ( Figure 1 ).
[0026] Administration: The selected depression-sensitive mice were orally administered with 3,5-dimethoxy-4'-hydroxystilbene dispersed in 0.5% CMC-Na aqueous solution, while the control group and model group were given equal volume of 0.5% CMC-Na solution.
[0027] Social avoidance behavior: Social behavior was evaluated after 2 and 5 consecutive days of drug administration. Before the experiment, the mice were placed in a behavioral test room to adapt to the light and temperature for more than 30 minutes. C57 mice were placed in an open field of 40×40×40 cm, and an empty mesh cage was placed in the social area. The activity of the C57 mice was recorded within 150 seconds, and the C57 mice were removed after the end. A CD-1 mouse was placed in the mesh cage for the second period of time, and the activity was also recorded for 150 seconds. The social coefficient (SI) was calculated as the ratio of the time that the C57 mouse entered the social area during the second period to the time that it entered the social area during the first period of time. The results showed that the social coefficient of the model group mice was significantly decreased compared with the control group, and the 3,5-dimethoxy-4'-hydroxystilbene gavage group had a significant improvement on social avoidance behavior after 2 and 5 consecutive days of drug administration ( Figure 2 A, 2D).
[0028] Impact on Desperate Behavior:
[0029] Forced swimming test (FST) was used to evaluate the despair behavior of mice: C57 mice were placed in a 5-liter (11.8 cm in diameter, 27.5 cm in height) glass beaker (water level was 18-20 cm high, water temperature was 23-25°C), the mice were visually isolated from each other, and the activity of the mice was recorded for 6 minutes. Two blinded personnel analyzed the time the mice spent motionless in the water within 4 minutes, where activity was defined as swimming and climbing, and stillness was defined as floating or paddling slightly to keep the head out of the water. The results showed that: there was no significant improvement after oral administration of 3,5-dimethoxy-4'-hydroxystilbene for 2 days; after continuous administration for 5 days, oral administration of 3,5-dimethoxy-4'-hydroxystilbene could significantly shorten the forced swimming immobility time ( Figure 2 B, 2E).
[0030] The tail suspension test (TST) was used to evaluate the despair behavior of mice: C57 mice were individually taped to the tip of their tails 1 cm away with medical tape and fixed in a tail suspension box, with their heads about 20 cm above the ground. The mice were visually isolated from each other, and their activities were recorded by video for 6 minutes. Two blinded individuals analyzed the immobility time of the mice in the last 4 minutes, where immobility was defined as complete stillness or only slight movement of the limbs. The results showed that oral administration of 3,5-dimethoxy-4'-hydroxystilbene for 2 and 5 days could significantly shorten the immobility time of the tail suspension test ( Figure 2 C, 2F).
[0031] Conclusion: Intragastric administration of 3,5-dimethoxy-4'-hydroxystilbene can rapidly and significantly improve the depressive-like behavior of mice induced by social defeat stress, and has a significant antidepressant effect.
[0032] Example 23: Rapid antidepressant effect of 5-dimethoxy-4'-hydroxystilbene administered orally on chronic restraint stress model mice
[0033] The chronic restraint stress model was induced using C57BL / 6J mice (male, 7-8 weeks old, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd., weighing 21±3 g) under a standard housing environment (free access to food and water, alternating day and night, 12 hours each), and adaptively housed for one week.
[0034] Establishment of animal model: A 50mL EP tube was punched for restraint stress. During modeling, C57 mice were placed in a 50mL EP tube with holes at a fixed time every day, and attention was paid to spacing between each mouse and keeping them blind to each other for 4-6 hours every day for 21 consecutive days. After modeling, the mice were evenly divided into a CRS model group and a 3,5-dimethoxy-4'-hydroxystilbene gavage group for experiments. Tail suspension test and forced swimming test were performed 2 days and 5 days after administration respectively; open field test ( Figure 3 ).
[0035] Administration: The mice in the 3,5-dimethoxy-4'-hydroxystilbene administration group were orally administered with 3,5-dimethoxy-4'-hydroxystilbene dispersed in 0.5% CMC-Na aqueous solution, while the control group and the model group were administered with an equal volume of 0.5% CMC-Na solution.
[0036] Effects on despair behavior in mice:
[0037] The tail suspension test (TST) was used to evaluate the despair behavior of mice: C57 mice were individually taped to the tip of their tails 1 cm away with medical tape and fixed in a tail suspension box, with their heads about 20 cm above the ground. The mice were visually isolated from each other, and their activities were recorded by video for 6 minutes. Two blinded individuals analyzed the immobility time of the mice in the last 4 minutes, where immobility was defined as complete stillness or only slight movement of the limbs. The results showed that mice given 3,5-dimethoxy-4'-hydroxystilbene by gavage for 5 days could significantly improve their immobility time in the tail suspension test ( Figure 4 A, 4D).
[0038] Forced swimming test (FST) was used to evaluate the despair behavior of mice: C57 mice were placed in a 5-liter (11.8 cm in diameter, 27.5 cm in height) glass beaker (water level was 18-20 cm high, water temperature was 23-25°C), the mice were visually isolated from each other, and the activity of the mice was recorded for 6 minutes. The time the mice spent motionless in the water within 4 minutes was analyzed by two blinded personnel, where activity was defined as swimming and climbing, and stillness was defined as floating or paddling slightly to keep the head above the water. The results showed that mice given 3,5-dimethoxy-4'-hydroxystilbene by gavage significantly improved their immobility time in the forced swimming test after 2 and 5 consecutive days of administration ( Figure 4 B, 4E).
[0039] Effects on anxiety behavior in mice:
[0040] The open field test was used to evaluate the anxiety behavior of mice: The experiment was conducted in an opaque acrylic box with a size of 42cm×42cm×42cm and an open top, with the central area of 24×24cm as the central area. The mice were placed in the center of the open field, and the distance (cm) the mice moved within 5 minutes was recorded as the evaluation standard for the spontaneous activity level of the animals. The time the mice spent in the central area within 5 minutes was recorded as an indicator for evaluating anxiety-like behavior. Between the tests of every two mice, the excrement left in the test box was cleaned, and the test box was wiped with 75% alcohol to remove residual odors. The results showed that oral administration of 3,5-dimethoxy-4'-hydroxystilbene for 5 consecutive days significantly increased the time and distance that mice spent in the central area ( Figure 4 A. Figure 5 ).
[0041] Effect on the body weight of mice: After oral administration of 3,5-dimethoxy-4'-hydroxystilbene for 5 consecutive days, the body weight of mice remained stable and no longer decreased compared with that before administration, indicating that it can slow down the weight loss trend of mice ( Figure 4 D), showed good weight maintenance effect.
[0042] Conclusion: Intragastric administration of 3,5-dimethoxy-4'-hydroxystilbene can rapidly and significantly improve the depressive-like behavior of chronic restraint stress model mice and has a significant antidepressant effect.
[0043] For those skilled in the art, the present disclosure is not limited to the foregoing illustrative embodiments and can be embodied in other specific forms without departing from its essential attributes. It is therefore intended that all aspects be considered as illustrative and not restrictive, and that reference be made to the following claims rather than to the foregoing embodiments.
Claims
1. Application of 3,5-dimethoxy-4'-hydroxystilbene in the preparation of rapid antidepressant drugs.
2. The use according to claim 1, characterized in that: The administration route of the therapeutic drug for exerting a rapid antidepressant effect is oral administration.
3. The use according to claim 2, characterized in that: The effective rapid antidepressant dose of the therapeutic drug is 120 mg / kg.
4. The application according to claim 1, characterized in that The depression is social frustration-induced depression and chronic restraint-induced depression.
5. The application according to claim 4, characterized in that: The rapid antidepressant effect time is 5 consecutive days of administration.
6. A rapid depression treatment drug, characterized in that: Its active ingredient includes 3,5-dimethoxy-4'-hydroxystilbene.
7. The rapid depression treatment drug according to claim 6, characterized in that: The invention also includes pharmaceutical excipients for preparing 3,5-dimethoxy-4'-hydroxystilbene into pharmaceutically acceptable preparations.
8. The preparation according to claim 7 is selected from tablets, enteric-coated tablets, sustained-release tablets, capsules, enteric-coated capsules, powders, dispersible tablets, oral liquids, syrups, granules, dripping pills, oral patches, inhalation sprays, suppositories, micropellets, microcapsules, injections, lyophilized preparations, liposomes, microspheres or other sustained-release or controlled-release preparations.