Role of Hyperglycemia in Intracerebral Hemorrhage

描述(由申请人提供)：糖尿病与中风风险增加2-6倍有关，中风是导致死亡和成人残疾的主要原因。卒中常与脑出血(ICH)有关，脑出血是出血性卒中的主要事件，也可在最初的缺血事件后自发发生，尤其是在溶栓治疗期间。糖尿病和高血糖都与脑出血后较差的临床结果相关，包括早期和长期死亡率增加，接受组织纤溶酶原激活剂(TPA)治疗的中风患者出现症状性脑出血，以及血肿量和血肿扩大，这些都是导致较差临床结果的重要和独立的决定因素。虽然大量的临床资料表明糖尿病和高血糖是临床预后较差的因素，而且近50%的急性卒中患者入院时就有高血糖，但葡萄糖对脑出血的影响及其相关机制尚不清楚。此外，关于降糖在脑出血中的临床益处的信息是有限的，也是有争议的，并且潜在的降糖治疗窗口是未知的。最近，我们报道了在脑出血的啮齿动物模型中，高血糖增加了血肿的形成，这种反应是由血浆激肽释放酶介导的。这种反应的机制包括葡萄糖敏感的血浆激肽释放酶介导的抑制血小板激活，这干扰了胶原诱导的GPVI受体的激活。这些研究揭示了血浆激肽释放酶在抑制血小板聚集中的新功能，这是脑血管损伤后建立止血的早期事件。在初步研究中，我们已经证明，在tPA和高血压诱导的自发性脑出血模型中，高血糖也会增加血肿面积，我们已经开始绘制血浆激肽释放酶抑制血小板活化的功能域。这些令人兴奋的发现表明，血浆激肽释放酶的作用是葡萄糖敏感的，这种酶在凝血系统中具有以前未被认识到的作用。这笔赠款将在一系列临床前研究中，利用血糖控制和抑制PK以减少脑出血的新策略来研究潜在的治疗机会，以开发和表征使用多种实验模型和分子干预的结果。介导血浆激肽释放酶作用的机制将通过鉴定该蛋白上介导抗血小板作用的结构域来确定。 我们已经证明，这一效应不需要血浆激肽释放酶的催化活性。由于与脑出血相关的主要并发症是其对水肿的影响，我们将研究胰岛素和血浆激肽释放酶抑制在预防和逆转脑出血所致水肿方面的作用。这笔赠款将检验这样一种假设，即血浆激肽释放酶对止血和血肿周围水肿的直接作用是糖尿病和高血糖患者脑出血预后差的原因之一。

DESCRIPTION (provided by applicant): Diabetes is associated with a 2 to 6-fold increased risk of stroke, which is a leading cause of mortality and adult disability. Stroke is often associated with intracerebral hemorrhage (ICH), which occurs as the primary event in hemorrhagic stroke and can also occur spontaneously following an initial ischemia event, especially during thrombolytic intervention. Both diabetes and hyperglycemia are associated with worse clinical outcomes following ICH, including increased early and long-term mortality, occurrence of symptomatic ICH in stroke patients treated with intravenous tissue plasminogen activator (tPA), and increased hematoma volume and expansion, which are significant and independent determinants of poor clinical outcomes. Although a large amount of clinical data has associated diabetes and hyperglycemia with poor clinical outcomes, and nearly 50% of all acute stroke patients have hyperglycemia upon admission, the effects of glucose and its related mechanisms on ICH are poorly understood. Moreover, information on the clinical benefit of glucose lowering in ICH is limited and controversial, and the potential therapeutic window for glucose lowering is unknown. Recently we have reported that hyperglycemia increases hematoma formation in rodent models of ICH and that this response is mediated by plasma kallikrein. The mechanisms for this response involved a glucose sensitive plasma kallikrein-mediated inhibition of platelet activation, which interfered with collagen-induced GPVI receptor activation. These studies have revealed a novel function of plasma kallikrein in the inhibition of platelet aggregation, which is an early event in establishing hemostasis following cerebral vascular injury. In preliminary studies, we have demonstrated that hyperglycemia also increases hematoma area in both tPA and in hypertension-induced models of spontaneous ICH, and we have begun to map the functional domain on plasma kallikrein that is responsible for its inhibitory effects of platelet activation. These exciting findings have suggested that plasma kallikrein actions are glucose sensitive and that this enzyme has previously unrecognized effects in the coagulation system. This grant will examine the potential therapeutic opportunities using glucose control and new strategies to inhibit PK to reduce ICH in a series of preclinical studies to develop and characterize findings using multiple experimental models and molecular interventions. The mechanisms that mediate the effects of plasma kallikrein will be characterized by identifying the structural domain on this protein that mediates this anti-platelet effect, which we have shown does not require plasma kallikrein's catalytic activity. Since a major complication associated with ICH is its effects on edema, we will examine the effects of insulin and plasma kallikrein inhibition on the prevention and reversal of ICH-induced edema. This grant will examine the hypothesis that the direct effects of plasma kallikrein on hemostasis and peri-hematomal edema contribute to the poor ICH outcomes in diabetes and hyperglycemia.