We propose to conduct a comprehensive, milestone-driven program of translational research targeted at the validation of a novel azulenyl nitrone antioxidant compound -- stilbazulenyl nitrone (STAZN) -- as a neuroprotective therapeutic agent for three interrelated, prevalent acute neurological disorders in which reactive oxygen species contribute to tissue injury: ischemic stroke, traumatic brain injury (TBI), and parenchymal intracerebral hemorrhage (ICH). No clinically established neuroprotective therapeutic is currently available for these disorders. STAZN has the advantages of high lipophilicity and an oxidation potential within the physiologic range; it has shown great promise in pilot studies. This proposal builds upon a fruitful collaboration between the Cerebral Vascular Disease Research Center at the University of Miami and a productive laboratory of synthetic organic chemistry at Florida International University. The intent of the program is to establish a compelling body of preclinical evidence supporting the neuroprotective efficacy of STAZN as a prelude to clinical trials in stroke and trauma. Focal cerebral ischemia will be studied in rat models of both transient and permanent middle cerebral artery (MCA) suture occlusion and in recanalizable photothrombotic MCA occlusion, which engenders reperfusion injury. TBI studies will be performed in the standard moderate-to-severe fluid percussion model. Striatal intracerebral hematoma is produced by double blood injection. We shall conduct comprehensive dose-finding studies, elucidate the therapeutic time-window of efficacy, and evaluate both acute and chronic endpoints using both quantitative histopathological as well as neurobehavioral strategies. Gender- and age-related responses will be considered. Pharmacokinetic studies will document STAZN plasma curves and brain levels. The NINDS program staff has provided valuable input to us in shaping this proposal. Two world-renowned authorities in oxygen-radical biochemistry and vascular pharmacology drawn from both academia and the pharmaceutical industry will serve as External Advisors to guide us throughout this project.
