Estrogen effects on complement-mediated brain injury in intracerebral hemorrhage

描述（由申请人提供）：脑出血（ICH）是一种常见且往往致命的卒中亚型，可导致幸存者出现严重的神经功能缺损。在过去的十年中，脑出血后脑损伤的机制已被确定。现在我们知道有几个过程导致了血块周围的脑损伤。这些包括凝血级联激活与凝血酶的生产，补体级联激活脑实质中，血红蛋白和铁诱导的毒性。尽管我们对ICH引起的损伤的认识有所增加，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。我们的初步数据表明，雌激素可减少小鼠和大鼠脑出血后的脑水肿。雌激素对心肌缺血再灌注损伤的保护机制尚不清楚，最近的研究表明雌激素可减轻补体介导的心肌缺血再灌注损伤。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。为了验证这些假设，我们将进行以下具体目标：1）确定雌激素是否减少ICH诱导的脑损伤; 2）确定雌激素是否可以减少膜攻击复合物的形成、红细胞溶解和铁超载; 3）确定雌激素是否减弱炎症反应。我们的总体目标是了解脑出血后雌激素诱导的神经保护机制。雌激素的急性应用可能为脑出血的治疗提供新的途径，因此了解雌激素保护脑出血的机制具有重要意义。由于脑出血和脑缺血中脑损伤的机制不同，因此不可能直接将脑缺血研究中的雌激素数据互换。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有力的脑保护作用。我们发现在脑出血前后给予雌激素可减少脑水肿。雌激素诱导的保护机制尚不清楚。最近的研究表明，雌激素可减轻补体介导的心脏缺血再灌注损伤。本研究主要探讨雌激素对脑出血后补体介导的脑损伤的影响。由于ICH诱导的损伤机制与缺血不同，因此确定雌激素在ICH中保护作用的潜在机制是重要的。

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.