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
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
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DOI：
10.3109/10715762.2014.911853
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发表时间：
2014-07-01
影响因子：
3.3
通讯作者：
Sun, X.
中科院分区：
文献类型：
--
作者：
Meng, X.;Wang, M.;Sun, X.
三七皂苷R1（NGR 1）是从三七中分离得到的一种新的植物雌激素。我们最近发现NGR 1通过雌激素受体（ER）依赖性激活Akt/Nrf 2通路在体外显示出抗氧化应激的神经保护作用。然而，NGR 1是否对脑缺血再灌注（I/R）损伤具有神经保护作用尚不清楚。在这项研究中，我们使用了在体内和体外模型的脑I/R损伤，证明大脑中动脉闭塞和再灌注大鼠，以及氧-葡萄糖剥夺，然后在原代皮层神经元复氧（OGD/R）。这些模型用于评估NGR 1神经保护作用。用NGR 1（20 mg/kg; i.p.）显著改善神经功能结局并减少脑梗死体积。用NGR 1（25 μ M）预处理原代皮层神经元24小时可防止OGD/R诱导的细胞凋亡和氧化应激。NGR 1通过抑制线粒体膜电位破坏、caspase-3激活和DNA片段化来抑制细胞凋亡。NGR 1通过抑制NADPH氧化酶和NADPH衍生的超氧化物和抑制体内和体外丙二醛、蛋白质羰基和8-羟基脱氧鸟苷的产生来预防氧化应激。NGR 1通过增加ER α、ER β、磷酸化Akt、磷酸化GSK 3 β、核Nrf 2和HO-1在体内和体外的表达，诱导ER依赖性Akt/Nrf 2通路活化。用ICI-182780、LY 294002或Snpp预处理在体外消除NGR 1介导的抗氧化应激和细胞凋亡的神经保护作用。总之，NGR 1在体内和体外对脑I/R损伤具有神经保护作用。NGR 1神经保护的机制涉及通过ER依赖性激活Akt/Nrf 2途径抑制NADPH氧化酶活性和线粒体功能障碍。
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 mu M) 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 ER alpha, ER beta, phospho-Akt, phospho-GSK3 beta, nuclear Nrf2, and HO-1 expression in vivo and in vitro. Pretreatment with ICI-182780, LY294002, or Snpp abolished NGR1-mediated neuroprotection against oxidative stress and apoptosis in vitro. In conclusion, NGR1 showed neuroprotection against cerebral I/R injury in vivo and in vitro. The mechanism of NGR1 neuroprotection involves inhibition of NADPH oxidase activity and mitochondrial dysfunction via ER-dependent activation of Akt/Nrf2 pathways.