New approach to sustained neuroprotection and enhanced recovery following acute ischemic stroke

缺血性中风是一种毁灭性的健康问题，每年在美国约有795,000名患者受到影响， 使其成为该国导致死亡和残疾的主要原因之一。最近的临床进展表明 机械血管内血栓切除术(EVT)的使用，在急性中风治疗中大有希望，或 如果没有标准的护理，溶栓治疗会显著改善预后。尽管取得了这些有希望的进展， 长期的神经后遗症在中风后患者群体中持续存在。因此，使用神经保护剂 药物与目前的再灌注方法相结合，为改善中风提供了新的希望 结果。事实上，在实验性中风模型中，&gt；1000药物已被证明可以减少中风损伤，但 都未能转化为临床益处。卒中治疗学术行业圆桌会议(STAIR)召开 ，并提供了重要的指导方针，以提高临床前模型的严谨性，以改善翻译 成功。最近，STAIR IX-X根据血管内治疗提供了最新情况，建议增加 结合EVT再灌注辅助治疗的研究。目前的研究是临床前研究。 这遵循了描述一种与EVT结合使用的新型神经保护剂的阶梯标准 大血管闭塞(LVO)后。 楼梯小组发现了导致翻译失败的多个因素，其中最主要的是过度- 对结果的急性组织学测量的依赖，以及实验和实验之间较差的一致性 临床研究设计。为了解决我们的啮齿动物模型的长期功能结果，我们已经超越了 对运动障碍的测量，并将认知恢复添加到我们的结果测量中，以评估 可能会在生活质量方面带来实际的改善。来自我们小组的实验证据，以及 其他研究表明，tMCAo会导致包括海马体在内的大脑不同区域的突触紊乱。 这一点，加上越来越多的证据表明，AIS(中风后)后认知障碍和记忆力丧失 认知障碍：PSCI)，使突触功能障碍(突触保护)成为治疗的新靶点 神经保护策略。 我们已经开发出一种药物，这种药物1)提供急性神经保护，2)导致持续 突触保护，增强长期认知恢复。我们将当前的提案集中在 急性损伤、迟发性神经细胞死亡、慢性功能障碍转化与治疗的相互作用 旨在保护突触以提供持续的功能益处的方法。这件事的首要前提是 建议缺血性卒中导致大脑中动脉区域(皮质/皮质下)的急性损伤，延迟弥漫性 神经元损伤和食欲不振，导致慢性认知功能减退。我们会 评估我们的新型制剂TAT-M2NX的剂量方案，该方案可提供最佳的长期功能恢复 并探讨tMCAo激活TRPM2通道的机制(S)。

Ischemic stroke is a devastating health problem, affecting approximately 795,000 patients in the US every year, making it one of the leading causes of death and disability in the country. Recent clinical advances have shown great promise in acute stroke therapy, with the use of mechanical endovascular thrombectomy (EVT), with or without standard of care thrombolysis, significantly improving outcomes. Despite these promising advances, long-term neurologic sequelae persist in the post-stroke patient population. Therefore, the use of neuroprotective agents in combination with current methods of reperfusion provides renewed hope for the improvement of stroke outcomes. Indeed, >1000 drugs have been shown to reduce stroke injury in experimental stroke models, but have failed to translate to clinical benefit. The Stroke Therapy Academic Industry Roundtable (STAIR) convened in 1999 and provided important guidelines to improve the rigor of pre-clinical models to improve translational success. More recently, STAIR IX-X provided updates in light of endovascular therapy, advising increased research into adjunct therapies to be combined with EVT reperfusion. The current study is a pre-clinical study that follows the STAIR criteria to characterize a novel neuroprotectant to be utilized in combination with EVT following large vessel occlusion (LVO). The STAIR group identified multiple factors contributing failure to translate, chief among them being over- reliance on acute histological measurements of outcome and poor correspondence between experimental and clinical study designs. To address long-term functional outcomes in our rodent model, we have moved beyond measurements of motor deficits and add cognitive recovery to our outcome measures to assess therapies that may provide real-world improvements in ‘quality of life’ outcomes. Experimental evidence from our group, and others, show that tMCAo induces synaptic derangements in various brain regions, including the hippocampus. This, coupled with the increasing evidence of cognitive impairments and memory loss following AIS (post-stroke cognitive impairment: PSCI), makes synaptic dysfunction (synaptoprotection) a novel new target for neuroprotective strategies. We have developed a drug that 1) provides acute neuroprotection and 2) causes sustained synaptoprotection that enhances long-term cognitive recovery. We focus the current proposal on the interaction between acute injury, delayed neuronal cell death, conversion to chronic dysfunction and therapeutic approaches aimed at synaptoprotection to provide sustained functional benefit. The overarching premise of this proposal is that ischemic stroke causes acute injury within the MCA territory (cortical/subcortical), delayed diffuse neuronal injury and syanptotoxicity which contributes to the conversion to chronic cognitive decline. We will assess dosing regimen of our novel agent, tat-M2NX, that provides optimal long-term functional recovery following tMCAo and assess the mechanism(s) of tMCAo-induced activation of TRPM2 channels.