OXIDATIVE STRESS AND NEURONAL INJURY IN CEREBRAL ISCHEMIA

脑缺血中的氧化应激和神经元损伤

• 批准号: 6356582
• 负责人: PAK H CHAN
• 金额: $ 18.7万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2002-09-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6356582
• 关键词: NMDA receptors; antioxidants; apoptosis; brain injury; cell death; cellular pathology; cerebral ischemia /hypoxia; cytotoxicity; free radical oxygen; gel electrophoresis; genetic strain; genetically modified animals; glutamates; laboratory mouse; neurons; nitric oxide; oxidative stress; reperfusion; superoxide dismutase; transfection

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.

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元 脑缺血和再灌注后的细胞死亡。 我们有 证明脑梗塞和神经系统缺陷 在过表达的转基因小鼠中明显改善 与人类cuzn-杀氧化剂歧化酶（Cuzn-Sod）活性相比 给他们的非转基因同窝。 其他研究也有 暗示了程序性细胞死亡的发生（凋亡） 通过核体核小体DNA碎片在大脑之后 缺血。现在，许多细胞培养研究表明 氧化应激在程序性细胞死亡中起作用，因为 过表达的抗氧化剂基因，例如Bcl-2或补充剂 超氧化物歧化酶可以通过降低神经元细胞死亡 凋亡途径。 我们的假设是脑诱导的氧化应激 与神经元细胞死亡有关的缺血和再灌注 通过坏死和凋亡途径。 这是我们的目标 使用过表达人的转基因小鼠检验我们的假设 Cuzn-Sod（SOD-1）和敲除突变体，其中含有（纯合） 或一半（杂合）SOD-A活性。 自线粒体以来 已知是氧自由基产生的位置，我们也是 假设增加对线粒体的氧化应激增加 线粒体毒素或通过无效的突变 敲除突变体中的线粒体锰酸酯（SOD-2）将 增加神经元对坏死和/或凋亡的敏感性 脑缺血和再灌注。 为了剖析 一氧化氮在相关的缺血性脑损伤中的作用 使用超氧化物自由基，SOD-1转基因的各种组合 将使用神经元NOS敲除突变体。 我们认为这些是独特而新鲜的方法，可以提供 洞悉对发病机理的氧化机制 脑缺血后的坏死和凋亡 再灌注。