Drug-Enhanced Rehabilitation in Recovery from Stroke

中风恢复中的药物强化康复

• 批准号: 7099654
• 负责人: WILLIAM A. WOLF
• 金额: $ 30.76万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-25 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099654
• 关键词: amphetamines; cAMP response element binding protein; combination therapy; developmental neurobiology; disease /disorder model; drug screening /evaluation; fibroblast growth factor; laboratory rat; medical rehabilitation related tag; nervous system regeneration; neural plasticity; neurotransmitter receptor; nonhuman therapy evaluation; pharmacokinetics; physical therapy; receptor expression; rehabilitation; sensorimotor system; stroke; stroke therapy

DESCRIPTION (provided by applicant): Stroke occurs in 600,000 U.S. citizens every year and is the leading cause of neurologic disability worldwide. Most stroke victims are left with permanent sensorimotor deficits as the result of ischemia-induced brain damage. Physical therapy (PT) remains the primary strategy to improve recovery, but there is a clear need to improve rehabilitation strategies. Promising investigational studies indicate that the stimulant drug amphetamine (AMPH) can enhance the rate and extent of sensorimotor recovery when paired with PT (AMPH/PT). However, AMPH adjunct therapy remains investigational due to concerns over its side effect profile and addiction potential. Alternatives are not available because there is little understanding of the mechanism underlying the clinical benefits of AMPH. The objective of this application is to understand the pharmacology and neurobiological mechanisms underlying AMPH enhancement of PT-aided sensorirnotor recovery following stroke. Our preliminary data indicate that AMPH/PT following brain damage leads to improved motor recovery that is associated with enhanced neurite outgrowth from corticomotor cells. We also demonstrate that AMPH activates cAMP response element binding protein (CREB), a transcription factor involved in neural plasticity and neurite outgrowth via growth factor activation. We will test the hypothesis that AMPH enhances sensorimotor recovery through specific receptor activation that leads to neurite outgrowth and formation of new motor pathways. Aims I and I! will focus on the pharmacology of AMPH. In Aim I we will establish the role of noradrenergic alphal and dopaminergic D1 and D2 receptors in mediating AMPH-enhanced sensorimotor recovery in rats that have received permanent middle cerebral artery occlusion. Motor recovery will be assessed using a battery of sensorimotor tasks. In Aim II we will ascertain whether selective stimulation of alphal, D1 or D2 receptors can emulate AMPH enhancement of sensorimotor recovery. Aim III will establish that recovery of function is associated with neurite outgrowth and determine the origin of this new growth. Aim IV will focus on key signaling molecules modulated by AMPH and which are critical mediators of neuronal plasticity. First, we will determine that drug-enhanced motor recovery is associated with activation of CREB in corticomotor cells. Next we will establish a role for basic fibroblast growth factor in mediating AMPH enhanced recovery of function as well as neurite outgrowth. From Aims I and II we will identify potential drug candidates that can rapidly translate into clinical use. From Aims III and IV we will identify potential targets for future therapy. Together our findings will lead to optimization of pharmacological approaches to enhance functional recovery after stroke.

描述（由申请人提供）：中风每年发生在60万美国公民中，是全球神经残疾的主要原因。由于缺血引起的脑损伤，大多数中风受害者都有永久性的感觉运动缺陷。物理疗法（PT）仍然是改善恢复的主要策略，但显然需要改善康复策略。有前途的研究研究表明，与PT配对时，刺激性药物苯丙胺（AMPH）可以提高感觉运动恢复的速率和程度。但是，由于对其副作用概况和成瘾潜力的担忧，AMPH辅助疗法仍在研究中进行研究。替代方案之所以没有，是因为对AMPH临床益处的基础机制几乎没有理解。该应用的目的是了解中风后PT辅助感官恢复的AMPH增强的药理学和神经生物学机制。我们的初步数据表明，脑损伤后的AMPH/PT导致运动恢复的改善，这与皮质运动细胞的神经突生长有关。我们还证明了AMPH激活CAMP响应元件结合蛋白（CREB），这是一种通过生长因子激活参与神经可塑性和神经突生长的转录因子。我们将检验以下假设：AMPH通过特定的受体激活增强了感觉运动恢复，从而导致神经突生长和新运动途径的形成。目标我和我！将专注于AMPH的药理学。目的我将确定去甲肾上腺素能α和多巴胺能D1和D2受体在介导的大鼠中间大脑中动脉闭塞的大鼠中的Amph增强感觉运动恢复中的作用。将使用一系列感觉运动任务评估运动恢复。在AIM II中，我们将确定对α，D1或D2受体的选择性刺激是否可以模仿感觉运动恢复的AMPH。 AIM III将确定功能的恢复与神经突生长有关，并确定这种新增长的起源。 AIM IV将集中于由AMPH调节的关键信号分子，它们是神经元可塑性的关键介体。首先，我们将确定具有药物增强的运动恢复与皮质运动细胞中CREB的激活有关。接下来，我们将确立基本成纤维细胞生长因子介导AMPH增强功能恢复以及神经突生长的作用。从目标I和II中，我们将确定可以快速转化为临床用途的潜在候选药物。从AIMS III和IV中，我们将确定未来治疗的潜在靶标。我们的发现一起将导致优化药理方法，以增强中风后功能恢复。