Expanding the therapeutic window for stroke treatment.

描述（由申请人提供）：中风是美国的一个主要健康问题，每年有80万人死亡或衰弱。目前，只有一种治疗方法，需要在中风发作的前三个小时内进行。我们的实验室正在研究可以延长这一治疗窗口的治疗方法。我们的研究表明，有效的中风后治疗必须同时具有神经保护和抗炎特性。我们已经发现，当在大鼠中风后24小时递送时，σ受体的激活使梗塞面积减少超过80%。这些受体通过抑制缺血诱导的细胞内钙升高、增加神经兴奋性和酸敏感离子通道激活来减少神经元死亡。σ受体活化也通过阻断炎性细胞毒素从小胶质细胞的活化、迁移和释放而抗炎。该提案的目的是扩展我们的初步发现，即σ受体激活在当前三小时窗口之外的时间点是有用的中风治疗。初步研究将确定缺血性损伤后这些化合物的适当剂量和治疗窗口。拟议的研究探讨了缺血性损伤后延迟时间点σ受体激活促进的行为恢复。此外，我们将在我们的中风模型中测试σ受体配体奥匹哌醇。Opipramol在欧洲的临床应用已超过40年，这将加速其临床试验的进展。σ受体激动剂是在发作后数小时至数天治疗中风的潜在化合物，以通过增加神经存活和阻断炎症反应来阻止缺血区域的扩张。 中风在美国是一个主要的健康问题，只有一种FDA批准的治疗方法，其治疗窗口有限。由于中风治疗没有进展，需要创新的方法来发现新的药物来对抗这种病理状态。我们已经发现，DTG（一种σ受体激动剂）的全身给药具有神经保护和抗炎特性，其在大鼠中风后24小时保护免于中风诱导的脑损伤。该建议将进一步检查DTG在中风大鼠中的治疗能力。另一种σ受体激动剂奥匹哌醇也将被检查其在中风中的治疗效果。奥匹哌醇作为抗焦虑药已在人体中使用超过40年。

DESCRIPTION (provided by applicant): Stroke is a major health problem in the US with 800,000 people killed or debilitated each year. Currently, there is only one treatment, which needs to be administered within the first three hours of stroke onset. Our laboratory is examining treatments that would extend this therapeutic window. Our studies have shown that effective post-stroke treatment must possess both neuroprotective and anti-inflammatory properties. We have found that activation of sigma receptors decrease infarct area by over 80% when delivered 24 hours post- stroke in the rat. These receptors decrease neuronal death by depressing ischemia-induced intracellular calcium elevations, increased neuroexcitability and acid-sensing ion channel activation. Sigma receptors activation is also anti-inflammatory by blocking activation, migration and release of inflammatory cytotoxins from microglia. The goal of this proposal is to extend our initial findings that sigma receptor activation is a useful stroke treatment at timepoints beyond the current three hour window. The initial studies will determine the proper dose and therapeutic window for these compounds following an ischemic insult. The proposed study examines behavioral recovery promoted by sigma receptor activation at delayed time points following an ischemic insult. Moreover, we will test the sigma receptor ligand opipramol in our stroke model. Opipramol has been used clinically for over 40 years in Europe, which would accelerate its progression to clinical trials. Sigma receptor agonists are potential compounds to treat stroke many hours to days after onset to arrest the expansion of ischemic area through increasing neurosurvival and blocking the inflammatory response. Stroke is a major health problem in the USA with only one FDA-approved treatment, which has a limited therapeutic window. Since there have been no advances in stroke therapies, innovative approaches are needed to discover new agents to combat this pathologic condition. We have found that systemic administration of DTG, a sigma receptor agonist, has neuroprotective and anti-inflammatory properties that protects against stroke-induced brain injury at 24 hours post-stroke in rats. This proposal will further examine the therapeutic capability of DTG in stroked rats. Another sigma receptor agonist, opipramol, will also be examined for its therapeutic effectiveness in stroke. Opipramol has been used in humans for over 40 years as an anxiolytic agent.