Carlsson Thomas, Carta Manolo, Winkler Christian, Björklund Anders, Kirik Deniz
CNS Disease Modeling Unit, Department of Experimental Medical Science, Lund University, 221 84 Lund, Sweden.
J Neurosci. 2007 Jul 25;27(30):8011-22. doi: 10.1523/JNEUROSCI.2079-07.2007.
Clinical trials in patients with Parkinson's disease have shown that transplants of fetal mesencephalic dopamine neurons can form a new functional innervation of the host striatum, but the clinical benefits have been highly variable: some patients have shown substantial recovery in motor function, whereas others have shown no improvement and even a worsening in the 3,4-dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinetic side effects. Differences in the composition of the grafted cell preparation may contribute to these discrepancies. In particular, the number of serotonin neurons contained in the graft can vary greatly depending on the dissection of the fetal tissue. Importantly, serotonin neurons have the ability to store and release dopamine, formed from exogenously administered L-DOPA. Here, we have evaluated the effect of transplants containing serotonin neurons, or a mixture of dopamine and serotonin neurons, on L-DOPA-induced dyskinesias in 6-hydroxydopamine-lesioned animals. As expected, dopamine neuron-rich grafts induced functional recovery, accompanied by a 60% reduction in L-DOPA-induced dyskinesia that developed gradually over the first 10 weeks. Rats with serotonin-rich grafts with few dopamine neurons, in contrast, showed a progressive worsening of their L-DOPA-induced dyskinesias over time, and no functional improvement. The antidyskinetic effect of dopamine-rich grafts was independent of the number of serotonin neurons present. We conclude that serotonin neurons in the grafts are likely to have a detrimental effect on L-DOPA-induced dyskinesias in cases in which the grafts contain no or few dopamine neurons.
帕金森病患者的临床试验表明，胎儿中脑多巴胺神经元移植可在宿主纹状体形成新的功能性神经支配，但临床益处差异很大：一些患者运动功能有显著恢复，而另一些患者则无改善，甚至左旋多巴（L-DOPA）诱导的运动障碍副作用恶化。移植细胞制剂组成的差异可能导致这些差异。特别是，移植中所含5-羟色胺神经元的数量可能因胎儿组织的解剖不同而有很大差异。重要的是，5-羟色胺神经元有能力储存和释放由外源性给予的L-DOPA形成的多巴胺。在此，我们评估了含有5-羟色胺神经元或多巴胺与5-羟色胺神经元混合物的移植对6-羟基多巴胺损伤动物L-DOPA诱导的运动障碍的影响。正如预期的那样，富含多巴胺神经元的移植诱导了功能恢复，同时L-DOPA诱导的运动障碍在最初10周内逐渐减少了60%。相比之下，含多巴胺神经元少而富含5-羟色胺神经元的移植大鼠，其L-DOPA诱导的运动障碍随时间逐渐恶化，且无功能改善。富含多巴胺的移植的抗运动障碍作用与存在的5-羟色胺神经元数量无关。我们得出结论，在移植不含或含少量多巴胺神经元的情况下，移植中的5-羟色胺神经元可能对L-DOPA诱导的运动障碍有不利影响。
