Schizandrin A protects against cerebral ischemia-reperfusion injury by suppressing inflammation and oxidative stress and regulating the AMPK/Nrf2 pathway regulation.

Inflammation and oxidative stress are considered major factors in the pathogenesis of ischemic stroke. Increasing evidence has demonstrated that Schizandrin A (Sch A), a lignin compound isolated from Schisandra chinesnesis, exhibits prominent anti-inflammatory and antioxidant activities. In this study, we investigated the antiinflammatory and antioxidant effects of Sch A against cerebral ischemia/reperfusion (I/R) injury as well as the underlying molecular mechanisms. Sch A treatment significantly improved the neurological score and reduced infarct volume 24 h after reperfusion. It dose-dependently inhibited the expression of cyclooxygenase-2 and inducible nitric oxide synthase, reduced the release of pro-inflammatory cytokines (tumor necrosis factor-alpha interleukin [IL]-1 beta and IL-6), and increased anti-inflammatory cytokines (transforming growth factor-beta and interleukin-10). Furthermore, it increased the activity of superoxide dismutase and catalase, decreased reactive oxygen species production and 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine levels. Transcription of nuclear factor erythroid 2-related factor 2 (Nrf2) and downstream genes (heme oxygenase-1 and NAD[P]H: quinone oxidoreductase 1) increased. Knockdown of Nrf2 by siRNA inhibited the neuroprotective effects of Sch A. In addition, Sch A increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) both in vivo and in vitro. Activation of the Nrf2 pathway as well as the protective effects of Sch A in an oxygen and glucose deprivation-induced injury model was abolished by AMPK knockdown. Our study indicates that Sch A protects against cerebral I/R injury by suppressing inflammation and oxidative stress, and that this effect is regulated by the AMPK/Nrf2 pathway.