Ginsenoside Rg1 ameliorates depression-like behaviors in mice by inhibiting astrocyte pyroptosis via Cx43-dependent restoration of mitophagy flux.

Abstract

BACKGROUND: Ginsenoside Rg1 (GRg1), a principal neuroactive constituent of ginseng, has demonstrated promising antidepressant potential. Beyond its well-documented roles in mitigating oxidative stress, suppressing neuroinflammation, and protecting mitochondrial function, our study further demonstrates that GRg1 exerts its protective effects on the organism by upregulating the expression of connexin 43 (Cx43) in astrocytes. However, it remains unknown whether Cx43 mediates the antidepressant effects of GRg1 by regulating astrocyte pyroptosis. OBJECTIVE: This study aimed to elucidate the role of the Cx43-mitophagy-pyroptosis axis in the antidepressant mechanism of GRg1. METHODS: The model of depression was established using an 8-week chronic unpredictable stress (CUS). The optimal therapeutic dose of GRg1 was determined in vivo. Subsequently, we employed Western blotting, immunofluorescence, and fMRI to assess the effects of GRg1 on Cx43 expression and its protective effects on astrocytes. The causal role of Cx43 was verified using Cx43mice. Furthermore, we used corticosterone (CORT) to stimulate primary mouse astrocytes and conducted in vitro studies on the relationship between the "Cx43-mitophagy-pyroptosis" pathway and depression. CONCLUSION: GRg1 exerts its antidepressant effects by upregulating Cx43 expression, which restores mitophagy flux and facilitates the clearance of damaged mitochondria. This process, in turn, suppresses NLRP3 inflammasome activation and subsequent GSDMD-N-mediated astrocyte pyroptosis.