CN115624555A - Application of hyodeoxycholic acid in preparation of antidepressant drug - Google Patents
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Abstract
The invention discloses application of hyodeoxycholic acid in preparation of antidepressant drugs. The hyodeoxycholic acid provided by the invention can be applied to clinical depression treatment, initiates a new clinical application of hyodeoxycholic acid, and provides a new effective, rapid and safe selected drug for anti-depression treatment. In addition, the hyodeoxycholic acid has good effects on moderate and mild depression, still shows a rapid and significant anti-depression effect on a major depression model mouse with a high depression score, and is treated by administration for 3 days and 7 days, the mouse ethological score is very close to that of a normal group of mice, so that the hyodeoxycholic acid has a very significant treatment effect on depression.
Description
Title:
the invention discloses application of hyodeoxycholic acid in preparation of antidepressant drugs.
Background
Hyodeoxycholic acid is an organic compound with molecular formula C 24 H 40 O 4 Cholanic acid extracted from pig bile is white or slightly yellowish powder, bitter in taste and slightly fishy in smell. Hyodeoxycholic acid has effects of inhibiting cholic acid formation and dissolving fat, reducing cholesterol and triglyceride in blood, and is suitable for hyperlipidemia and atherosclerosis (Chinese nerve regeneration research: english edition, 2019,14 (11): 9.), and has certain antibacterial effect on Bordetella pertussis, diptheria bacillus, staphylococcus aureus, etc. (world latest medical information Abstract, 2019 (97)), and also can be used as antiinflammatory agent for treating chronic bronchitis, infantile viral upper respiratory inflammation (world latest medical information Abstract, 2019 (97)), etc.
According to the records of the compendium of materia medica, the pig gall can treat diabetes (namely diabetes), and the latest research shows that hyodeoxycholic acid can increase the secretion of GLP-1 and has a remarkable hypoglycemic effect (Social Science Electronic Publishing).
In the related application, the current clinical treatment of depressive disorder/depression mainly takes monoamine reuptake inhibitors as main components, and the monoamine reuptake inhibitors comprise monoamine oxidase inhibitors, tricyclic and tetracyclic antidepressants, selective 5-HT reuptake inhibitors and NE reuptake inhibitors, but the antidepressant drugs generally have the main problems of slow effect (at least 2-4 weeks), large toxic and side effects, low efficiency, easy relapse after treatment, even easy suicide induction and the like. Clinically, antidepressant medicaments with good efficacy, quick response and small toxic and side effects are urgently needed. Although hyodeoxycholic acid may be used as an anti-inflammatory agent ingredient, there is no report in any publication that hyodeoxycholic acid, or derivatives thereof, is useful for the treatment of depressive disorders/depression.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide application of hyodeoxycholic acid in preparation of antidepressant drugs.
The purpose of the invention can be realized by the following technical scheme:
application of hyodeoxycholic acid in preparation of antidepressant is provided.
Preferably, the hyodeoxycholic acid is used for preparing the antidepressant drug with quick response.
The application of the composition containing hyodeoxycholic acid in the preparation of antidepressant drugs.
Preferably, the composition containing hyodeoxycholic acid is used for preparing a rapid-acting antidepressant drug.
Preferably, the composition containing hyodeoxycholic acid further contains pharmaceutical excipients for preparing hyodeoxycholic acid into pharmaceutically acceptable preparations.
As a further preference of the invention, the pharmaceutically acceptable preparation is selected from tablets, capsules, powders, oral liquids, syrups, granules, dripping pills, oral patches, inhalation sprays, suppositories, pellets, microcapsules, injections, lyophilized preparations, liposomes, microspheres or other sustained or controlled release preparations.
The experimental study of the invention finds that hyodeoxycholic acid has a very significant therapeutic effect on social frustration stress model mouse (CSDS) depression. Firstly, the following discovery: after 3 days of administration of HDCA (40 mg/kg, 120 mg/kg) by intragastric administration in mice, the social fear and behavior despair of the mice were found to be significantly improved by low and high doses of HDCA through examination of Social Interaction Test (SIT) Forced Swim Test (FST) and sugar water preference (SPT). After 7 days of administration, social interaction experiments (SIT), tail suspension experiments (TST) and sugar water preference experiments (SPT) show that HDCA with low and high doses can remarkably improve social phobia, behavior despair and anorgasmia behaviors of mice, the effect of the HDCA is similar to that of ketamine which is a positive drug injected into abdominal cavity, and the behavioral scores of the mice are very close to those of mice in a normal group after administration treatment for 3 days and 7 days. In addition, the traditional Chinese medicine composition still shows a remarkable antidepressant effect on major depressive model mice with high depressive scores.
Further using this model, the mice were administered HDCA (40 mg/kg, 120 mg/kg) by gavage for 1 day and 3 days before their rapid antidepressant action was examined. The results show that after the intragastric administration for 1 day, the low and high doses both significantly increase the SI value, significantly reduce the immobility time of mice in tail suspension and swimming experiments, and improve the social frustration and depression-like behaviors of the mice; after 3 days of gavage administration of hyodeoxycholic acid, the low and high doses both significantly increase the SI value, significantly reduce the immobility time of mice in tail suspension and swimming experiments, enhance the sugar water preference of the mice, improve the social frustration and depression-like behaviors of the mice, and have an anti-depression effect similar to that of the positive drug ketamine. In addition, a chronic restraint stress model (CRS) and a chronic corticosterone stress model (CORT) are adopted to evaluate the rapid antidepressant effect of the hyodeoxycholic acid, and the CRS high-dose group is found to remarkably reduce the immobility time of the mice in a swimming experiment and improve the despair behavior of the mice after the hyodeoxycholic acid is administrated for 1 day; after 3 days of administration, the low and high doses both obviously reduce the immobility time of mice in tail suspension and swimming experiments, improve the sugar water preference rate of the mice and improve the despair behavior of the mice, and the effect is similar to that of the positive drug ketamine injected into the abdominal cavity.
The three depression model researches clearly suggest that the hyodeoxycholic acid has the effect of quickly, comprehensively and remarkably treating depression, and the action mechanism of the hyodeoxycholic acid needs to be deeply researched and verified.
The key points of the technology of the invention are as follows: three generally accepted classic depression models, such as a chronic social frustration (CSDS) model, a chronic restraint stress model (CRS) and a chronic corticosterone stress model (CORT), are used for evaluating the antidepressant effect of the hyodeoxycholic acid through four core indexes, namely social interaction, forced swimming, tail suspension test and sugar water preference, and remarkable drug effect is achieved.
The invention has the following effects:
the hyodeoxycholic acid provided by the invention can be applied to clinical depression treatment, initiates a new clinical application of hyodeoxycholic acid, and provides a new effective, rapid and safe selected drug for anti-depression treatment. The hyodeoxycholic acid has a good effect on moderate and mild depression, still shows a rapid and significant anti-depression effect on a major depression model mouse with a high depression score, and is treated by administration for 1 day, 3 days and 7 days, the mouse ethological score is very close to that of a normal group of mice, and the hyodeoxycholic acid is prompted to have a very significant treatment effect on depression.
Drawings
FIG. 1 model of Chronic social frustration
FIG. 2 grouping and Pre-dose SI scores
Wherein Ctrl represents a normal control group, SS represents a social frustration model group, SS + HDCA-L represents a social frustration model complex hyodeoxycholic acid low dose administration group (40 mg/kg), SS + HDCA-H represents a social frustration model complex hyodeoxycholic acid high dose administration group (120 mg/kg), and RES represents a depression resistance group. Statistical analysis was performed using one-way ANOVA, ### p<0.001,ss vs Ctrl statistical difference; * P is<0.001, statistical difference between SS + HDCA-H and RES; n.s. statistical differences were not significant.
FIG. 3.HDCA dosing for 3 days ethology A. Social interaction test site B. Social interaction test SI scoring C. Stationary time of forced swimming test
Wherein Ctrl represents a normal control group, SS represents a social frustration model group, SS + HDCA-L represents a social frustration model compound hyodeoxycholic acid low dose administration group (40 mg/kg), SS + HDCA-H represents a social frustration model compound hyodeoxycholic acid high dose administration group (120 mg/kg), and RES represents a depression resistance group. Statistical analysis was performed using one-way ANOVA, # statistical differences between SS and Ctrl ( # p<0.05 ); * Statistical differences (. P.) for groups other than Ctrl<0.05，**p<0.01 ); n.s. statistical differences were not significant.
Figure 4. Behavioural a. Social interaction experiment SI score b. Tail suspension experiment immobilization time c. Sugar water preference rate with 7 days hdca dosing
Wherein Ctrl represents a normal control group, SS represents a social frustration model group, SS + HDCA-L represents a social frustration model complex hyodeoxycholic acid low dose administration group (40 mg/kg), SS + HDCA-H represents a social frustration model complex hyodeoxycholic acid high dose administration group (120 mg/kg), and RES represents a depression resistance group. Statistical analysis was performed using one-way ANOVA, # statistical differences between SS and Ctrl ( # p<0.05, ## p<0.01, ### p<0.001 ); * Statistical differences in groups other than Ctrl (. P)<0.05,**p<0.01，***p<0.001 ); n.s. statistical differences were not significant.
FIG. 5, 1 day and 3 days after gavage of hyodeoxycholic acid after chronic social frustration stress model (CSDS) modeling, social frustration score of mice can be significantly improved
A. C, E: social scores (SI values), immobility time in tail suspension experiments and immobility time in forced swim experiments for groups of mice 1 day after gavage HDCA administration;
B. d, F, G: social scores (SI values) of groups of mice 3 days after gavage HDCA administration; the immobility time in the tail suspension experiment, the immobility time in the forced swimming experiment and the sweet water preference rate.
Wherein Ctrl represents a normal control group, SS represents a social frustration model group, SS + HDCA-L represents a social frustration model complex hyodeoxycholic acid low dose administration group (40 mg/kg), SS + HDCA-H represents a social frustration model complex hyodeoxycholic acid high dose administration group (120 mg/kg), SS + KET represents a social frustration model complex positive drug ketamine administration group (10 mg/kg), RES represents a depression resistance group, statistical analysis was performed using one-way ANOVA,. P <0.05,. P <0.01,. P <0.001 is significant for statistical differences; n.s. statistical differences were not significant.
FIG. 6 shows that 1 day and 3 days after administration of hyodeoxycholic acid by gavage after Chronic Restraint Stress (CRS) molding, behavior despair scores of mice can be significantly improved
A. D, the immobility time of each group of mice in the tail suspension experiment and the immobility time in the forced swimming experiment when the model building is finished and the drug is not applied;
b, immobility time of each group of mice in a forced swimming experiment after 1 day of intragastric administration;
C. e, F: immobility time in tail suspension experiment, immobility time in forced swimming experiment and sugar water preference rate in each group of mice after 3 days of gavage administration.
Wherein, ctrl represents a normal control group, CRS represents a restraint stress group, CRS + HDCA-L represents a restraint stress model complex hyodesoxycholic acid low dose administration group (40 mg/kg), CRS + HDCA-H represents a restraint stress model complex hyodesoxycholic acid high dose administration group (120 mg/kg), CRS + KET represents a restraint stress model complex positive drug ketamine administration group (10 mg/kg), statistical analysis is performed by using one-way ANOVA, p <0.05, p <0.01, p <0.001 is statistical difference and has significance; n.s. statistical differences were not significant.
FIG. 7 shows that 3 days after gavage of hyodeoxycholic acid after chronic corticosterone stress (CORT) modeling, behavior despair scores of mice can be significantly improved
A. D, the immobility time of each group of mice in the tail suspension experiment and the immobility time in the forced swimming experiment under the condition of no drug administration after the molding is finished;
b, immobility time of each group of mice in a tail suspension experiment after 1 day of gastric lavage administration;
C. e, F: immobility time in tail suspension experiment, immobility time in forced swimming experiment and sugar water preference rate in each group of mice after 3 days of gavage administration.
Where Ctrl represents a normal control group, CORT represents a corticosterone model group, CORT + HDCA-L represents a corticosterone model complex hyodesoxycholic acid low dose administration group (40 mg/kg), CORT + HDCA-H represents a corticosterone model complex hyodesoxycholic acid high dose administration group (120 mg/kg), and CORT + KET represents a corticosterone model complex positive drug ketamine administration group (10 mg/kg). Statistical analysis was performed using one-way ANOVA with statistical differences of p <0.05, p <0.01, p < 0.001; n.s. statistical differences were not significant.
Detailed Description
Example 1 establishment of a model of Chronic social frustration Depression to obtain depressed mice
Establishing an animal model: CD-1 mice (retired mice, male, 4-6 months, body weight 48 +/-5 g) are continuously screened for 3 days, and aggressive CD-1 mice are screened for modeling. C57BL/6J mice (male, 6-7 weeks, 20. + -.2 g body weight) were randomly divided into model and control groups. For the model group mice, the CD-1 mice and the C57 mice were separated by a transparent plastic partition plate with holes, the C57 mice were placed on the same side of the CD-1 mice each day for 10min of attack at the same time period, and after that, the C57 mice were placed on the opposite side of the transparent partition plate to keep the two mice in olfactory and visual contact. After 24h, the C57BL/6J mice were removed and placed in another new CD-1 mouse cage and the procedure repeated for 10 days as shown in FIG. 1. Control group C57 mice were fed on a standard diet until CSDS molding was complete. And screening depressed mice through social interaction experiments, randomly and averagely dividing the depressed mice successfully modeled into three groups, wherein the social score SI values are not different, the CSDS susceptibility (SS) group, the hyodeoxycholic acid low dose group (SS + HDCA-L,40 mg/kg) and the hyodeoxycholic acid high dose group (SS + HDCA-H,120 mg/kg) are continuously administrated for 7 days, and the antidepressant effect is investigated and evaluated on the 3 rd day and the 7 th day respectively, as shown in figure 2.
Example 2 behavioral indicators for HDCA administration for 3 days (social interaction test, forced swimming)
Social interaction experiments, where C57BL/6J mice exposed to social frustration pressure develop a socially avoidable, depression-like phenotype, the social avoidance behavior of the mice can be assessed using a social interaction experiment (SIT) that is largely divided into no CD-1 mice present (first phase) and CD-1 mice present (second phase), with the level of depression assessed by the ratio SI of the length of time that the C57BL/6J mice enter the social area in the two phases, as shown in fig. 3A. The results show that both low and high doses of HDCA significantly improved social fear in mice, as shown in figure 3B.
Forced swim experiments despair behavior of mice was induced by forcing them to swim in deep water, immobility time of the test mice was recorded to evaluate their depression level, the mice were placed individually in a 5 liter glass beaker (diameter 17.8 cm, height 27.5 cm) containing 18 to 20 cm of water (23 ℃ -25 ℃) and the camera was used to take the behavior of the mice within 6min and analyze the immobility time 4min later (two experimenters not related to the subject were analyzed and averaged). The results show a significant improvement in depression-like behavior in mice 3 days after gavage HDCA administration, as shown in figure 3C.
Example 3 behavioral indicators for 7 days of HDCA administration (social interaction test, tail suspension test, syrup preference)
Social interaction experiments were performed as shown in example 2, and the results showed that both low and high doses of HDCA significantly improved social fear in mice, as shown in fig. 4A.
Tail suspension experiment despair behavior of mice was induced by suspending the mouse tail and recording the immobility time of the mice to evaluate their level of depression. A C57BL/6J mouse tip 1/3 part is wound by a medical white tape, the mouse tip is suspended in a tail suspension box, the behavior within 6min after the suspension is recorded by a camera, and the immobility time of 4min after the suspension is analyzed (two experimenters irrelevant to the subject analyze and take the average value). The results showed a significant improvement in depression-like behavior in mice 7 days after gavage HDCA administration, as shown in figure 4B.
Anhedonia is one of the major symptoms of depressive disorder/depression, manifested by a decrease in the consumption of sucrose solution, and the level of depression in mice was assessed using a sugar water preference experiment. The mice are given one bottle of 2% sucrose water and one bottle of drinking water respectively after 24 hours of adaptation in advance, and the positions of the two water bottles are changed every 12 hours to prevent position preference. During formal experiments, the weights of the syrup and the drinking water respectively drunk by the mice within 12h at night are weighed and recorded, and the syrup preference rate calculation formula is as follows: the drinking weight of sugar water/(drinking weight of sugar water + drinking water) × 100%, and the results showed that administration of hyodeoxycholic acid by gavage increased the sugar water preference rate of C57 mice (fig. 4C), and improved anhedonia behavior.
Example 4 Rapid antidepressant Effect of Hyodeoxycholic acid on Chronic social frustration stress model mice
Depressed-like mice were obtained by the aforementioned social frustration stress model (CSDS) method, and behavioral tests including social interaction test (SI), tail Suspension Test (TST), forced Swim Test (FST), and sugar water preference test (SPT) were performed by intraperitoneal injection of ketamine as a positive control group 1 day and 3 days after gavage administration of low (40 mg/kg), high dose HDCA (120 mg/kg). The results show that after 1 day of gavage administration of hyodeoxycholic acid, the SI values of both low and high doses are significantly increased, the immobility time of mice in tail suspension and swimming experiments is significantly reduced (fig. 5A, 5C and 5E), and the social frustration and depression-like behaviors of the mice are improved; after 3 days after the hyodesoxycholic acid is administrated by gastric lavage, the SI value is obviously increased by low and high doses, the immobility time of a mouse in tail suspension and swimming experiments is obviously reduced, the sugar water preference of the mouse is improved, the social frustration and depression-like behaviors of the mouse are improved, and the antidepressant effect is similar to that of a positive drug ketamine.
Example 5 Rapid antidepressant Effect of Hyodeoxycholic acid on Chronic restraint stress model mice
This example obtained depressed-like mice by establishing restraint stress (CRS), placing the building block C57/6J mice in a self-made 50mL EP tube restraint device daily for 4h of stress (9-13). The molding was continued for 21 days, during which the blank group was fasted and deprived of water. Depressive behavioural tests (including forced swim and tail suspension experiments) were performed on day 22 and group dosing was performed (fig. 6A, 6D). After 1 and 3 days of intragastric administration of low (40 mg/kg), high dose HDCA (120 mg/kg), ketamine was administered intraperitoneally as a positive control group and behavioral tests were performed, including tail-overhang, forced swim, and sugar water preference. The results show that high-dose HDCA significantly reduced the immobility time of mice in swimming experiments after 1 day of gavage administration of hyodeoxycholic acid (fig. 6B), improving the despair behavior of mice; after 3 days after the hyodeoxycholic acid is administrated by gastric lavage, the low dose and the high dose both obviously reduce the immobility time of the mice in tail suspension and swimming experiments, improve the sugar water preference rate of the mice (figures 6E, 6C and 6F), improve the depression-like behavior of the mice, and have similar antidepressant effect to the positive drug ketamine.
Example 6 Rapid antidepressant Effect of Hyodeoxycholic acid on Chronic corticosterone stress model mice
In this example, a depressed mouse was obtained by establishing chronic corticosterone stress (CORT), weighing 10mg of corticosterone powder, adding to 1mL of ethanol, and dissolving by vigorous shaking to obtain a 10mg/mL cortisone ethanol solution. Then added to 99mL of drinking water and diluted to 0.1mg/mL of corticosterone in 1% ethanol. The drinking water from the model-building mice was replaced with 0.1mg/mL corticosterone in 1% ethanol in water for 21 days. During the period, the blank control group normally gives drinking water. Depressive behavioural tests (including tail-overhang and forced swimming tests) were performed on day 22 and group dosing was performed (fig. 7A, 7D). After 1 and 3 days of intragastric administration of low (40 mg/kg), high dose HDCA (120 mg/kg), ketamine was administered intraperitoneally as a positive control group and behavioral tests were performed, including tail-overhang, forced swim, and sugar water preference. The results show that HDCA did not significantly improve the despair behavior of mice after 1 day gavage with hyodeoxycholic acid (fig. 7B); after 3 days of administration of hyodeoxycholic acid by gavage, the low and high doses both significantly reduce the immobility time of mice in tail suspension and swimming experiments, improve the sugar water preference rate of the mice (fig. 7C, 7E and 7F), improve the despair behavior of the mice, and have similar antidepressant effect to the positive drug ketamine.
Claims (6)
1. Application of hyodeoxycholic acid in preparation of antidepressant is provided.
2. Use according to claim 1, characterized in that hyodeoxycholic acid is used for the preparation of a fast-acting antidepressant medicament.
3. Application of a composition containing hyodeoxycholic acid in preparing antidepressant is provided.
4. Use according to claim 3, characterized in that the composition comprising hyodeoxycholic acid is used for the preparation of a fast-acting antidepressant medicament.
5. The use according to claim 3, characterized in that the composition comprising hyodeoxycholic acid further comprises pharmaceutical excipients for the preparation of hyodeoxycholic acid in pharmaceutically acceptable formulations.
6. The use according to claim 5, wherein the pharmaceutically acceptable formulation is selected from the group consisting of tablets, capsules, powders, oral liquids, syrups, granules, pills, buccal patches, inhalation sprays, suppositories, pellets, microcapsules, injections, lyophilized formulations, liposomes, microspheres or other sustained or controlled release formulations.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060135403A1 (en) * | 2002-12-24 | 2006-06-22 | Francine Gervais | Therapeutic formulations for the treatment of beta-amyloid related diseases |
| CN103958540A (en) * | 2011-09-08 | 2014-07-30 | 萨奇治疗股份有限公司 | Neuroactive steroids, compositions, and uses thereof |
| CN105769876A (en) * | 2016-03-08 | 2016-07-20 | 上海中医药大学 | Medical application of bile acid ingredient and bear bile |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060135403A1 (en) * | 2002-12-24 | 2006-06-22 | Francine Gervais | Therapeutic formulations for the treatment of beta-amyloid related diseases |
| CN103958540A (en) * | 2011-09-08 | 2014-07-30 | 萨奇治疗股份有限公司 | Neuroactive steroids, compositions, and uses thereof |
| CN105769876A (en) * | 2016-03-08 | 2016-07-20 | 上海中医药大学 | Medical application of bile acid ingredient and bear bile |
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