Novel Neuroprotective/Anti-inflammatory Therapy for Ischemic Stroke

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DESCRIPTION (provided by applicant): Stroke is leading cause of morbidity and mortality in the US. Research on the pathophysiological basis of stroke has produced new paradigms for prevention and treatment, but translation of these approaches into improved clinical outcomes has proved to be painfully slow. Preventive strategies focus primarily on reducing or controlling risk factors such as diabetes, hypertension, cardiovascular disease, and lifestyle; in patients with severe stenosis, carotid endarterectomy may be indicated. Cerebral angioplasty is used investigationally, but the high restenosis rates observed following coronary angioplasty suggest this approach may pose unacceptable risk for many patients. Therapeutic strategies focus primarily on acute treatment to reduce injury in the ischemic penumbra, the region of reversibly damaged tissue surrounding an infarct. Thrombolytic therapy has been shown to improve perfusion to the ischemic penumbra, but it must be administered within three hours of the onset of infarction. However, new clinically useful agents must be efficacious when given at considerably longer intervals after the onset of ischemia as most stroke patients do not arrive for medical treatment but for several hours, much later than the short, efficacious window of other agents such as the thrombolytics. Targeting Poly (ADP-ribose) polymerase (PARP-1) in the setting of ischemic stroke may provide therapeutic benefit over a long time window, as research studies have demonstrated that PARP-1 inhibition will protect the neurovasculature from the primary ischemic insult and also later when additional cells die as the result of the induced inflammatory response. In this proposed study we will investigate the acute and long-term effects of our lead compound, ANG-2864 in rat models of temporary and permanent ischemic stroke. PUBLIC HEALTH RELEVANCE: Stroke is leading cause of morbidity and mortality in the US. Research on the pathophysiological basis of stroke has produced new paradigms for prevention and treatment. Drugs that inhibit the enzyme, Poly (ADP- ribose) polymerase (PARP-1) in the setting of ischemic stroke may provide therapeutic benefit over a longer time window, as studies have demonstrated that PARP-1 inhibition will protect neuronal cells from the primary ischemic insult and also later when additional cells die as the result of the induced inflammatory response