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，需要在中风发作的头三个小时内进行治疗。我们的实验室正在研究能够延长这一治疗窗口期的治疗方法。我们的研究表明，有效的脑卒中后治疗必须同时具有神经保护和抗炎特性。我们发现，在大鼠中风24小时后，激活西格玛受体可使梗死面积减少80%以上。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感离子通道激活来减少神经元死亡。通过阻断小胶质细胞炎症细胞毒素的激活、迁移和释放，Sigma受体激活也具有抗炎作用。这项提议的目标是扩展我们最初的发现，即在目前的三小时窗口之外的时间点激活西格玛受体是一种有用的中风治疗方法。初步研究将确定这些化合物在缺血性损伤后的适当剂量和治疗窗口。提出的研究考察了在缺血损伤后延迟时间点由sigma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sigma受体配体opipramol。Opipramol在欧洲已经临床使用了40多年，这将加速其临床试验的进展。西格玛受体激动剂是治疗中风发作数小时至数天后的潜在化合物，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。

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.