Suppression of NADPH oxidase- and mitochondrion-derived superoxide by Notoginsenoside R1 protects against cerebral ischemia–reperfusion injury through estrogen receptor-dependent activation of Akt/Nrf2 pathways

作者：Xiangbao Meng, M. Wang, X. Wang, G. Sun, J Ye, Haiyang Xu, Xinyan Sun · 发表于：Free Radical Research · 年份：2014 · DOI：10.3109/10715762.2014.911853 · 被引用次数：110 · 研究领域：Ginseng Biological Effects and Applications、Sesame and Sesamin Research、Pomegranate: compositions and health benefits

Notoginsenoside R1 (NGR1) is a novel phytoestrogen that is isolated from Panax notoginseng. We have recently found that NGR1 showed neuroprotection in vitro against oxidative stress through estrogen receptor (ER)-dependent activation of Akt/Nrf2 pathways. However, whether NGR1 has neuroprotective effect against cerebral ischemia-reperfusion (I/R) injury in vivo is unknown. In this study, we used in vivo and in vitro models of cerebral I/R injury that demonstrate middle cerebral artery occlusion and reperfusion in rats, as well as oxygen-glucose deprivation followed by reoxygenation (OGD/R) in primary cortical neurons. These models were used to evaluate NGR1 neuroprotection. Three-day pretreatment with NGR1 (20 mg/kg; i.p.) significantly improved neurologic outcomes and reduced cerebral infarct volume. Pretreatment of primary cortical neurons with NGR1 (25 μM) for 24 h prevented apoptosis and oxidative stress induced by OGD/R. NGR1 inhibited apoptosis by inhibiting mitochondrial membrane potential disruption, caspase-3 activation, and DNA fragmentation. NGR1 prevented oxidative stress by suppressing NADPH oxidase- and mitochondrion-derived superoxide and inhibiting production of malondialdehyde, protein carbonyl, and 8-hydroxydeoxyguanosine in vivo and in vitro. NGR1 induced ER-dependent activation of Akt/Nrf2 pathways by increasing ERα, ERβ, phospho-Akt, phospho-GSK3β, nuclear Nrf2, and HO-1 expression in vivo and in vitro. Pretreatment with ICI-182780, LY294002, or Snpp abol...