Mechanisms of early brain injury after subarachnoid hemmorrhage

描述（由申请人提供）：蛛网膜下腔出血（SAH）是卒中的常见亚型，发病前几天死亡率高（约35%）。SAH后早期脑损伤的原因是复杂的，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后早期脑损伤是主要的治疗目标。众所周知，SAH期间的血液释放量与神经功能缺损和不良临床结果相关。虽然血红蛋白作为SAH延迟性血管痉挛的有力因素已被广泛研究，但血红蛋白及其降解产物（尤其是铁）在SAH诱导的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)脑铁超载发生在SAH大鼠模型中；2)铁螯合剂去铁胺可降低sah诱导的铁过载、氧化应激和死亡率；3)实验性SAH后脑内补体级联被激活，膜攻击复合物水平升高，可能在红细胞溶解、铁超载和脑损伤中起作用。然而，我们在补体活化、红细胞溶解、脑铁超载和SAH后早期脑损伤方面的知识空白需要填补。因此，在本应用中，我们建议检查以下具体目的：1)确定去铁胺是否减轻SAH诱导的脑水肿、血脑屏障破坏、脑积水和血管痉挛，这些是SAH结局的主要因素；2)确定阻断补体激活是否能减少SAH后红细胞溶解、脑铁积累和脑损伤。我们项目的目的是研究SAH后早期脑损伤的机制。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。

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.