Repositioning Drugs to Treat Ischemic Stroke at Delayed Time Points

项目摘要 缺血性脑中风每年以惊人的速度袭击大约75万美国人。 成本只有一种治疗方法被批准，并且要求在很短的时间内进行治疗。 在大多数情况下（约90%），帧（目前在美国3小时内）大大限制了其适用性。通过 我们将重点关注在延迟时间点（≥ 24小时）改善卒中结局的药物， 这是一种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- 衍生的神经营养因子（BDNF）促进体外缺血神经元的恢复，促进功能性 在损伤后延迟时间点（≥24小时）给药时，卒中动物模型的恢复情况，及其 水平与中风患者的功能恢复呈正相关。由于加工和分泌的 体外激活神经胶质细胞和神经元细胞中的Sigma-1受体（S1 R）伴侣可增强BDNF 在体内的大脑中，我们试图发现现有的药物，凭借它们与大脑的相互作用， S1 R可能在延迟时间点重新用于缺血性卒中的功能恢复。我们的目标 包括开发体外和体内测定平台，以合理地指导用于在体外和体内测定的候选物的选择， 在啮齿动物局灶性脑缺血模型中的体内评价。这项探索性应用的结果将 为未来资助机制支持的重点转化药物再利用工作奠定基础。

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.