Anti-apoptotic compounds for treatment of brain ischemia

在美国，中风是第三大死因，有一种迫在眉睫的 需要开发新的、安全有效的脑缺血治疗方法。分子 局灶性脑缺血后迟发性神经细胞死亡的激活机制 最近阐明的和可能的药物靶点已经确定。这些包括激活的蛋白质 线粒体程序性细胞死亡途径(细胞凋亡)，如Caspase-8及其蛋白底物Bid。 Bid是一种促凋亡的Bcl2家族蛋白，当被Caspase-8切割激活时，它与 线粒体膜，并启动一系列细胞事件，导致Caspase-3和 -7和随之而来的神经细胞死亡。其目标是提供药理学工具，用于开发 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Caspase-3/7和8的活性。在我们的初步数据支持下，我们 还建议开发能够拮抗黄曲霉毒素促凋亡活性的有机小分子。 出价。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独使用时的效果。 代理和组合。我们的假设是，通过阻断多种细胞死亡机制，通过 非选择性Caspase抑制剂与Bid拮抗剂联合激活细胞代偿性死亡 脑缺血后的通路将在很大程度上减弱。我们的研究不仅将提供有价值的代理人 用于验证提出的药物靶点和我们的中心假设，但也具有巨大的潜力 直接翻译在开发脑缺血中风新疗法中的作用。

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.