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

Depression ranks among the most common neuropsychiatric disorders globally. Current studies examining the roles of inflammation and mitochondrial autophagy in the antidepressant efficacy of paeoniflorin (PF) are sparse. This study aimed to elucidate PF’s antidepressant mechanism by promoting autophagy and inhibiting NLRP3 inflammasome activation using chronic unpredictable mild stimulation (CUMS)-induced C57BL/6 mouse models in vivo and corticosterone (CORT)-induced HT22 cell models in vitro. Results demonstrated that PF enhanced the viability of HT22 cells following CORT exposure, restored mitochondrial membrane potential (MMP), reduced reactive oxygen species accumulation, increased LC3 fluorescence intensity, and suppressed inflammatory cytokine secretion and inflammation activation. Additionally, PF ameliorated depressive behaviors induced by CUMS and improved damage in hippocampal neurons. It also reduced the expression of NLRP3, ASC, Caspase-1, IL-1β, and the assembly of the NLRP3 inflammasome. Moreover, PF upregulated the expression of autophagy-related proteins in the hippocampus, facilitating the clearance of damaged mitochondria and enhancing autophagy. The role of autophagy in PF’s antidepressant effects was further confirmed through the use of the autophagy inhibitor 3-methyladenine (3-MA), which reduced the efficacy of PF. In conclusion, PF effectively improved depressive behaviors in CUMS-induced mice and reduced NLRP3-mediated inflammation both in vivo and in vitro, likely via the induction of autophagy.