FREE RADICAL INJURY IN REVERSIBLE BRAIN ISCHEMIA

中风是最常见的威胁生命的神经系统疾病。确实有 估计有200万中风幸存者(美国心脏协会， 1986年)，许多人需要昂贵的急性和慢性多学科护理。 尽管对生物化学、病理生理学和 临床表现为脑缺血，我们尚无有效的急性 为患者提供药物干预。 最典型的中风综合征是由动脉血栓闭塞引起的。 大脑中动脉。急性栓塞性闭塞通常发生在 通过内源性纤溶机制溶解血栓，允许 缺血组织的再灌流。矛盾的是，再灌注可能会导致 建议通过产生氧自由基来损伤人体。角色 自由基在急性缺血性神经元损伤中的作用仍然难以捉摸，主要是 由于测量各种短暂的自由寿命的技术困难 活体内的自由基物种。此外，可靠的局灶性脑缺血模型 很难确定。 这项研究计划的目的是阐明氧自由基的作用。 可逆局灶性缺血期间的自由基，通过表征其 缺血期间和缺血后的时间和空间特征 通过了解它们与已知兴奋性氨基酸的关系 以及一氧化氮的相关机制。未来几年将把重点放在 阐明自由基物种的特定靶点，包括其作用 急性缺血性损伤中的神经元线粒体。特别是这些 实验将结合这项成熟的技术，脑组织 微透析，建立可靠的大鼠局灶性脑缺血模型。这 实验设计允许原位回收稳定的自由基 加合物和药理物质的给药。引航员 研究已经证明了技术上的可行性。 更好地了解氧自由基在体内的作用 缺血性神经元死亡会导致高度特异的 外源性自由基清除剂或药理能力 操纵已知的调节因素。最终的结果将会减少 中风死亡率、发病率和财政成本。

Stroke is the most common life-threatening neurologic disease. There are an estimated 2.0 million stroke survivors (American Heart Association, 1986), many requiring costly acute and chronic multidisciplinary care. Despite increasing knowledge of the biochemistry, pathophysiology, and clinical manifestation of cerebral ischemia, we have no effective acute pharmacologic intervention to offer patients. The most typical stroke syndrome is caused by embolic occlusion of the middle cerebral artery. Acute embolic occlusion is commonly followed by resolution of the clot by endogenous fibrinolytic mechanisms, allowing for reperfusion of the ischemic tissue. Paradoxically, reperfusion may incur injury through the proposed production of oxygen free radicals. The role of free radicals in acute ischemic neuronal injury remains elusive, mostly due to the technical difficulty of measuring the various short-lived free radical species in vivo. Additionally, reliable focal ischemic models have been difficult to establish. The aim of this research proposal is to elucidate the role of oxygen free radicals during reversible focal ischemia, by characterizing their temporal and spatial characteristics during and after ischemic conditions and by understanding their relationship to known excitatory amino acids and nitric oxide related mechanisms. Latter years will focus on elucidating specific targets of free radical species including the role of neuronal mitochondria in acute ischemic damage. Specifically these experiments will couple the well established technique, brain tissue microdialysis, to a reliable focal ischemia model in the rat. This experimental design allows for the in situ recovery of stable free radical adducts, and the administration of pharmacological substances. Pilot studies have demonstrated technical feasiblity. A better understanding of the in vivo role of oxygen free radicals in ischemic neuronal death would lead to the development of highly specific exogenous free radical scavengers or the ability to pharmacologically manipulate known modulatory factors. The ultimate result would be reduced stroke mortality, morbidity and fiscal costs.