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

Abstract

Introduction and Objectives: Neuroprotection is an important strategy for ischemic stroke treatment. Cajaninstilbene acid (CSA), a unique stilbenoid with a styryl group, is a potential neuroprotective agent. Hence, t his 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.