Enhanced Mitochondrial Function to Increase Effectiveness of Post-Stroke Rehabilitation

增强线粒体功能以提高中风后康复的有效性

• 批准号: 10490270
• 负责人: Rick G Schnellmann
• 金额: --
• 依托单位: SOUTHERN ARIZONA VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490270
• 关键词: Adrenergic Agonists; Adult; Aftercare; Age; Age Years; Animal Model; Animals; Area; Asthma; Biogenesis; Brain Injuries; Chemicals; Chronic Phase; Clinical; Corpus striatum structure; Dose; Effectiveness; Euthanasia; Exhibits; FDA approved; Forelimb; Functional disorder; Goals; Homeostasis; Human; Impairment; Injury; Ischemia; Ischemic Stroke; Lead; Link; Measures; Mitochondria; Motor; Motor Cortex; Motor Skills; Mus; Neuronal Injury; Neurons; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Phase; Population; Procedures; Process; Recovery; Recovery of Function; Rehabilitation therapy; Rodent; Stroke; Testing; Therapeutic; Tissues; Training; Translating; aged; behavior test; behavioral outcome; beta-2 Adrenergic Receptors; brain tissue; cognitive recovery; drug discovery; efficacy evaluation; experience; experimental study; formoterol; functional plasticity; improved; male; mitochondrial dysfunction; molecular marker; motor function improvement; motor impairment; motor recovery; neuron loss; neuronal survival; novel therapeutics; post stroke; programs; repaired; side effect; stroke recovery; stroke rehabilitation; stroke survivor; stroke therapy; therapeutically effective; translational clinical trial; young adult

The long-term goal of this project is to identify new therapeutics that are effective after a stroke has occurred to stimulate recovery of cognitive and motor function. Stroke-induced dysfunction is the result of neuronal injury and death, and mitochondrial dysfunction is implicated in these processes. Currently, drug therapy to treat stroke is limited to TPA, which must be administered within 6h of a stroke. This window is too short and TPA has significant side effects. In addition, therapies are needed that not only treat the initial phase of stroke induced cellular dysfunction but also will enhance the chronic phase recovery of function and produce enduring benefits. Our preliminary studies revealed that mitochondrial dysfunction occurred in ipsilesion cortex and striatum following experimental focal sensorimotor cortex (SMC) ischemic stroke and persisted over the first week. Consequently, we propose that therapeutics that increase mitochondrial biogenesis (MB) will promote recovery from stroke in both adult and aged mice. As part of our drug discovery program to identify chemicals that induce MB, formoterol, a specific long-acting β2-adrenergic receptor (β2AR) agonist, was identified. Formoterol is an FDA-approved drug to treat asthma. Preliminary studies demonstrated that formoterol induced MB in naïve animals. Additionally, our preliminary studies revealed that formoterol administered 24h after stroke improved forelimb motor recovery after six days. Finally, preliminary studies demonstrated that daily formoterol administration, beginning 24h after experimental stroke and continuing daily during forelimb rehabilitative treatment (RT) for 15 days, improved forelimb motor recovery compared to vehicle administration with or without RT. More specifically, we hypothesize that stimulating MB with formoterol after stroke will 1) improve mitochondrial function early after stroke, thus decreasing motor impairments and 2) during RT will improve the efficacy of RT by supporting experience-dependent neuronal remodeling and repair in adult and aged mice. We hypothesize that the combination of formoterol and RT will be most beneficial in aged stroke animals. Specific Aim 1: Elucidate the optimal formoterol dose to induce MB, restore MF, and improve behavioral outcomes after experimental stroke in adult and aged mice. Specific Aim 2: Determine the efficacy of formoterol and forelimb rehabilitative training (RT) following experimental stroke to enhance MF, MB, structural plasticity and behavioral outcomes in adult mice. Specific Aim 3. Determine the efficacy of formoterol and forelimb rehabilitative training (RT) following experimental stroke to enhance MF, MB, structural plasticity and behavioral outcomes in aged mice. Successful completion of these studies will provide strong evidence for the dose, timing and persistence of formoterol-induced recovery from stroke and a possible mechanism underlying these findings, providing new targets for rehabilitative training adjunctive treatments. Since formoterol is already an FDA approved drug, successful completion of these studies could rapidly lead to translational clinical trials for young and older human stroke survivor.

该项目的长期目标是确定中风后有效的新疗法 发生的是刺激认知和运动功能的恢复。中风引起的功能障碍 是神经元损伤和死亡的结果，线粒体功能障碍与这些有关 过程。目前，治疗中风的药物疗法仅限于TPA，必须给予 中风6小时内。该窗口太短，TPA具有显着的副作用。此外， 需要疗法，不仅需要治疗中风的初始阶段引起的细胞功能障碍 但还将增强功能的慢性阶段恢复并产生持久的益处。 我们的初步研究表明，线粒体功能障碍发生在Ipsilesion Cortex和 实验性局灶性感觉运动皮层（SMC）缺血性中风并持续存在的纹状体 在第一周。因此，我们提出了增加线粒体的疗法 生物发生（MB）将促进成年小鼠和老年小鼠的中风恢复。作为我们的一部分 药物发现计划，以识别影响MB，Formoterol（一种特定长效的化学物质） 鉴定出β2-肾上腺素能受体（β2AR）激动剂。 Formoterol是FDA批准的药物 治疗哮喘。初步研究表明，福莫特罗在幼稚的动物中诱导MB。 此外，我们的初步研究表明，中风后24小时给予福洛托罗 六天后改善了前肢运动恢复。最后，初步研究表明 每日福兰特罗醇，从实验中风后24小时开始，每天继续 在前肢康复治疗（RT）中，有15天，改善了前肢运动恢复 与有或没有RT的车辆给药相比。更具体地说，我们假设 中风后用福莫特罗刺激MB 1）早点改善线粒体功能 中风，从而减少运动障碍，2）在RT期间将提高RT的效率 支持成人和老年小鼠的经验依赖性神经元重塑和修复。我们 假设福莫特罗和RT的组合在老年人中最有益 动物。 特定目标1：阐明最佳福特赛剂量以诱导MB，恢复MF和 在成年小鼠和老年小鼠实验中风后改善行为结果。 特定目标2：确定福莫特罗和前肢康复训练的效率 （RT）实验中风以增强MF，MB，结构可塑性和 成年小鼠的行为结果。 特定目标3。确定福特赛和前肢康复训练的效率 （RT）实验中风以增强MF，MB，结构可塑性和 老年小鼠的行为结果。 这些研究的成功完成将为剂量，时机和 甲旋酚诱导的中风恢复和依据的持续性 这些发现为康复培训辅助治疗提供了新的目标。自从 Formoterol已经是FDA批准的药物，这些研究的成功完成可能 迅速导致对年轻人和年长的人类中风幸存者进行翻译的临床试验。