BIOCHEMICAL MECHANISMS OF BRAIN INJURY

脑损伤的生化机制

基本信息

批准号：
3413427
负责人：
EARL F ELLIS
金额：
$ 15.95万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-04-01 至 1996-03-31
项目状态：
已结题

项目摘要

Previous experiments indicate that following experimental concussive brian injury oxygen free radicals produced during cyclooxygenase metabolism of arachidonic acid cause endothelial lesions, dilation, reduce responsiveness to hypocapnia and abnormal responsiveness to acetylcholine in acid cause endothelial lesions, dilation, reduced responsiveness to hypocapnia and abnormal responsiveness to acetylcholine in cerebral arterioles. We now have evidence that specific agonists, including acetylcholine and bradykinin, may be in part responsible for stimulating arachidonic acid metabolism following injury. We therefore wish to test the following hypotheses (see figure). Hypothesis 1: Following concussive brain injury receptor-mediated mechanisms contribute to an increase metabolism of polyunsaturated fatty acids and the production of oxygen radicals which cause cerebrovascular and brain dysfunction. Hypothesis 2: Pharmacologic inhibition of fatty acid metabolism, free radical production or free radical action will reduce the cerebrovascular dysfunction caused by traumatic brain injury (TBI). Our general aims are to understand 1) factors responsible for initiation and regulation of fatty acid metabolism following injury, 2) the pathways and products of this metabolism, 3) the cerebrovascular consequences of increased fatty acid metabolism and radical production and 4) how pharmacologic intervention can prevent, reduce or reverse the injury process. To accomplish our aims we will utilize microscopy and radioimmunoassay to correlate simultaneous in vivo arteriolar diameter responses and in vivo cyclooxygenase and lipoxygenase synthetic responses. We will also employ gas chromatography/mass spectrometry to identify and measure fatty acids and their metabolites. Little is known about regulation of the changes in fatty acid metabolism and the concomitant cerebrovascular consequences of increased oxygen radical production following brain injury. The proposed studies will address these problems and are consistent with our long term goal of elucidating chemical mediators of, and therapeutic agents for, brain injury.

先前的实验表明，以下实验脑震荡的Brian损伤氧自由基在花生四烯酸的环氧合酶代谢引起内皮病变，扩张，降低对低碳酸痛和异常的反应性酸中对乙酰胆碱的反应性会导致内皮病变，扩张，降低对低碳酸氢症和异常的反应性对脑动脉中乙酰胆碱的反应。我们现在有证据表明，包括乙酰胆碱和包括的特定激动剂松曲蛋白，可能部分负责刺激蛛网膜菌受伤后的酸代谢。因此，我们希望测试以下假设（见图）。假设1：以下脑震荡脑损伤受体介导的机制有助于多不饱和脂肪酸和产生引起脑血管和大脑的氧自由基功能障碍。假设2：脂肪酸的药理抑制代谢，自由基生产或自由基动作将减少受外伤引起的脑血管功能障碍受伤（TBI）。我们的总体目的是了解1）负责的因素脂肪酸代谢的起始和调节之后受伤，2）这种新陈代谢的途径和产物，3）脂肪酸代谢增加的脑血管后果和根本生产和4）药物干预如何防止，减少或扭转伤害过程。完成我们的目的我们将利用显微镜和放射免疫测定法进行关联同时体内小动脉直径和体内环氧合酶和脂氧合酶合成反应。我们也会采用气相色谱/质谱识别和测量脂肪酸及其代谢产物。关于调节脂肪酸的变化知之甚少代谢和伴随的脑血管后果脑损伤后氧自由基产生增加。这拟议的研究将解决这些问题并保持一致我们的长期目标是阐明的化学介质和脑损伤的治疗剂。