Reduction of zinc accumulation in mitochondria contributes to decreased cerebral ischemic injury by normobaric hyperoxia treatment in an experimental stroke model.
Reduction of zinc accumulation in mitochondria contributes to decreased cerebral ischemic injury by normobaric hyperoxia treatment in an experimental stroke model.
复制标题
在实验性中风模型中，通过常压高氧治疗，线粒体中锌积累的减少有助于减少脑缺血损伤
DOI：
10.1016/j.expneurol.2015.04.005
复制
发表时间：
2015-10
影响因子：
5.3
通讯作者：
Liu KJ
中科院分区：
文献类型：
--
作者：
Dong W;Qi Z;Liang J;Shi W;Zhao Y;Luo Y;Ji X;Liu KJ
脑缺血会中断对受影响组织的氧气供应。我们以前的研究报道，常压高氧(NBO)可以将缺血性卒中大鼠半暗带内的间质氧分压(PO2)维持在生理水平，从而提供显著的神经保护作用。然而，NBO治疗半影区的机制尚不完全清楚。最近的研究表明，锌是细胞内和细胞间信号转导的重要媒介，在神经元中积聚，导致神经元缺血性损伤。在这项研究中，我们利用短暂性脑缺血大鼠模型，研究NBO是否可以调节锌在半影区的积累，并防止半影区组织中线粒体的损伤。结果显示，NBO可显著降低缺血区半影区锌染色阳性细胞数和锌染色强度，但对缺血区无明显影响。此外，从半影区分离的线粒体中锌的蓄积可被NBO或锌特异性螯合剂N，N，N‘，N’-四(2-吡啶甲基)乙二胺(TPEN)大大减弱。NBO或TPEN对脑缺血后半暗带线粒体膜电位有稳定作用。NBO或TPEN可显著减少缺血诱导的半影区组织线粒体细胞色素C的释放。这些发现证明了NBO神经保护的新机制，特别是对半暗带组织的保护，为NBO治疗急性缺血性中风的潜在临床益处提供了进一步的证据。
Cerebral ischemia interrupts oxygen supply to the affected tissues. Our previous studies have reported that normobaric hyperoxia (NBO) can maintain interstitial partial pressure of oxygen (pO2) in the penumbra of ischemic stroke rats at the physiological level, thus affording significant neuroprotection. However, the mechanisms that are responsible for the penumbra rescue by NBO treatment are not fully understood. Recent studies have shown that zinc, an important mediator of intracellular and intercellular neuronal signaling, accumulates in neurons and leads to ischemic neuronal injury. In this study, we investigate whether NBO could regulate zinc accumulation in the penumbra and prevent mitochondrial damage in penumbral tissue using a transient cerebral ischemic rat model. Our results showed that NBO significantly reduced zinc staining positive cells and zinc-staining intensity in penumbral tissues, but not in the ischemic core. Moreover, ischemia-induced zinc accumulation in mitochondria, isolated from penumbral tissues, was greatly attenuated by NBO or a zinc specific chelator, N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). NBO or TPEN administration stabilized the mitochondrial membrane potential in the penumbra after cerebral ischemia. Finally, ischemia-induced cytochrome C release from mitochondria in penumbral tissues was significantly reduced by NBO or TPEN treatment. These findings demonstrate a novel mechanism for NBO's neuroprotection, especially to penumbral tissues, providing further evidence for the potential clinical benefit of NBO for acute ischemic stroke.