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

Abstract

Abstract Depression is one of the most common neuropsychiatric disorders. The antidepressant mechanism of paeoniflorin (PF) is related to mitochondrial autophagy and inflammation has been little reported. This study aimed to investigate the anti-depressive mechanism of PF by promoting autophagy and inhibit NLRP3 activation in chronic unpredictable mild stimulation (CUMS) -induced C57BL/6 mice models in vivo and CORT-induced HT22 cell models in vitro. The reactive oxygen species (ROS) accumulation was quantified by DCFH-DA probe and detection of mitochondrial membrane potential with JC-1. Autophagy was evaluated in the hippocampus by investigating autophagosomes under transmission electron microscope (TEM) and detecting Beclin1, Parkin, P62 and LC3II/I through western blotting and immunofluorescence. NLRP3 inflammasome activation was evaluated by the expression of IL-1β, NLRP3, ASC and Caspase-1. Finally, the autophagy inhibitor 3-methyladenine (3-MA) was used to elucidate the role of autophagy in the antidepressant mechanism of PF. The results showed that PF could promote autophagic activation and cell viability of HT22 cells induced by CORT, and weaken the accumulation of ROS. Additionally, PF could alleviate CUMS induced depressive behavior and improve hippocampus damage. Moreover, it also increases the expression of autophagy related proteins in hippocampus and promote the elimination of damaged mitochondria and the generation of autophagosome. In addition, PF inhibit the expression of NLRP3 and the synthesis of NLRP3 inflammasome. The efficacy of PF was weakened by 3-MA treatment. In conclusion, PF improves CUMS-induced depressive behavior in mice and inhibits NLRP3 inflammatory mediated inflammation in vivo and in vitro, these effects may be mediated by PF induced autophagy.