Enhanced Mitochondrial Function to Increase Effectiveness of Post-stroke Rehabilitation

摘要 该项目的长期目标是确定在中风发生后有效的新疗法。 促进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的结果 和死亡，线粒体功能障碍与这些过程有关。目前，药物疗法主要用于治疗 中风仅限于TPA，必须在中风后6小时内服用。此窗口太短，且TPA 有明显的副作用。此外，治疗方法不仅需要治疗中风的初始阶段-- 诱导的细胞功能障碍还会增强慢性期的功能恢复并产生持久 福利。 我们的初步研究表明，线粒体功能障碍发生在大脑皮质和纹状体。 在成年大鼠局灶性感觉运动皮质(SMC)缺血区，并持续至第一周。 因此，我们认为增加线粒体生物发生(MB)的疗法将促进 成年和老年大鼠中风后的恢复情况。作为我们识别化学物质的药物发现计划的一部分 福莫特罗是一种特异性的长效β2肾上腺素能受体(β2AR)激动剂。 福莫特罗是FDA批准的治疗哮喘的药物。初步研究表明福莫特罗- 在幼稚大鼠体内诱导甲基亚甲基。另外，我们的初步研究表明福莫特罗在24小时后给药 中风改善了6天后的前肢运动恢复。最后，初步研究表明，每天 福莫特罗给药，从实验性卒中后24小时开始，在前肢持续每天 康复治疗(RT)15天，与车辆管理相比，改善了前肢运动恢复 使用或不使用RT。更具体地说，我们假设中风后用福莫特罗刺激MB将 改善中风后早期的线粒体功能，从而减少运动损伤；2)在RT期间 通过支持成人和大鼠经验依赖性神经元重塑和修复提高RT的疗效 老龄大鼠。我们推测福莫特罗联合RT治疗老年卒中最有益 动物。 具体目标1：阐明福莫特罗诱导MB、恢复MF和改善的最佳剂量 成年和老年大鼠实验性卒中后的行为结果。 具体目标2：确定福莫特罗和前肢康复训练(RT)的疗效 实验性卒中可增强成年大鼠的MF、MB、结构可塑性和行为结局。 具体目标3.确定福莫特罗和前肢康复训练(RT)的疗效 实验性卒中提高老龄大鼠的MF、MB、结构可塑性和行为结局 这些研究的成功完成将为药物的剂量、时机和持久性提供强有力的证据。 福莫特罗诱导的卒中康复和这些发现背后的可能机制，提供了新的 康复训练辅助治疗的目标。由于福莫特罗已经是FDA批准的药物， 这些研究的成功完成迅速导致了针对年轻人和老年人的转化型临床试验 中风幸存者。

ABSTRACT 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 celluar dysfunction but also will enhance the chronic phase recovery of function and produce enduring benefits. Our preliminary studies revealed that mitochondrial dysfunction occurred in ispilesion cortex and striatum following focal sensorimotor cortex (SMC) ischemic lesion in adult rats, and persisted over the first week. Consequently, we propose that therapeutics that increases mitochondrial biogenesis (MB) will promote recovery from stroke in both adult and aged rats. 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 rats. Additional 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 rats. 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 rats. 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 rats. 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 rats 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 rapidly lead to translational clinical trials for young and older human stroke survivor.