Mechanism Of Anti-depressant Effects Of Agomelatine On Mice With Chronic Restraint Stress

Objective:To study the anti-depressant effect of Agomelatine(AGO)on Chronic Restraint Stress(CRS)induced mice,and preliminarily investigate its mechanisms.Methods:C57BL/6N mice were randomly divided into control(CON),CRS,agomelatine(AGO)and fluoxetine(FLX)group.Specifically,mice in the CON and CRS group were subjected to CRS and intragastric administration of 8.0 mL/kg saline daily,AGO and FLX group were administered to mice at doses of 60 mg/kg body weight/day and 15 mg/kg body weight/day.Drugs were administered half an hour before CRS regimen.After stress exposure,a battery of well-established behavioral tests aiming at measuring anxiety-like behavior(Open Field Test,OFT;Elevated Plus Maze,EPM)and depression-like behaviors(Sucrose Preference Test,SPT;Forced Swimming Test,FST)were conducted.Meanwhile,the expression BDNF/TrkB signaling pathway,apoptosis(such as Beclinl、LC3II and p62)and autophagy(such as Bcl2 and Bax markers were assessed using Western Blot or immunofluorescence.Results:(1)Compared with CON group,statistical analysis revealed that CRS resulted in retardation of the body weight gain starting with day 9.Behavioral tests showed that mice in the CRS group showed significant longer freezing time in FST and lower sucrose preference compared with the control mice.Unfortunately,no significant effect was observed in EPM and OFT.Meanwhile,Western Blot and immunofluorescence results showed that the expression of BDNF/TrkB,Beclinl%LC3Ⅱ and the ratio of Bc12/Bax were decreased,hippocampal p62 levels were increased.(2)Compared with CRS group,AGO can attenuate the depressive-like behavior that significantly appeared in both sucrose preference and forced swimming tests.Additionally,a noticeable upregulation of BDNF/TrkB,autophagy such as Beclinl and LC3Ⅱ,the ratio of Bcl2/Bax were indicated.An obvious decrease expression of p62 were observed in AGO administration mice.Conclusion:1.CRS-induced depressive-like behaviors and not anxiety-like behaviors.2.AGO can protect the CRS mice from depression.3.AGO may funnel its antidepressant effect through BDNF/TrkB signaling pathway,by maintaining essential autophagy and inhibiting excessive apoptosis.