Neuroregeneration Laboratories, McLean Hospital/Harvard Medical school, Belmont, MA 02478, USA.
J Parkinsons Dis. 2012;2(2):107-13. doi: 10.3233/JPD-2012-12102.
The transplantation of dopamine-rich tissue into the putamen of patients with Parkinson's disease shows much potential for use as a therapeutic strategy. However, a number of grafted individuals subsequently developed a set of abnormal involuntary movements (AIMs), unrelated to the dyskinesia caused by L-DOPA treatment, which have been termed graft-induced dyskinesia. Given the small number of patients, pre-clinical modeling of graft-induced dyskinesia in animal models will be critical to determine the underlying mechanisms and amelioration potential of this technique. Here we show that abnormal involuntary movements of the limbs, trunk and face can be observed in transplanted hemi-parkinsonian mice following amphetamine administration, similar to those previously described to model graft-induced dyskinesias in rats. C57Bl6 and CD1 mice were first rendered hemi-parkinsonian with 6-hydroxydopamine, treated with L-DOPA for 21 days until dyskinetic, and then transplanted with a single cell suspension of embryonic ventral mesencephalon (VM E12.5) tissue from corresponding strains into the denervated striatum. At 16 weeks post-transplantation, a single injection of amphetamine-elicited dyskinesia in a subgroup of mice of both strains, behavioural pattern not observed pre-transplantation. The number of surviving dopaminergic cells in the graft did not differ between those that developed AIMs and those that did not. The movements were phenotypically comparable to those seen in the rat model and parallels can be drawn to the human form of the movements, although the mouse model maybe less reproducible than the rat equivalent. This mouse model will facilitate assessment of graft-induced dyskinesia with mouse-derived stem cell lines and exploration of mechanisms using transgenic mice in future studies.
将富含多巴胺的组织移植到帕金森病患者的壳核中显示出作为一种治疗策略的巨大潜力。然而，一些移植的个体随后出现了一组异常的不自主运动（AIMs），与 L-DOPA 治疗引起的运动障碍无关，这些运动障碍被称为移植诱导的运动障碍。鉴于患者人数较少，在动物模型中对移植诱导的运动障碍进行临床前建模对于确定该技术的潜在机制和改善潜力将至关重要。在这里，我们表明，在给予安非他命后，半帕金森病小鼠的肢体、躯干和面部会出现异常的不自主运动，类似于先前描述的用于模拟大鼠移植诱导的运动障碍的模型。首先，用 6-羟多巴胺使 C57Bl6 和 CD1 小鼠半帕金森病化，用 L-DOPA 治疗 21 天，直到出现运动障碍，然后将胚胎腹侧中脑（VM E12.5）组织的单细胞悬浮液移植到去神经纹状体中。在移植后 16 周，亚组的两种品系的小鼠单次注射安非他命可诱发运动障碍，而在移植前未观察到这种行为模式。在出现 AIMs 和未出现 AIMs 的小鼠中，移植中存活的多巴胺能细胞数量没有差异。这些运动与在大鼠模型中观察到的运动在表型上是可比的，尽管与人类形式的运动相比，该模型可能不如大鼠模型那么可重复，但仍可以进行比较。这种小鼠模型将促进未来研究中使用小鼠来源的干细胞系评估移植诱导的运动障碍，并探索使用转基因小鼠的机制。
