FREE RADICAL INJURY IN REVERSIBLE BRAIN ISCHEMIA

可逆性脑缺血中的自由基损伤

• 批准号: 6187067
• 负责人: Nina J. Solenski
• 金额: $ 11.16万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6187067
• 关键词: NMDA receptors; adduct; biological signal transduction; brain cell; brain injury; cerebral ischemia /hypoxia; disease /disorder model; electron transport; enzyme activity; enzyme inhibitors; excitatory aminoacid; free radical oxygen; glutamate receptor; high performance liquid chromatography; histochemistry /cytochemistry; hydroxyl radical; laboratory rat; microdialysis; mitochondria; neurons; nitric oxide; nitric oxide synthase; oxidative phosphorylation; receptor expression; reperfusion

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.

脑卒中是最常见的威胁生命的神经系统疾病。 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。 尽管越来越多的生物化学，病理生理学， 临床表现为脑缺血，我们没有有效的急性 为患者提供药物干预。 最典型的中风综合征是由脑血栓闭塞引起的 大脑中动脉急性栓塞性闭塞通常伴随着 通过内源性纤维蛋白溶解机制溶解凝块， 缺血组织的再灌注。偶然的是，再灌注可能导致 建议通过氧自由基的产生来伤害。的作用 自由基在急性缺血性神经元损伤中的作用尚不清楚， 由于测量各种短寿命自由基的技术困难， 自由基物种在体内。此外，可靠的局灶性缺血模型 很难建立。 这项研究的目的是阐明无氧的作用， 自由基在可逆性局灶性缺血，通过表征其 缺血状态期间和之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 和一氧化氮相关的机制。未来几年将专注于 阐明自由基物质的特定靶点，包括 急性缺血性损伤中的神经元线粒体。特别是这些 实验将结合成熟的技术，脑组织 微透析，建立了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 加合物和药理学物质的给药。试点 研究表明了技术可行性。 更好地理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性的 外源性自由基清除剂或抗氧化能力 操纵已知的调节因子。最终的结果将是减少 中风死亡率、发病率和财政成本。

项目成果

Attenuation of free radical generation during reversible focal cerebral ischemia with the nitric oxide inhibitor, L-NAME (L-N(G)-nitro-L-arginine methyl ester).

使用一氧化氮抑制剂 L-NAME（L-N(G)-硝基-L-精氨酸甲酯）可减少可逆性局灶性脑缺血期间自由基的产生。

• DOI: 10.1016/s0006-8993(00)02088-6
• 发表时间: 2000
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Solenski,NJ;Kwan,A
• 通讯作者: Kwan,A