Repositioning Drugs to Treat Ischemic Stroke at Delayed Time Points

项目摘要 每年大约有75万美国人以惊人的速度发作缺血性中风 成本。只批准了一种治疗方法，并要求在很短的时间内进行 框架(目前在美国不超过3小时)极大地限制了其在大多数情况下的适用性(约90%)。通过 专注于在延迟时间点(≥24小时)改善中风预后的药物，我们将解决 未得到满足的医疗需求有可能影响大量中风患者的健康。大脑- 衍生神经营养因子(BDNF)促进体外缺血神经元的弹性，促进功能 在侮辱后延迟时间点(≥24小时)给药的卒中动物模型的恢复，及其 水平与中风患者的功能恢复呈正相关。因为加工和分泌的 体外激活神经胶质细胞和神经细胞Sigma-1受体(S1R)伴侣可增强BDNF 在活体的大脑中，我们试图发现现有的药物，这些药物通过它们与 S1R可能在延迟时间点用于缺血性卒中后的功能恢复。我们的目标 包括开发体外和体内测试平台，以合理指导IN候选人的选择 局灶性脑缺血啮齿动物模型的活体评价。此探索性应用程序的发现将 为未来筹资机制支持的有重点的转化性药物再利用努力奠定基础。

Project Summary Ischemic cerebral stroke attacks approximately three quarters of a million Americans each year at a staggering cost. Only one treatment has been approved and the requirement that it be administered within a narrow time frame (currently within 3 hrs in the USA) drastically limits its applicability in the majority of cases (~90%). By focusing on medicines for improved stroke outcomes at delayed time points (≥ 24 hours), we will be addressing an unmet medical need that has the potential to impact the health of large numbers of stroke victims. Brain- derived Neurotropic Factor (BDNF) promotes the resilience of ischemic neurons in vitro, promotes functional recovery in animal models of stroke when administered at delayed time points after the insult (≥24 hrs), and its levels positively correlate with functional recovery in stroke patients. Since the processing and secretion of BDNF can be enhanced by activating the Sigma-1 receptor (S1R) chaperone in glial and neuronal cells in vitro and in the brain in vivo, we seek to discover existing medications, which by virtue of their interactions with the S1R, might be repurposed for the functional recovery from ischemic stroke at delayed time points. Our aims include developing an in vitro and in vivo assay platform to rationally guide the selection of candidates for in vivo evaluation in a rodent model of focal cerebral ischemia. The findings from this exploratory application will set the stage for a focused translational drug repurposing effort supported by a future funding mechanism.