Icariin,a flavonoid extracted from the traditional Chinese herb Herba Epimedii that can cross the blood-brain barrier freely,has been demonstrated to inhibit neuroinflammation and attenuate oxidative stress damage.Our previous studies have demonstrated that icariin exerts an antidepressant-like activity in a social defeat mouse model.But it is unknown whether icariin is beneficial to therapy of depression by modulating oxidative stress balance and neuroinflammation.This study aimed to investigate the effects of icariin on the depressive-like behaviors in an unpredictable chronic mild stress (CMS) model of depression in rats.Rats exposed to CMS showed behavioral deficits in physical state,sucrose preference test (SPT) and forced swimming test (FST) and exhibited a significant increase in oxidative-nitrosative stress markers,inflammatory mediators ((tumor necrosis factor-a (TNF-a) and interleukin-1β (IL-1β)) along with activation of nuclear factor kappa B (NF-κB) signaling pathway and enhanced inducible nitric oxide synthase (iNOS) protein expression in hippocampus,which be reversed by chronic treatment with icariin (20 or 40mg/kg).Interestingly,icariin negatively regulated the activation of nod-like receptor protein 3 (NLRP3) inflammasome/caspase-1/IL-1 β axis in the hippocampus of CMS model rats.These results confirmed that icariin exerted antidepressant-like effects,which may be mediated,at least in part,by enhancement of antioxidant status and anti-inflammatory effect of the brain tissue via inhibition of NF-κB signaling activation and NLRP3-inflammasome/caspase-1/IL-1β axis.Our findings may provide a new aspect to understand the antidepressant action of icariin,which is targeted on the NLRP3-inflammasom in brain.