Anti-apoptotic compounds for treatment of brain ischemia

中风是美国第三大死亡原因， 需要开发新的、安全的和有效的脑缺血疗法。分子 局灶性脑缺血后迟发性神经元细胞死亡被激活的机制已经被 最近已经阐明并鉴定了可能的药物靶点。其中包括激活 线粒体程序性细胞死亡途径（细胞凋亡），如胱天蛋白酶-8及其蛋白质底物Bid。 Bid是一种促凋亡Bcl-2家族蛋白，当被Caspase-8裂解激活时，Bid与Bcl-2家族蛋白相互作用。 线粒体膜，并启动级联的细胞事件，导致半胱天冬酶-3的激活， -7和随后的神经元细胞死亡。其目的是为药物开发提供药理学工具， 脑卒中的新疗法，我们建议识别和优化非选择性有机小分子 能够阻断或降低半胱氨酸蛋白酶-3/7和8的活性。根据我们的初步数据，我们 还建议开发能够拮抗促凋亡活性的小有机分子， Bid.最后，我们建议在中风动物模型中测试我们的化合物作为单一药物使用时的功效。 代理商和组合。我们的假设是，通过阻断多种细胞死亡机制， 将非选择性半胱天冬酶抑制剂与Bid拮抗剂组合， 脑缺血后的通路将大大减弱。我们的研究不仅能提供 用于验证所提出的药物靶点和我们的中心假设，但也具有巨大的潜力， 直接转化为脑缺血性卒中新疗法的开发。

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.