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

急性缺血性中风后持续神经保护和促进康复的新方法

• 批准号: 10584833
• 负责人: Paco S Herson
• 金额: $ 169.37万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584833
• 关键词: Acute; Address; Affect; Brain; Brain region; Cause of Death; Chronic; Clinical; Clinical Research; Country; Coupled; Diffuse; Dose; Failure; Functional disorder; Guidelines; Health; Hippocampus (Brain); Histologic; Impaired cognition; Industry; Injury; Ischemic Stroke; Light; Measurement; Mechanics; Memory Loss; Methods; Neurologic; Neuronal Injury; Neuroprotective Agents; Outcome; Outcome Measure; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Quality of life; Recovery; Recovery of Function; Regimen; Reperfusion Therapy; Research; Research Design; Rodent Model; Stroke; Synapses; Therapeutic; Translating; United States; Update; acute stroke; cognitive recovery; disability; endovascular thrombectomy; experimental study; functional outcomes; improved; improved outcome; motor deficit; neuron loss; neuroprotection; novel; novel strategies; novel therapeutics; patient population; post stroke; post stroke cognitive impairment; preclinical study; response; standard of care; stroke model; stroke outcome; stroke therapy; success; sulfated glycoprotein 2; thrombolysis

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.

缺血性中风是一种毁灭性的健康问题，每年影响美国约795，000名患者， 使其成为该国死亡和残疾的主要原因之一。最近的临床进展表明， 使用机械血管内血栓切除术（EVT）， 无需标准治疗溶栓，显著改善结局。尽管取得了这些有希望的进展， 长期神经系统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 药物联合目前的再灌注方法为改善中风提供了新的希望 成果。事实上，超过1000种药物已被证明可以减少实验性中风模型中的中风损伤，但 未能转化为临床效益。中风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， 成功最近，STAIR IX-X根据血管内治疗提供了更新，建议增加 研究辅助治疗与EVT再灌注相结合。本研究为临床前研究 遵循STAIR标准，以表征与EVT联合使用的新型神经保护剂 大血管闭塞（LVO）。 STAIR小组确定了导致翻译失败的多种因素，其中最主要的是过度- 依赖于急性组织学测量的结果和实验和 临床研究设计。为了解决啮齿动物模型的长期功能结果，我们已经超越了 运动缺陷的测量，并将认知恢复添加到我们的结果测量中，以评估 可能会在现实世界中改善“生活质量”结果。我们小组的实验证据， 其他研究表明，tMCAo诱导包括海马在内的各种脑区的突触紊乱。 这一点，再加上越来越多的证据表明，认知障碍和记忆丧失后，AIS（中风后 认知障碍（PSCI），使突触功能障碍（突触保护）成为一种新的新靶点， 神经保护策略 我们已经开发出一种药物，1）提供急性神经保护，2）引起持续的 突触保护，增强长期认知恢复。我们把目前的建议集中在 急性损伤、迟发性神经元细胞死亡、向慢性功能障碍的转化和治疗之间的相互作用 旨在提供持续功能益处的突触保护方法。这一切的首要前提是 建议缺血性卒中导致MCA区域（皮质/皮质下）内的急性损伤，延迟弥漫性损伤， 神经元损伤和突触毒性，这有助于转化为慢性认知能力下降。我们将 评估我们的新型药物tat-M2 NX的给药方案，以提供最佳的长期功能恢复 在tMCAo之后，并评估tMCAo诱导TRPM 2通道激活的机制。