Role of Nitric Oxide in Subarachnoid Hemorrhage (SAH)

一氧化氮在蛛网膜下腔出血 (SAH) 中的作用

• 批准号: 7047912
• 负责人: JOSHUA B BEDERSON
• 金额: $ 31.45万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7047912
• 关键词: apoptosis; brain circulation; brain disorder chemotherapy; brain injury; cerebral ischemia /hypoxia; enzyme activity; enzyme inhibitors; laboratory rat; neurons; nitric oxide; nitric oxide synthase; nonhuman therapy evaluation; protein biosynthesis; subarachnoid hemorrhage; subarachnoid space; terminal nick end labeling; ultrasound blood flow measurement

DESCRIPTION (provided by applicant): Acute ischemic brain injury associated with Subarachnoid hemorrhage (SAH) is the most important determinant of outcome after SAH, but its mechanisms are poorly understood and effective treatments do not exist. The goal of this study is to characterize alterations in cerebral Nitric oxide (NO) levels and NO synthase (NOS) pathways after SAH and to determine their contribution to SAH-induced acute cerebral ischemic injury. Three primary hypotheses will be tested: 1) SAH is accompanied by acute triphasic alterations in the NO/NOS pathway that cause ischemic neuronal injury. 2) CBF changes and neuronal apoptosis can be used to study participation of NO in ischemic injury after SAH 3) Participation of NO in ischemic neuronal injury after SAH can be pharmacologically manipulated to decrease ischemic damage. In this proposal cerebral NO levels will be determined and activity and protein levels of NOS isozymes, endothelial (eNOS), neuronal (nNOS) and inducible (iNOS), will be studied after experimental SAH. The influence of NO levels on CBF and apoptosis in each putative phase of SAH will be examined. NO donors and NOS inhibitors will be administered to study the phase-dependent modulation of NO and NOS activity and expression on markers of cerebral ischemia. The experimental design will focus on three major questions: 1) What are the time dependent alterations in cerebral NO levels and their relation to NOS expression and activity during the first 72 hours after SAH? 2) Can changes in CBF and neuronal apoptosis be used as pathophysiological end points to study involvement of NO in ischemic injury after SAH? and 3) Can pharmacological modulation of cerebral NO levels and NOS expression and activity be used to decrease the intensity of ischemic neuronal injury after SAH? This study will increase our understanding of acute SAH induced cerebral ischemia and aid in the development of pharmacological treatments designed to prevent this ischemic injury.

描述（由申请人提供）：与亚蛛网膜下腔出血相关的急性缺血性脑损伤（SAH）是SAH后结果最重要的决定因素，但其机制知之甚少，并且不存在有效的治疗方法。这项研究的目的是表征SAH后脑一氧化氮水平（NO）水平（NO）水平的改变，并确定它们对SAH诱导的急性急性脑缺血性损伤的贡献。将测试三个主要假设：1）SAH伴随着导致缺血性神经元损伤的NO/NOS途径中的急性三个假设。 2）CBF的变化和神经凋亡可用于研究SAH后NO参与缺血性损伤的参与3）在SAH可以通过药理操纵后，NO参与缺血性神经元损伤以降低缺血性损害。在此提案中，将在实验性SAH后研究NOS同工酶，内皮（ENOS），神经元（NNOS）和诱导（INOS）的活性和蛋白质水平的水平。将检查NO水平对SAH的每个推定阶段中CBF和凋亡的影响。不会施用任何供体和NOS抑制剂来研究NO和NOS活性的相位依赖性调节以及对脑缺血标志物的表达。实验设计将集中在三个主要问题上：1）在SAH之后的前72小时内，大脑NO级别的时间依赖性变化以及它们与NOS表达和活动的关系是什么？ 2）CBF和神经元凋亡的变化是否可以用作研究SAH后NO参与缺血性损伤的病理生理终点？ 3）可以使用药理学调节NO水平，NOS表达和活性来降低SAH后缺血性神经元损伤的强度？这项研究将增加我们对急性SAH诱发的脑缺血的理解，并有助于开发旨在防止这种缺血性损伤的药理治疗。