Ginsenoside Rg1 ameliorates depressive-like behavior by inhibiting NLRP3 inflammasome activation in mice exposed to chronic stress

Microglia-mediated inflammatory process is recognized as a target in the treatment of depression. Ginsenoside Rg1 (GRg1), the active ingredient of traditional ginseng, regulates microglial phenotypes to resist stress-induced inflammatory responses. Here we used a mouse model of stress-induced depression to investigate the involvement of microglial Nod-like receptor protein 3 (NLRP3) in the antidepressant effects of GRg1. Male C57BL/6J mice were exposed to chronic mild stress (CMS) for three weeks, followed by intraperitoneal injection of GRg1 (20 mg/kg) or the antidepressant imipramine (20 mg/kg) for another three weeks. Depressive-like behaviors were assessed by sucrose preference test, forced swimming test, and tail suspension test. Microglial phenotypes were assessed in terms of morphological features and cytokine profiles; inflammasome activity, in terms of levels of complexes containing NLRP3, apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1; and neurogenesis, in terms of numbers of proliferating, differentiating, and mature neurons identified by immunostaining. GRg1 reduced abnormal animal behaviors caused by CMS, such as anhedonia and desperate behaviors, without affecting locomotor behaviors. GRg1 also reduced the number of ASC-specks, implying inhibition of inflammasome activation, which was associated with weaker activation of pro-inflammatory microglia. At the same time, GRg1 rescued impairment of hippocampal neurogenesis in vivo and in vitro, which correlated with modulation of microglial phenotypes. GRg1 exert antidepressant effects by preventing stress from activating the NLRP3 inflammasome in microglia, promoting a proneurogenic phenotype and allowing adult hippocampal neurogenesis.