Mechanisms of early brain injury after subarachnoid hemmorrhage

蛛网膜下腔出血后早期脑损伤的机制

• 批准号: 8703823
• 负责人: GUOHUA XI
• 金额: $ 33.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703823
• 关键词: Acute; Attenuated; Biliverdine; Blood; Blood - brain barrier anatomy; Brain; Brain Edema; Brain Injuries; Brain hemorrhage; Carbon Monoxide; Cell Death; Cerebral Ischemia; Cerebral hemisphere hemorrhage; Cerebrovascular Circulation; Cerebrum; Cessation of life; Chelating Agents; Clinical; Coagulation Process; Cognitive deficits; Complement; Complement 3; Complement Activation; Complement Membrane Attack Complex; Cytolysis; Data; Deferoxamine; Development; Edema; Erythrocytes; Female; Goals; Heme; Hemoglobin; Hour; Hydrocephalus; Injury; Intracranial Hypertension; Iron; Iron Chelation; Iron Overload; Ischemia; Knowledge; Lead; Modeling; Mus; Neurologic; Neurons; Outcome; Oxidative Stress; Oxygenases; Patients; Perforation; Perfusion; Play; Protein Isoforms; Proteins; Quality of life; Rattus; Reporting; Research; Role; Stroke; Subarachnoid Hemorrhage; Subarachnoid Space; Surface; Survivors; Testing; Vasospasm; aged; brain cell; brain tissue; complement system; experience; functional outcomes; functional status; heme oxygenase-1; improved; intraventricular hemorrhage; male; mortality; neurotoxicity; therapeutic target

DESCRIPTION (provided by applicant): Subarachnoid hemorrhage (SAH) is a common subtype of stroke and the mortality rate is high (~35%) in the first several days. The causes of early brain injury following SAH are complicated including brain edema formation, blood-brain barrier disruption, increased intracranial pressure/brief global cerebral ischemia, and neurotoxicity caused by blood components. Research suggests that early brain injury following SAH is a primary therapeutic target. It is well known that the amount of blood released during SAH correlates with neurological deficits and poor clinical outcome. Although hemoglobin has been intensively studied as a potent factor for delayed vasospasm in SAH, the role of hemoglobin and its degradation products (especially iron) in SAH-induced early brain injury is not well studied. Our recent studies have demonstrated: 1) Brain iron overload occurs in a rat model of SAH; 2) Deferoxamine, an iron chelator, reduces SAH-induced iron overload, oxidative stress and mortality; 3) The complement cascade is activated and membrane attack complex levels are increased in the brain after experimental SAH which may play a role in erythrocyte lysis, iron overload and brain injury. However, major gaps in our knowledge regarding complement activation, erythrocyte lysis, brain iron overload and early brain injury after SAH need to be filled. In this application, therefore, we propose to examine the following Specific Aims: 1) To determine whether deferoxamine attenuates SAH-induced brain edema, blood-brain barrier disruption, hydrocephalus and vasospasm, major factors in SAH outcome; 2) To determine whether blocking complement activation reduces erythrocyte lysis, brain iron accumulation and brain injury after SAH. The purpose of our project is to examine mechanisms of early brain injury after SAH. Data from the proposed studies may lead to new therapies for SAH. The long-term goal of our studies is to limit brain damage in SAH patients.

描述(申请人提供)：蛛网膜下腔出血(SAH)是中风的一种常见亚型，最初几天的死亡率很高(~35%)。SAH后早期脑损伤的原因很复杂，包括脑水肿形成、血脑屏障破坏、颅内压升高/短暂的全脑缺血以及血液成分引起的神经毒性。研究表明，SAH后的早期脑损伤是主要的治疗目标。众所周知，蛛网膜下腔出血期间释放的血量与神经功能缺失和不良的临床结果相关。虽然血红蛋白作为蛛网膜下腔出血后迟发性血管痉挛的一个重要因素已被广泛研究，但关于血红蛋白及其降解产物(尤其是铁)在蛛网膜下腔出血所致早期脑损伤中的作用尚未得到很好的研究。我们最近的研究表明：1)SAH大鼠模型发生脑铁超载；2)铁络合剂去铁胺可降低SAH引起的铁超载、氧化应激和死亡率；3)实验性SAH后脑内补体级联被激活，膜攻击复合体水平增加，这可能在红细胞溶解、铁超载和脑损伤中起作用。然而，我们在补体激活、红细胞溶解、脑铁超载和SAH后早期脑损伤方面的主要知识空白需要填补。因此，在这一应用中，我们建议检查以下具体目标：1)确定去铁胺是否可以减轻SAH所致的脑水肿、血脑屏障破坏、脑积水和血管痉挛，这些都是SAH预后的主要因素；2)确定阻断补体激活是否减少了SAH后的红细胞溶解、脑铁蓄积和脑损伤。本课题旨在探讨蛛网膜下腔出血后早期脑损伤的机制。来自拟议研究的数据可能会导致SAH的新疗法。我们研究的长期目标是限制SAH患者的脑损伤。