With stroke representing the third leading cause of death in the United States, there is an impending need for the development of novel, safe and effective therapies for cerebral ischemia. The molecular mechanisms by which delayed neuronal cell death following focal cerebral ischemia is activated have been recently elucidated and possible drug targets have been identified. These include proteins that activate mitochondrial programmed cell death pathways (apoptosis) such as Caspase-8 and its protein substrate, Bid. Bid is a pro-apoptotic Bcl-2 family protein that when activated by cleavage by Caspase-8 interacts with the mitochondrial membrane and initiates a cascade of cellular events that lead to the activation of Caspase-3 and -7 and consequent neuronal cell death. With the goal of providing pharmacological tools for development of novel therapies for cerebral stroke, we propose to identify and optimize non-selective small organic molecules capable of blocking or reducing the activity of Caspases-3/7 and 8. Supported by our preliminary data, we also propose to develop small organic molecules that are capable of antagonizing the pro-apoptotic activity of Bid. Finally, we propose to test the efficacy of our compounds in animal models of stroke when used as single agents and in combination. Our hypothesis is that by blocking multiple cell-death mechanisms by means of combining non-selective Caspase inhibitors with Bid antagonists, the activation of compensatory cell-death pathways post-cerebral ischemia will be largely attenuated. Our studies not only will provide valuable agents for the validation of the proposed drug targets and our central hypotheses but also hold great potential for a direct translation in the development of novel therapies for cerebral ischemic stroke.
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