OXIDATIVE STRESS AND NEURONAL INJURY IN CEREBRAL ISCHEMIA

最近的研究表明，氧自由基，如 超氧化物、羟基和一氧化氮参与神经细胞 脑缺血再灌流后细胞死亡。我们有 证明了脑梗塞和神经功能障碍 在过度表达的转基因小鼠中显著改善 人铜锌超氧化物歧化酶(CuZn-SOD)活性的比较 给它们的非转基因后代。其他研究也有 牵涉到细胞程序性死亡(细胞凋亡)的发生 脑损伤后通过核小体间DNA断裂 缺血症。大量的细胞培养研究现在表明 氧化应激在程序性细胞死亡中发挥作用，因为 过表达的抗氧化剂基因，如bcl2或补充剂 超氧化物歧化酶可通过减少神经细胞死亡 细胞凋亡途径。 我们的假设是脑组织引起的氧化应激 脑缺血再灌流与神经细胞死亡 通过坏死和凋亡两条途径。这是我们的目标 用过量表达人类基因的转基因小鼠来验证我们的假设 CuZn-SOD(SOD-1)和不含NO的基因敲除突变体(纯合) 或者是(杂合子)超氧化物歧化酶活性的一半。因为线粒体 是已知的产生氧自由基的场所，我们还 假设线粒体氧化应激通过以下途径增加 要么是线粒体毒素，要么是由于 基因敲除突变体中的线粒体超氧化物歧化酶(sod-2)将 增加神经元对坏死和/或凋亡的易感性 在脑缺血和再灌流后。为了解剖 一氧化氮在缺血性脑损伤中的作用 具有超氧阴离子自由基、多种组合的SOD-1转基因 神经元型一氧化氮合酶基因敲除突变体将被使用。 我们相信，这些都是独特而新鲜的方法，将提供 对红斑狼疮发病机制的认识 脑缺血再灌注后的坏死和凋亡 再灌流。

Recent studies have demonstrated that oxygen radicals such as superoxide, hydroxyl, and nitric oxide, are involved in neuronal cell death following cerebral ischemia and reperfusion. We have demonstrated that cerebral infarction and neurological deficits are significantly ameliorated in transgenic mice overexpressing human CuZn-superoxide dismutase (CuZn-SOD) activity, as compared to their non-transgenic littermates. Other studies have implicated the occurrence of programmed cell death (apoptosis) through internucleosomal DNA fragmentation following cerebral ischemia. Numerous cell culture studies have now suggested that oxidative stress plays a role in programmed cell death, since an overexpressed antioxidant gene such as bcl-2 or a supplement with superoxide dismutase can reduce neuronal cell death through the apoptosis pathway. Our hypothesis is that oxidative stress induced by cerebral ischemia and reperfusion in involved in neuronal cell death through both the necrosis and apoptosis pathways. It is our aim to test our hypothesis using transgenic mice overexpressing human CuZn-SOD (SOD-1) and knockout mutants that contain no (homozygous) or one-half of (heterozygous) SOD-a activity. Since mitochondria is known to be the site of oxygen radicals production, we also hypothesize that increased oxidative stress to mitochondria by either mitochondrial toxins or by the null mutation of mitochondrial manganese SOD (sod-2) in knockout mutants will increase neuronal susceptibility to necrosis and/or apoptosis following cerebral ischemia and reperfusion. In order to dissect out the role of nitric oxide in ischemic brain injury associated with superoxide radicals, various combinations of SOD-1 transgenic and neuronal NOS knockout mutants will be employed. We believe these are unique and fresh approaches that will provide insights into the oxidative mechanisms of the pathogenesis of necrosis and apoptosis following cerebral ischemia and reperfusion.