NOVEL INHIBITORS OF BRAIN ISCHEMIA

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.