Agomelatine Softens Depressive-Like Behavior through the Regulation of Autophagy and Apoptosis

Depression is a common and disabling mental disorder with high recurrence rate. Searching for more effective treatments for depression is a long-standing primary objective in neuroscience. Agomelatine (AGO) was reported as an antidepressant with unique pharmacological effects. However, its effects and the underlying mechanism are still unclear. In this study, we sought to evaluate the antidepressant effects of AGO on the chronic restraint stress (CRS) mouse model and preliminarily investigate its effects on the gut microbial metabolites. The CRS model mice were established in 28 days with AGO (60 mg/kg/day, by oral) or fluoxetine (15 mg/kg/day, by oral) administration. The number of behavioral tests was conducted to evaluate the effect of AGO on depression-like behavior alleviation. Meanwhile, the expression of the BDNF/TrkB/pERK signaling pathway, apoptosis, autophagy, and inflammatory protein markers were assessed using western blot and immunofluorescence. Our findings show that AGO can attenuate the depressive-like behavior that significantly appeared in both sucrose preference and forced swimming tests. Additionally, a noticeable upregulation of autophagy including Beclin1 and LC3II, microglial activity marker Iba-1, and BDNF/TrkB/pERK signaling pathways are indicated. An obvious decreased expression of NF-κB, iNOS, and nNOS as well as apoptosis including Bax is observed in AGO administration mice. On the other hand, we found that AGO impacted the rebalancing of short-chain fatty acids (SCFAs) in mouse feces. Altogether, these findings suggest that AGO can exert antidepressant effects in a different molecular mechanism.