Ephedrine ameliorates cerebral ischemia injury via inhibiting NOD-like receptor pyrin domain 3 inflammasome activation through the Akt/GSK3β/NRF2 pathway

Abstract

Ischemic stroke is a leading cause of death and long-term disability worldwide. The aim of this study is to explore the potential function of ephedrine in ischemic stroke and the underlying molecular mechanism. A middle cerebral artery occlusion (MCAO) rat model was established. The potential effects of ephedrine on MCAO rats and LPS-stimulated BV2 microglial cells were evaluated. Ephedrine reduced the infarct volume, cell apoptosis, brain water content, neurological score, and proinflammatory cytokines (TNF-α and IL-1β) production in MCAO rats. Ephedrine treatment also suppressed TNF-α and IL-1β production and NOD-like receptor pyrin domain 3 (NLRP3) inflammasome activation in BV2 microglial cells. The expression of NLRP3, caspase-1, and IL-1β was suppressed by ephedrine. Moreover, ephedrine treatment increased the phosphorylation of Akt and GSK3β and nuclear NRF2 levels in LPS-treated BV2 microglial cells. Meanwhile, LY294002 attenuated the inhibitory effects of ephedrine on NLRP3 inflammasome activation and TNF-α and IL-1β production. In addition, the level of pAkt was increased, while NLRP3, caspase-1, and IL-1β were decreased by ephedrine treatment in MCAO rats. In conclusion, ephedrine ameliorated cerebral ischemia injury via inhibiting NLRP3 inflammasome activation through the Akt/GSK3β/NRF2 pathway. Our results revealed a potential role of ephedrine in ischemic stroke treatment.