Department of Neurology, University Hospital Freiburg, 79106 Freiburg, Germany.
Neurobiol Dis. 2011 Sep;43(3):576-87. doi: 10.1016/j.nbd.2011.05.004. Epub 2011 May 13.
Fetal dopamine (DA) cell transplantation has shown to be efficient in reversing behavioral impairments associated with Parkinson's disease. However, the beneficial effects on motor behavior and L-DOPA-induced dyskinesia have varied greatly in between clinical trials and patients within the same trial. Recently, the inclusion of serotonin (5-HT) neurons in the grafted tissue has been suggested to play an important negative role, in particular, on the effect of L-DOPA-induced dyskinesia. In the present study we have evaluated the influence of different ratios of DA neurons in relation to 5-HT neurons in the graft on spontaneous motor behavior and L-DOPA-induced dyskinesia in a rat model of Parkinson's disease. We show that using the standard dissection method that gives rise to a DA:5-HT ratio in the graft of 2:1 to 1:2 there is significant and consistent improvement in spontaneous motor behavior and reversal of L-DOPA-induced dyskinesia. Increasing the ratio of 5-HT neurons in the graft, to a DA:5-HT ratio of in between 1:3 and 1:10, still induces significant reduction of L-DOPA-induced dyskinesia, suggesting that the detrimental effect of 5-HT neurons on L-DOPA-induced dyskinesia is prevented even by small numbers of DA neurons in the graft. Nonetheless, while the post-synaptic responses were normalized following peripheral L-DOPA delivery in animals with low DA:5-HT ratio, we observed a pharmacological indication of hyperactive pre-synaptic response in these animals. These data suggests that 5-HT cells within a graft are neither detrimental nor beneficial for functional effects of DA-rich transplants; however, in absence of sufficient numbers of DA neurons, the 5-HT neurons may induce negative effects following L-DOPA therapy. In summary, our data indicate that for future clinical trials the inclusion of 5-HT neurons in grafted tissue is not critical as long as there are sufficient numbers of DA cells in the graft.
胎儿多巴胺（DA）细胞移植已被证明能有效逆转帕金森病相关的行为障碍。然而，在临床试验之间以及同一试验中的患者之间，对运动行为和左旋多巴诱导的运动障碍的有益效果差异很大。最近，移植组织中包含 5-羟色胺（5-HT）神经元被认为起着重要的负面作用，特别是对左旋多巴诱导的运动障碍的影响。在本研究中，我们评估了移植组织中 DA 神经元与 5-HT 神经元的不同比例对帕金森病大鼠模型自发运动行为和左旋多巴诱导的运动障碍的影响。我们表明，使用标准的分离方法，使移植组织中的 DA：5-HT 比例为 2：1 至 1：2，会显著且一致地改善自发运动行为，并逆转左旋多巴诱导的运动障碍。增加移植组织中 5-HT 神经元的比例，使 DA：5-HT 比例在 1：3 至 1：10 之间，仍然会导致左旋多巴诱导的运动障碍显著减少，这表明即使移植组织中的 DA 神经元数量较少，5-HT 神经元对左旋多巴诱导的运动障碍的有害影响也会被阻止。尽管在低 DA：5-HT 比例的动物中，外周给予左旋多巴后突触后反应正常化，但我们观察到这些动物的突触前反应存在药理学上的过度活跃迹象。这些数据表明，移植组织中的 5-HT 细胞对富含 DA 的移植体的功能效果既没有不利影响也没有有益影响；然而，在缺乏足够数量的 DA 神经元的情况下，5-HT 神经元可能会在左旋多巴治疗后产生负面影响。总之，我们的数据表明，对于未来的临床试验，只要移植组织中有足够数量的 DA 细胞，移植组织中包含 5-HT 细胞就不是关键因素。
