Icariin exerts an antidepressant effect in an unpredictable chronic mild stress model of depression in rats and is associated with the regulation of hippocampal neuroinflammation

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