NOVEL INHIBITORS OF BRAIN ISCHEMIA

描述(申请人提供)：在美国，中风是导致死亡和残疾的主要原因，每年影响大约75万人。中风的特征是部分或完全缺乏血液流向大脑的某个区域，该区域失去了氧气和营养，成为缺血、无影响区域的核心。使用溶栓剂及时重建脑缺血血流是目前治疗急性卒中的一种策略。然而，这种方法的有效性受到脑内出血(ICH)风险增加的限制。结果表明，选择性抑制内源性凝血途径，同时维持外源性凝血机制，可能在恢复血管通畅的同时预防增加脑出血的风险。我们先前已经证明，淀粉样蛋白前体(APP)的重组蛋白抑制物(KPI)结构域是内源性凝血途径的Xia和IXa因子的有效抑制因子，而对外源性凝血途径及其过程几乎没有影响。我们认为，该KPI结构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，我们将测量合成KPI结构域在局灶性脑缺血损伤小鼠模型中减少纤维蛋白沉积和改善行为表现的效果。

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.