Astragaloside IV ameliorates neuroinflammationinduced depressive-like behaviors in mice via the PPARγ/NF-κB/NLRP3 inflammasome axis

Major depressive disorder is a common but devastating mental disorder, and recent evidence shows that neuroinflammation may play a pivotal role in the etiology of depression. Astragaloside IV (AS-IV) is an active component purifed from Astragalus membranaceus (Fisch) Bge, which has shown anti-inflammatory, anti-oxidative and anti-apoptotic effects. In this study, we explored whether AS-IV produced antidepressant effects via its inhibition of neuroinflammation in mouse models of depression. Depressive-like behaviors including decreased sucrose consumption, reduced locomotor activity and increased immobility time were induced in mice using repeated restraint stress (RRS). We found that administration of AS-IV (16, 32 and 64 mg·kg^-1·d^-1, ig) significantly attenuated RRS-induced depressive-like behaviors. Furthermore, AS-IV administration significantly reduced the levels of TNF-α and IL-1β, increased PPARγ expression and GSK3β phosphorylation, decreased NF-κB phosphorylation, and reduced NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and caspase-1 p20 generation in the hippocampus of the mice. LPS-induced depression-like behaviors were induced by LPS injection (1 mg·kg^-1·d^-1, ip), which were ameliorated by administration of AS-IV (20, 40 mg·kg^-1·d^-1, ig). The results of the LPS-induced mouse model were in accordance with those acquired from the RRS-induced mouse model: LPS injection significantly increased TNF-α and IL-1β expression in the mouse hippocampus, which was reversed by administration of AS-IV. Moreover, administration of AS-IV significantly increased PPARγ expression and GSK3β phosphorylation, and decreased NF-κB phosphorylation and NLRP3 inflammasome. These results suggest that AS-IV is a potential drug against depression, and its antidepressant effects are partially mediated by inhibition of neuroinflammation via the upregulation of PPARγ expression.