LEVODOPA DYSKINESIAS: IMPACT OF DOPAMINE NEURONS

左旋多巴运动障碍：多巴胺神经元的影响

• 批准号: 6751903
• 负责人: KATHY Steece STEECE-COLLIER
• 金额: $ 30.99万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6751903
• 关键词: Parkinson' s disease; abnormal involuntary movement; brain morphology; caudate nucleus; dopamine; homologous transplantation; innervation; laboratory rat; levodopa; nervous system transplantation; neurochemistry; neuropsychology; neurotransmitter metabolism; transplantation immunology

DESCRIPTION (provided by applicant): Recent findings from long-term clinical grafting trials for Parkinson's disease (PD) show that a portion of graft recipients develop aggravated post-graft dyskinesias. These dyskinesias are severe, debilitating and strongly indicate that mechanisms underlying them need to be elucidated. Freed, Fahn and coworkers have hypothesized that grafted-mediated dyskinesias result from graft overgrowth. However, their own PET and post-mortem data, as well as the data from others, do not support this view. We propose an alternative hypothesis that post-graft worsening of dyskinesias result from local "hot spots" of hyperdopaminergic function interacting with the levodopa primed brain. We plan to test this hypothesis by comparing neural grafting strategies that induce either a) widespread or b) local hyperdopaminergic function upon dopa-induced dyskinesias AND the role of dopa priming in a rat model of parkinsonism. We, and others have demonstrated that unilaterally dopamine (DA) depleted rats chronically treated with levodopa exhibit dyskinesias with characteristics remarkably similar to the dyskinesias seen in human PD. Further, this animal model importantly displays basal ganglia mechanisms that allow for DA grafts to either accentuate (Steece-Collier et al, submitted) or ameliorate these dyskinesia indices, similar to that seen in human graft recipients. Prior to continued clinical use, a systematic evaluation of the interaction of neural grafting with levodopa dyskinesias is needed to ensure that this experimental therapy is both safe and effective. This rodent model provides a valuable first step in such a systematic evaluation of levodopa/graft interactions. These studies will provide important guidelines useful in developing primates studies where further hypotheses and verification can be tested.

描述（由申请人提供）：针对帕金森病（PD）的长期临床移植试验的最新发现表明，部分移植受者出现严重的移植后运动障碍。这些运动障碍是严重的、使人衰弱的，强烈表明需要阐明其背后的机制。 Freed、Fahn 和同事假设移植物介导的运动障碍是由移植物过度生长引起的。然而，他们自己的PET和尸检数据，以及其他人的数据，并不支持这一观点。我们提出了另一种假设，即移植后运动障碍恶化是由于高多巴胺能功能的局部“热点”与左旋多巴引发的大脑相互作用所致。我们计划通过比较在多巴引起的运动障碍上诱导a）广泛或b）局部多巴胺能亢进功能的神经移植策略以及多巴启动在帕金森病大鼠模型中的作用来检验这一假设。我们和其他人已经证明，长期接受左旋多巴治疗的单侧多巴胺 (DA) 耗尽的大鼠表现出运动障碍，其特征与人类 PD 中所见的运动障碍非常相似。此外，该动物模型重要地展示了基底神经节机制，允许 DA 移植物加重（Steece-Collier 等人提交）或改善这些运动障碍指数，类似于在人类移植受者中看到的情况。在继续临床使用之前，需要对神经移植与左旋多巴运动障碍的相互作用进行系统评估，以确保这种实验疗法既安全又有效。该啮齿动物模型为左旋多巴/移植物相互作用的系统评估提供了有价值的第一步。这些研究将为开展灵长类动物研究提供重要的指导方针，可以测试进一步的假设和验证。