NOVEL INHIBITORS OF BRAIN ISCHEMIA

描述（由申请人提供）：中风是美国死亡和残疾的主要原因，每年影响约75万人。中风的特点是部分或完全缺乏血液流向大脑的某个区域，该区域失去氧气和营养，成为缺血和受影响区域的核心。通过使用溶栓药物及时重建缺血脑血流是目前急性脑卒中的治疗策略。然而，这种方法的有效性受到脑出血（ICH）风险增加的限制。结果表明，在维持外源性凝血机制的同时，选择性抑制内源性凝血途径可能有效地恢复血管通畅，同时预防脑出血风险的增加。我们之前的研究表明，淀粉样蛋白g蛋白前体（APP）的重组Kunitz蛋白酶抑制剂（KPI）结构域是内源性凝血途径中XIa和IXa因子的有效抑制剂，而对外源性凝血途径及其过程的影响很小。我们认为，这种KPI区域的选择性抑制活性可能非常适合于治疗急性缺血性脑损伤。在第一阶段，我们将在局灶性缺血性损伤小鼠模型中测量合成KPI域治疗对减少纤维蛋白沉积和改善行为表现的影响。

DESCRIPTION (provided by applicant): Stroke is a leading cause of death and disability in the United States affecting approximately 750,000 individuals each year. Stroke is characterized by a partial or complete lack of blood flow to a region of the brain that becomes deprived of both oxygen and nutrients and becomes the core of the ischemic, inffacted region. The timely re-establishment of blood flow to ischemic brain by use of thrombolytic agents is a current treatment strategy for acute stroke. The efficacy of this approach, however, is limited by an increased risk for intracerebral hemorrhage (ICH). It was shown that selective inhibition of the intrinsic coagulation pathway, while maintaining the extrinsic coagulation mechanisms, might be efficacious in restoring vascular patency while preventing increased risk for intracerebral hemorrhage. We have previously shown that the recombinant Kunitz proteinase inhibitor (KPI) domain of the amyloid g-protein precursor (APP) is a potent inhibitor of factors XIa and IXa of the intrinsic coagulation pathway, and displays little effect on the extrinsic coagulation pathway and its processes. We propose that the selective inhibitory activity of this KPI domain may be well suited for treatment of acute ischemic brain injury. In Phase I, we will measure the effect of treatment with synthetic KPI domain to reduce fibrin deposition and improve behavioral performance in a mouse model for focal ischemic injury.