LEVODOPA DYSKINESIAS: IMPACT OF DOPAMINE NEURONS

描述(由申请人提供)：帕金森氏病(PD)长期临床移植试验的最新发现表明，部分移植受者会发展为严重的移植后运动障碍。这些运动障碍是严重的，使人虚弱，并强烈表明其背后的机制需要阐明。Freed、Fahn和他的同事假设，移植物介导的运动障碍是移植物过度生长的结果。然而，他们自己的PET和尸检数据，以及其他人的数据，都不支持这一观点。我们提出了另一种假说，移植物后运动障碍的恶化是由于高多巴胺能功能的局部“热点”与左旋多巴启动的大脑相互作用所致。我们计划通过比较神经移植策略来验证这一假设，这些神经移植策略在多巴诱导的运动障碍中诱导a)广泛的或b)局部的多巴胺能功能，以及在帕金森病大鼠模型中多巴启动的作用。我们和其他人已经证明，长期使用左旋多巴治疗的单侧多巴胺(DA)耗竭的大鼠表现出运动障碍，其特征与人类帕金森病的运动障碍非常相似。此外，这个动物模型重要地展示了基底节机制，允许DA移植物要么加重(Steess-Collier等人，提交)，要么改善这些运动障碍指数，类似于在人类移植物受体中看到的。在继续临床应用之前，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。该啮齿动物模型为系统评价左旋多巴/移植物相互作用提供了有价值的第一步。这些研究将为发展灵长类动物研究提供重要的指导方针，以便进一步的假设和验证可以得到检验。

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.