OXIDATIVE STRESS AND NEURONAL INJURY IN CEREBRAL ISCHEMIA

最近的研究表明，氧自由基，例如 超氧化物，羟基和一氧化氮，参与神经元 脑缺血和再灌注后的细胞死亡。 我们有 证明了脑梗死和神经功能缺损 在转基因小鼠中， 人铜锌超氧化物歧化酶（CuZn-SOD）活性 对非转基因的同窝出生的孩子。 其他研究 暗示程序性细胞死亡（凋亡）的发生 通过脑损伤后的核小体间DNA片段化 缺血大量的细胞培养研究表明， 氧化应激在程序性细胞死亡中起作用， 过表达的抗氧化剂基因如bcl-2或具有 超氧化物歧化酶可以通过 凋亡途径 我们的假设是大脑引起的氧化应激 缺血再灌注参与神经细胞死亡 通过坏死和凋亡途径。 是我们的宗旨 为了验证我们的假设，使用过表达人类 CuZn-SOD（SOD-1）和不含CuZn-SOD（SOD-1）的敲除突变体（纯合子） 或（杂合的）SOD-α活性的一半。 由于线粒体 是已知的氧自由基生产的网站，我们也 假设线粒体氧化应激增加， 线粒体毒素或者是 敲除突变体中的线粒体锰SOD（SOD-2）将 增加神经元对坏死和/或凋亡敏感性 脑缺血再灌注后。 为了解剖 一氧化氮在缺血性脑损伤中的作用 SOD-1转基因的各种组合 并且将使用神经元NOS敲除突变体。 我们相信，这些独特而新颖的方法将提供 深入了解氧化机制的发病机制， 脑缺血后的坏死和凋亡， 再灌注

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.