Hyperoside alleviates depressive-like behavior in social defeat mice by mediating microglial polarization and neuroinflammation via TRX1/NLRP1/Caspase-1 signal pathway.

The primary objective of this study was to investigate the potential pharmacological effects of Hyperoside (Hyp) extract on chronic social defeat stress (CSDS)-induced depression-like behavior in mice. We established CSDS mice to evaluate the antidepressant effects of Hyp. Additionally, We assessed the changes in neuroinflammatory factors in the TRX1/NLRP1/Caspase-1 signaling pathway using adeno-associated virus (AAV) and BV2 microglial cells. The expression levels of TRX1 protein and BDNF also increased by Hyp, while NLRP1 and Caspase-1 a significant decrease. Additionally, Hyp was found to inhibit TRX1 ubiquitination in the microglial inflammation model. In both in vivo and in vitro experiments, it was found that Hyp significantly promotes microglial polarization towards the M2 phenotype in the hippocampus and alleviates neuroinflammation, thereby improving depression-like behavior in CSDS mice. This is associated with the regulation of TRX1 ubiquitination, which inhibits the expression levels of NLRP1 and Caspase-1 proteins.