Increased NADPH oxidase-derived superoxide is involved in the neuronal cell death induced by hypoxia-ischemia in neonatal hippocampal slice cultures.
Increased NADPH oxidase-derived superoxide is involved in the neuronal cell death induced by hypoxia-ischemia in neonatal hippocampal slice cultures.
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DOI：
10.1016/j.freeradbiomed.2012.06.012
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发表时间：
2012-09-01
影响因子：
7.4
通讯作者：
Black, Stephen M.
中科院分区：
文献类型：
--
作者：
Lu, Qing;Wainwright, Mark S.;Harris, Valerie A.;Aggarwal, Saurabh;Hou, Yali;Rau, Thomas;Poulsen, David J.;Black, Stephen M.
关键词：
新生儿脑缺氧缺血（HI）导致神经元细胞死亡。以往的研究表明，活性氧（ROS）如超氧化物在这一过程中起着关键作用。然而，细胞来源尚未确定。在这项研究中，我们研究了烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶复合物在新生儿HI脑损伤中的作用，并阐明了其激活机制。大鼠海马切片暴露于氧葡萄糖剥夺（OGD）以模拟HI所见的条件。最初的研究证实了NADPH氧化酶衍生的超氧化物在与OGD相关的氧化应激中的重要作用。此外，NADPH氧化酶抑制剂apocynin抑制了ogd介导的凋亡细胞死亡的增加。NADPH氧化酶的激活依赖于p38丝裂原激活的蛋白激酶介导的磷酸化和p47phox亚基的激活。使用腺相关病毒反义结构选择性地降低p47phox在神经元中的表达，并表明这导致抑制与OGD相关的超氧化物和神经元细胞死亡的增加。我们还发现，在新生儿大鼠HI模型中抑制NADPH氧化酶或清除过氧化氢（H2O2）可减少脑损伤。因此，我们得出结论，NADPH氧化酶复合物的激活有助于HI期间的氧化应激，针对该复合物的治疗可以对新生儿HI相关的脑损伤表现出神经保护作用。
Neonatal brain hypoxia ischemia (HI) results in neuronal cell death. Previous studies indicate that reactive oxygen species (ROS) such as superoxide, play a key role in this process. However, the cellular sources have not been established. In this study we examined the role of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex in neonatal HI brain injury and elucidated its mechanism of activation. Rat hippocampal slices were exposed to oxygen glucose deprivation (OGD) to mimic the conditions seen in HI. Initial studies confirmed an important role for NADPH oxidase derived superoxide in the oxidative stress associated with OGD. Further, the OGD-mediated increase in apoptotic cell death was inhibited by the NADPH oxidase inhibitor, apocynin. The activation of NADPH oxidase was found to be dependent on the p38 mitogen-activated protein kinase mediated phosphorylation and activation of the p47phox subunit. Using an adeno-associated virus antisense construct to selectively decrease p47phox expression in neurons, and showed that this lead to inhibition both of the increase in superoxide and neuronal cell death associated with OGD. We also found that NADPH oxidase inhibition in a neonatal rat model of HI or scavenging hydrogen peroxide (H2O2) reduced brain injury. Thus, we conclude that activation of the NADPH oxidase complex contributes to the oxidative stress during HI and that therapies targeted against this complex could exhibit neuroprotection against the brain injury associated with neonatal HI.
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