NEUROPROTECTIVE REPERFUSION THERAPY WITH PNA

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This proposal describes the development of a novel agent for the treatment of stroke. The agent, polynitroxyl-albumin (PNA), is a potent antioxidant; the rationale for the therapy is that oxygen free radical formation in the vascular space initiates a cascade of toxic events leading to stroke injury. Preliminary results from middle cerebral artery occlusion (MCAO) studies in rodents have indicated that PNA protects against ischemic and reperfusion injury in the brain, that it reduces infarct volume following stroke, and that it may actually enhance cerebral perfusion via a vasodilator activity. PNA's protective activity is substantially greater than that of unmodified human serum albumin; PNA can therefore be thought of as a therapeutic colloid solution with antioxidant and vasodilator activities, or a 'neuroprotective therapeutic reperfusion agent'. The project will consist of studies on PNA's effects on cerebral hemodynamics and metabolism during stroke; diffusion- and perfusion-weighted magnetic resonance imaging studies of PNA~s effects on ischemic and reperfusion injury and cerebral blood flow; and studies to confirm that PNA reduces infarct volume following MCAO. If successful, this project will give an understanding of the mechanism of action of PNA, and lead to its complete preclinical development for stroke therapy in Phase II. PROPOSED COMMERCIAL APPLICATION There is no efficacious drug now on the market for stroke therapy, and thrombolytic therapy may turn out to be appropriate of relatively few stroke patients. Preliminary evidence suggests that PNA reduces stroke injury by promoting cerebral perfusion and protecting against reperfusion injury. If successfully developed PNA could significantly reduce the enormous human and health care costs of stroke.