Autophagy in neonatal hypoxia ischemic brain is associated with oxidative stress.
Autophagy in neonatal hypoxia ischemic brain is associated with oxidative stress.
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DOI：
10.1016/j.redox.2015.06.016
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发表时间：
2015-12
期刊：
影响因子：
11.4
通讯作者：
Black SM
中科院分区：
文献类型：
--
作者：
Lu Q;Harris VA;Kumar S;Mansour HM;Black SM
自噬在新生儿脑缺氧缺血（hypoxia ischemia，HI）时被激活，但其激活机制及其在HI相关神经元死亡中的作用尚不清楚。我们以前已经表明，活性氧（ROS）来源于烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶在HI介导的神经细胞死亡中起重要作用。因此，本研究的目的是确定ROS是否参与HI介导的新生儿脑损伤中自噬的激活，并确定这是一种保护性途径还是有害途径。最初的电子显微镜数据表明，自噬体的形成是升高的P7海马切片培养暴露于氧-葡萄糖剥夺（OGD）。这与LC 3 II mRNA和蛋白水平的增加相对应。自噬抑制剂，3-甲基腺嘌呤（3-MA）有效地减少LC 3 II水平和自噬体形成海马切片培养暴露于OGD。神经元细胞死亡显著减弱。最后，我们发现，使用夹竹桃麻素或gp 91 ds-tat的NADPH氧化酶的药理学抑制分别降低了海马切片培养物和大鼠脑中的自噬。因此，我们的研究结果表明，自噬的激活有助于新生儿HI脑损伤，这是氧化应激依赖性的。我们发现，自噬是通过NADPH氧化酶在新生儿HI上调。我们表明，抑制自噬是新生儿HI的神经保护。我们发现，激活增强新生儿HI中的神经元细胞死亡。
Autophagy is activated when the neonatal brain exposed to hypoxia ischemia (HI), but the mechanisms underlying its activation and its role in the neuronal cell death associated with HI is unclear. We have previously shown that reactive oxygen species (ROS) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase play an important role in HI-mediated neuronal cell death. Thus, the aim of this study was to determine if ROS is involved in the activation of autophagy in HI-mediated neonatal brain injury and to determine if this is a protective or deleterious pathway. Initial electron microscopy data demonstrated that autophagosome formation is elevated in P7 hippocampal slice cultures exposed to oxygen–glucose deprivation (OGD). This corresponded with increased levels of LC3II mRNA and protein. The autophagy inhibitor, 3-methyladenine (3-MA) effectively reduced LC3II levels and autophagosome formation in hippocampal slice cultures exposed to OGD. Neuronal cell death was significantly attenuated. Finally, we found that the pharmacologic inhibition of NADPH oxidase using apocynin or gp91ds-tat decreased autophagy in hippocampal slice cultures and the rat brain respectively. Thus, our results suggest that an activation of autophagy contributes to neonatal HI brain injury this is oxidative stress dependent. We show that autophagy is upregulated via NADPH oxidase in neonatal HI. We show that inhibiting autophagy is neuroprotective in neonatal HI. We show that activating enhances neuronal cell death in neonatal HI.