Paeoniflorin alleviates depression by inhibiting the activation of NLRP3 inflammasome via promoting mitochondrial autophagy

Depression is among the most common neuropsychiatric disorders worldwide. Currently, there are only a few reports on whether inflammation and mitophagy are involved in the antidepressant mechanism of paeoniflorin (PF). This study aimed to investigate the antidepressant mechanism of PF by promoting autophagy and inhibiting NLRP3 activation in chronic unpredictable mild stimulation (CUMS)-induced C57BL/6 mouse models in vivo and in corticosterone (CORT)-induced HT22 cell models in vitro. The results showed that PF could enhance the activity of HT22 cells induced by CORT, restore mitochondrial membrane potential (MMP), reduce the accumulation of reactive oxygen species (ROS), enhance the fluorescence intensity of LC3, and inhibit the secretion of inflammatory cytokines and the activation of inflammation. Additionally, PF alleviated CUMS-induced depressive behavior and improved hippocampal damage. Additionally, PF alleviated CUMS-induced depression and improve hippocampal neuron damage. Furthermore, it also inhibits the expression of NLRP3, ASC, Caspase-1, IL-1β and the assembly of NLRP3 inflammasome. Moreover, PF increases the expression of autophagy-related proteins in hippocampus, and promoted the clearance of damaged mitochondria and the production of autophagy. Finally, the autophagy inhibitor 3-methyladenine (3-MA) was used to elucidate the role of autophagy in the antidepressant effects of PF. The efficacy of PF was reduced by 3-MA treatment. In conclusion, PF improved CUMS-induced depressive behavior in mice and inhibited NLRP3-mediated inflammation in vivo and in vitro, probably via PF-induced autophagy.