Neuroprotective effect of cajaninstilbene acid against cerebral ischemia and reperfusion damages by activating AMPK/Nrf2 pathway

INTRODUCTION: Ischemic stroke is one of the leading causes of death worldwide. Recently, neuroprotection is regarded as an important preventative and therapeutic strategy for ischemic stroke. Cajaninstilbene acid (CSA), a unique stilbenoid with a styryl group, is a potential neuroprotective agent. OBJECTIVES: Hence, this study aimed to evaluate the neuroprotective effect and molecular mechanism of CSA against cerebral ischemia/reperfusion (I/R) damages. METHODS: Cerebral ischemia was modeled by oxygen and glucose deprivation (OGD) in SH-SY5Y cells or transient intraluminal suture middle cerebral artery occlusion (MCAO) in rats, and tert-butyl hydroperoxide (t-BHP) was used to induce oxidative stress in SH-SY5Y cells. CSA (2.5, 5 mg/kg) was intraperitoneally given upon reperfusion after 2 h of MCAO. The signaling pathways were analyzed by Western blotting and inhibitor blocking. RESULTS: CSA possessed significant neuroprotective activity, as evidenced by the reduced cell death in OGD/R or t-BHP injured SH-SY5Y cells, and decreased infarct volume and neurological deficits in MCAO/R rats. Further studies indicated that the protective effect was achieved via the antioxidant activity of CSA, which decreased the oxidative stress and its related mitochondrial dysfunction in SH-SY5Y cells. Notably, Nrf2 was activated in SH-SY5Y cells and MCAO/R rats by CSA, and the inhibition of Nrf2 by brusatol weakened CSA-mediated neuroprotection. Furthermore, after applying a series of kinase inhibitors, CSA-induced Nrf2 activation was markedly inhibited by BML-275 (an AMPK inhibitor), implying that AMPK was the dominant kinase to regulate the Nrf2 pathway for CSA’s neuroprotective effects with enhanced AMPK phosphorylation observed both in vivo and in vitro. CONCLUSION: CSA exerted neuroprotection via activating the AMPK/Nrf2 pathway to reduce I/R-induced cellular oxidative stress and mitochondrial disfunction. CSA could be a potential neuroprotective drug candidate for the treatment of ischemic stroke.