Estrogen effects on complement-mediated brain injury in intracerebral hemorrhage

描述(由申请人提供)：脑出血(ICH)是一种常见的、通常是致命的中风亚型，会导致幸存者严重的神经功能障碍。在过去的十年中，脑出血后脑损伤的机制已经被确定。现在我们知道，凝块周围的几个过程导致了脑损伤。这些包括凝血级联激活与凝血酶的产生，补体在脑实质中的级联激活，以及血红蛋白和铁诱导的毒性。尽管我们对脑出血引起的损伤有了更多的了解，但目前仍然没有治疗方法。雌激素在实验性脑缺血中具有很强的神经保护作用。我们的初步数据显示，雌激素可以减轻小鼠和大鼠脑出血后的脑水肿。雌激素诱导心肌保护的机制尚不清楚，最近的一项研究表明雌激素可减轻补体介导的心脏缺血再灌注损伤。我们的数据使我们假设雌激素也可能限制脑出血后补体介导的脑损伤。为了验证这些假说，我们将承担以下具体目标：1)确定雌激素是否可以减少脑出血所致的脑损伤；2)确定雌激素是否可以减少膜攻击复合体的形成、红细胞溶解和铁超载；3)确定雌激素是否可以减轻炎症反应。我们的总体目标是了解雌激素诱导的脑出血后神经保护的机制。了解雌激素诱导的保护作用背后的机制非常重要，因为急性使用雌激素可能是治疗脑出血的一种新方法。由于脑出血和脑缺血的脑损伤机制不同，因此不可能直接调换来自脑缺血研究的雌激素数据。公共卫生相关性：雌激素已被证明在实验性脑缺血中具有强大的脑保护作用。我们发现，脑出血前或脑出血后给予雌激素可减轻脑水肿。雌激素诱导的保护机制尚不清楚。最近的一项研究表明，雌激素可以减轻补体介导的心脏缺血再灌注损伤。本研究旨在探讨雌激素在脑出血后补体介导的脑损伤中的作用。由于脑出血的损伤机制不同于脑缺血，因此确定雌激素在脑出血中保护作用的机制是很重要的。

DESCRIPTION (provided by applicant): Intracerebral hemorrhage (ICH) is a common and often fatal subtype of stroke that produces severe neurologic deficits in survivors. Mechanisms of brain injury after intracerebral hemorrhage have been identified during the past decade. Now we know that several processes are responsible for brain injury around the clot. These include coagulation cascade activation with thrombin production, complement cascade activation in the brain parenchyma, and hemoglobin- and iron-induced toxicity. Despite our increased knowledge of ICH-induced injury, there is still no current therapeutic treatment. Estrogen has been shown to be strongly neuroprotective in experimental cerebral ischemia. Our preliminary data show that estrogen reduces brain edema after ICH in mice and in rats. The mechanisms involved in estrogen-induced protection are unknown, a recent study demonstrates that estrogen reduces complement-mediated ischemia-reperfusion injury in heart. Our data lead us to hypothesize that estrogen may also limit complement-mediated brain injury after ICH. To test these hypotheses, we will undertake the following Specific Aims: 1) Determine whether estrogen reduces ICH-induced brain damage; 2) Determine whether estrogen can reduce membrane attack complex formation, erythrocyte lysis and iron overload; 3) Determine whether estrogen attenuates inflammatory response. Our overall goal is to understand the mechanisms of estrogen-induced neuroprotection after ICH. It is important to understand the mechanisms behind the estrogen-induced protective effects since acute use estrogen could be a new therapy for ICH. It is not possible to directly transpose data on estrogen from cerebral ischemia studies since the mechanisms of brain injury in ICH and cerebral ischemia are different. PUBLIC HEALTH RELEVANCE: Estrogen has been shown to confer strong brain protection in experimental cerebral ischemia. We have found that brain edema is reduced when estrogen is given before or after ICH. The mechanisms involved in estrogen-induced protection are unknown. A recent study demonstrates that estrogen reduces complement-mediated ischemia-reperfusion injury in heart. This study will focuses on the effects of estrogen on complement-mediated brain injury after ICH. It is important to determine the mechanisms underlying the protective effects of estrogen in ICH as the mechanisms of ICH-induced injury differ from ischemia.