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.

缺血性中风是一个毁灭性的健康问题，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。最近的临床进展已显示 急性中风疗法的巨大希望，使用机械血管内血栓切除术（EVT），或 没有护理标准的溶栓，可显着改善结果。尽管有这些有希望的进步， 中风后患者人群的长期神经后遗症持续存在。因此，使用神经保护 与当前的再灌注方法结合使用的代理为中风的改善提供了新的希望 结果。确实，已经显示出> 1000种药物可减少实验中风模型中的中风损伤，但 未能转化为临床利益。中风疗法学术界圆桌会议（楼梯）召集了 在1999年，提供了重要的指南，以改善临床前模型的严格性，以改善翻译 成功。最近，楼梯IX-X根据血管内治疗提供了更新，咨询增加了 研究辅助疗法将与EVT再灌注结合使用。当前的研究是一项临床前研究 这是遵循楼梯标准的特征，以与EVT结合使用新型神经保护剂 在大容器阻塞（LVO）之后。 楼梯小组确定了多种因素无法翻译的因素，其中最主要的是 依赖急性组织学测量结果和实验和对应不佳的依赖 临床研究设计。为了解决啮齿动物模型中的长期功能结果，我们已经超越了 电动机的测量定义并在我们的结果指标中添加认知恢复，以评估疗法 可能会在“生活质量”成果方面改善现实世界。来自我们小组的实验证据，以及 其他人则表明，TMCAO在包括海马在内的各个大脑区域诱导了突触演变。 加上AIS后的认知障碍和记忆力丧失的越来越多的证据（冲程后） 认知障碍：PSCI），使突触功能障碍（突触保护）成为新的新目标 神经保护策略。 我们已经开发了一种药物1）提供急性神经保护和2）持续的原因 突触保护可以增强长期认知恢复。我们将当前的建议集中在 急性损伤，神经元细胞死亡，转化为慢性功能障碍和治疗之间的相互作用 旨在突触保护提供持续功能益处的方法。总体前提 提议是缺血性中风会在MCA领域（皮质/皮质下）内造成急性损伤，延迟弥漫 神经元损伤和共透毒性有助于转化为慢性认知能力下降。我们将 评估我们新型药物Tat-M2NX的给药方案，该方案可提供最佳的长期功能恢复 遵循TMCAO并评估TMCAO诱导的TRPM2通道激活的机制。