The principal investigator for this proposal, Dr. Xin Wang, is an Instructor of Neurosurgery at Brigham and Women's Hospital and Harvard Medical School. This proposal outlines a mentored transition of Dr. Wang research from screening novel drugs for Huntington's diseases (her current advisor's project) to searching for compounds that decrease the impact of ischemic stroke. The latter investigation will be the subject of her independent academic activity. From then on she will apply for R01 level funding. The primary mentor for this proposal, Dr. Robert Friedlander, is currently an independent clinical scientist and recognized leader with extensive published experience in the area of novel drug testing and therapy for neurological diseases. The co-mentor, Dr. Bruce Kristal, is an expert in mitochondrial dysfunction and the mitochondrial permeability transition as they relate to programmed cell death. The co-mentor, Dr. Michael Moskowitz is a world-renown expert in the area of different models of cerebral ischemia. A mentor committee consisting of Drs. Friedlander, Kristal and Moskowitz and five other scientists (Drs. Connolly, Stein, Glicksman, Li and Cudkowicz) will serve as the advisory committee for Dr. Wang and will carefully supervise Dr. Wang' progress. The environment in which the proposed work will be carried out (Harvard Medical School) is a world class scientific institution where both basic and clinical researches are conducted. In this project, Dr. Wang will screen the twenty-one inhibitors of cytochrome c release and eleven inhibitors of the mitochondrial permeability transition (mPT) in two systems of cultured neurons. She will select the eight most potently neuroprotective of these candidate drugs for testing in two mouse models of human disease: the R6/2 transgenic strain whose syndrome resembles Huntington's disease (HD) and middle cerebral artery occlusion (MCAO) in C57BL/6 that models stroke. Furthermore, Dr. Wang will evaluate the molecular mechanisms by which the newly identified candidate drugs exert their beneficial effects. As presented in the Preliminarily Result section, Dr. Wang has demonstrated that methazolamide and melatonin successfully inhibit cytochrome c release, thereby blocking neuronal cell death. This molecular effect correlates with these drugs' ability to decrease infarct size and reduced neurological impairment in the mouse model of stroke. She also presents data on the neuroprotective effects of nortriptyline and promethazine, compounds that inhibit mPT. The ulimate goal of these experiments in cultured cells and in mice is to suggest the parameters for clinical trials on patients who suffer HD and stroke. As all the compounds being tested are in current clinical use (to treat other syndromes!), they should be safe for eventual human trials.