Impact of dopamine to serotonin cell ratio in transplants on behavioral recovery and L-DOPA-induced dyskinesia

详细信息    查看全文

• 作者：Joanna Garcí ; a^a ; ^b ; Thomas Carlsson^c ; ¹ ; Má ; té ; D&#xf6 ; br&#xf6 ; ssy^b ; Guido Nikkhah^b ; Christian Winkler^a ; ^{christian.winkler@uniklinik-freiburg.de" rel="nofollow}
• 关键词：Parkinson's disease ; Cell transplantation ; Motor behavior ; L-DOPA-induced dyskinesia ; Serotonin
• 刊名：Neurobiology of Disease
• 出版年：2011
• 出版时间：September 2011
• 年：2011
• 卷：43
• 期：3
• 页码：576-587
• 全文大小：1596 K

文摘

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.