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效果

基本信息

  • 批准号:
    9288318
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-08-01 至 2021-07-31
  • 项目状态:
    已结题

项目摘要

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.
摘要 该项目的长期目标是确定中风后有效的新疗法, 刺激认知和运动功能恢复。脑卒中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,药物治疗 中风仅限于TPA,其必须在中风后6小时内施用。这个窗口太短,TPA 有明显的副作用此外,需要不仅治疗中风的初始阶段, 诱导细胞功能障碍,而且还将促进慢性期功能恢复,产生持久的 效益 我们的初步研究表明,缺血脑区皮层和纹状体线粒体功能障碍 在成年大鼠局灶性感觉运动皮层(SMC)缺血性损伤后,并持续超过第一周。 因此,我们提出,增加线粒体生物合成(MB)的疗法将促进 在成年和老年大鼠中从中风中恢复。作为我们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- 在未处理大鼠中诱导MB。另外,我们的初步研究表明,福莫特罗给药后24小时, 中风后6天改善前肢运动恢复。最后,初步研究表明, 福莫特罗给药,从实验性卒中后24小时开始,在前肢 康复治疗(RT)15天,与溶媒给药相比,改善了前肢运动恢复 更具体地说,我们假设在中风后用福莫特罗刺激MB将1) 改善中风后早期线粒体功能,从而减少运动障碍,2)RT期间将 通过支持成人经验依赖性神经元重塑和修复来提高RT的疗效, 老鼠会我们假设福莫特罗和RT联合治疗对老年脑卒中最有益 动物 具体目标1:阐明诱导MB、恢复MF和改善 成年和老年大鼠实验性中风后的行为结果。 具体目标2:确定福莫特罗和前肢康复训练(RT)的疗效, 实验性中风,以提高MF,MB,结构可塑性和成年大鼠的行为结果。 具体目标3。确定福莫特罗和前肢康复训练(RT)的疗效, 实验性脑卒中对老年大鼠MF、MB、结构可塑性和行为结果的影响 这些研究的成功完成将提供强有力的证据,剂量,时间和持久性 福莫特罗诱导的中风恢复和这些发现背后的可能机制,提供了新的 康复训练和康复治疗的目标。由于福莫特罗已经是FDA批准的药物, 这些研究成功完成迅速导致了年轻人和老年人的转化临床试验 中风幸存者

项目成果

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DeAnna L Adkins其他文献

DeAnna L Adkins的其他文献

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{{ truncateString('DeAnna L Adkins', 18)}}的其他基金

Prediction of Motor Outcome after Acute Stroke using Diffusional Kurtosis Imaging
使用扩散峰度成像预测急性中风后的运动结果
  • 批准号:
    8700634
  • 财政年份:
    2014
  • 资助金额:
    --
  • 项目类别:
Cortical Stimulation to Enhance Motor Recovery Following Traumatic Brain Injury
皮质刺激可增强脑外伤后的运动恢复
  • 批准号:
    8458566
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Cortical Stimulation to Enhance Motor Recovery Following Traumatic Brain Injury
皮质刺激可增强脑外伤后的运动恢复
  • 批准号:
    8245790
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Cortical Stimulation to Enhance Motor Recovery Following Traumatic Brain Injury
皮质刺激可增强脑外伤后的运动恢复
  • 批准号:
    8107835
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Cortical Stimulation to Enhance Motor Recovery Following Traumatic Brain Injury
皮质刺激可增强脑外伤后的运动恢复
  • 批准号:
    8372562
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Cortical Stimulation to Enhance Motor Recovery Following Traumatic Brain Injury
皮质刺激可增强脑外伤后的运动恢复
  • 批准号:
    8652839
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Cognitive Neurorehabilitation to Enhance Recovery After Stroke
认知神经康复促进中风后恢复
  • 批准号:
    7812111
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:

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