| Rationales: Depression,as a second Global Burden of Disease(GBD)next to the cardiovascular disease according to the WHO forecasts In the 2020,serious damage to human’s physical and mental health,has been rated as one of the 10 kinds of major diseases of major drug discovery special project.Compared with the foreign public antidepressants reached more than 50 varieties,alternative antidepressant drugs in the domestic only more than 20 varieties,and the top ten products are all antidepressant chemicals,TCM of anti-depression was rarely seen in the market.Currently listed TCM of anti-depression mostly are TCM syndrome of depression,such as relieving the Depressed Liver,mind-tranquilizing and so on.However,explicitly specify cure depression In the specifications of drugs only has Shuganjieyu capsule and Jinxiangshugan tablet.Therefore,based on market demand and the advantage of traditional Chinese medicine treatment of complex diseases,develop innovative TCM of anti-depression have great importance and significance.Our research group preliminary combined pharmacodynamic screening,chemical analysis and clinical observation have obtained the modified formula of xiaoyaosan : Chaigui Fang and its pilot scale production using the alcohol-water extraction method.This study choose Chaigui Fang extract for tested drug,from the point of the accompanying symptoms of depression and the side effects of antidepressant chemical drug to explore the antidepressant effect characteristic of Chaigui Fang extract.Objective: Screening antidepressant dose of Chaigui Fang extract in the main pharmacodynamics experiment under the new extraction process;discussing Chaigui Fang extract’s effect on concomitant nerve symptom of depression: cognitive dysfunction and anxiety;discussing Chaigui Fang extract’s effect on concomitant physical symptom of depression: low sexual desire,constipation and gastrointestinal decline;discussing Chaigui Fang extract whether have rebound phenomenon after withdrawal and its effect on the recrudescence of depressive-like symptom.Content and methods: 1.According to preliminary pharmacodynamic test set up six dose group of Chaigui Fang extract,immobility time of mice was observed by using the mice tail suspension test(TST)and forced swimming test(FST)to confirm antidepressant dose of Chaigui Fang extract in the main pharmacodynamics experiment.Then,the confirm dose apply to rat chronic unpredictable mild stress(CUMS)model of depression to specific its antidepressant effect.2.On the base of CUMS,studying CUMS stress and drug affect the ability of cognitive function and anxiety in rats by Morris water maze test and Elevated Plus Maze test.3.On the base of CUMS,studying CUMS stress and drug affect the ability of sexual function and gastrointestinal function by mating test,stool test,small intestine propulsion test and gastric emptying test.4.To establish the recurrent depressive rats model,selecting the core symptoms of depression sucrose consumption rate as evaluation parameters,studying Chaigui Fang extract whether have rebound phenomenon after withdrawal and its effect on the recrudescence of depressive-like symptom.Results: 1.The results of FST and TST show that the 1-5 doses of Chaigui Fang extract all could significantly reduce the immobility time(P < 0.01 or P < 0.05),combining the dose setting in repetitive dose toxicity testing,selecting dose 3 as middle dose in main pharmacodynamics experiment and set the high and low dose in accordance with equal ratio criterion.Under this dose,Chaigui Fang extract could significantly improve the weight loss,the reduce rate of sugar water preference and the weakenss of independent activity of CUMS model rats(P < 0.01 or P < 0.05).2.(1)The results of Morris water maze test show that Chaigui Fang extract could reduce the number of not-found the platform rats in day 1 on navigation period;significantly reduce explore latent periods(P < 0.01 or P < 0.05);increase the rating value of searching strategy in day 1-4 on navigation period;significantly increase the numbers across platform and distance percent during platform quadrant on space exploration period(P < 0.01 or P < 0.05).However the above is invalid under venlafaxine administration.(2)The results of Elevated Plus Maze test show that Chaigui Fang extract could significantly increase the times of the rats entering the open arms,the numbers of the rats entering the open arms,the distance of the rats entering the open arms,the numbers of rats probing,average speed,the total distance,the numbers of upright and reduce rats immobility time(P < 0.01 or P < 0.05).3.(1)The results of stool test,small intestine propulsion test and gastric emptying test show that Chaigui Fang extract could significantly improve CUMS-caused the increase of cacation and the reduce of fecal water content(P < 0.01 or P < 0.05);significantly reduce gastric remnant rate and increase small intestine propelling rate(P < 0.01 or P < 0.05);However the above is invalid even have negative effect under venlafaxine administration,reflecting venlafaxine has side effects of constipation and gastrointestinal decline.Chaigui Fang extract not only had no side effects but also has improve effect on above CUMS-caused gastroenteric symptom.(2)The results of mating test show that Chaigui Fang extract could significantly shorten climb back latency and increase the number of climb back(P < 0.01 or P < 0.05);increase the number of ejaculation,prolong ejaculation latency;However the above is invalid even have negative effect under venlafaxine administration,reflecting venlafaxine has side effects of lower sex drive.Chaigui Fang extract not only had no side effects but also has improve effect on sexual function.4.The results of depression recrudescence experiment show that compared with venlafaxine has rebound phenomenon,there on rebound phenomenon after Chaigui Fang extract A,B and A+B administration.Compared with the recurrence rate of venlafaxine group is 100 % after re-exposure to 2 weeks of CUMS,the recurrence rate of Chaigui Fang extract A+B group is 44.4 % and the recurrence rate of Chaigui Fang extract B group is 40 %,reflecting Chaigui Fang extract could prevent depressive-like symptom reappear to some extent.Conclusion: The dose screening and CUMS experiments indicate that Chaigui Fang extract has obvious antidepressant effect.And on the basis of that Chaigui Fang extract has three characteristics of antidepressant function:(1)Chaigui Fang extract could improve CUMS-caused depression rats concomitant with cognition impairment and anxiety;(2)On the basis of treatment of depression,Chaigui Fang extract have no venlafaxine-caused side effect of constipation,gastrointestinal decline and hyposexuality and improve the concomitant symptoms;(3)Chaigui Fang extract have no rebound phenomenon after withdrawal and could reduce depressive symptom recrudescence rate to some extent. |
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