Falkenstein Gero, Rosenthal Christoph, Reum Torsten, Morgenstern Rudolf, Döbrössy Máté, Nikkhah Guido
Laboratory of Molecular Neurosurgery, Department of Stereotactic and Functional Neurosurgery, Neurocenter, Albert-Ludwigs-University, Freiburg, Germany.
J Comp Neurol. 2009 Jul 1;515(1):41-55. doi: 10.1002/cne.22035.
The functional restorative capacity of fetal dopaminergic (DA) transplants is governed by a number of critical parameters including graft location, survival of DA neurons, and transplantation technique. In addition, there is an ongoing controversy whether "too much" or "too little" survival of DA neurons is responsible for the incomplete functional recovery observed in some transplanted Parkinson's disease (PD) patients. Here we investigated two implantation sites, the nucleus accumbens (NAc) and the caudate-putamen unit (CPU), and two different graft distributions within the CPU, i.e., two 0.75 microL deposits (CPU-2) versus six 0.25 microL deposits (CPU-6) in a rat model of PD. Grafts were derived from E14 rat ventral mesencephalon and the long-term functional outcome was evaluated with a wide range of complex-sensorimotor behavioral tests. The data show that forelimb stepping, balancing behavior, and skilled forelimb reaching behavior was more restored in CPU-6-grafted animals as compared to CPU-2 animals, although the number surviving dopaminergic neurons and dopamine release were similar in the two groups. Furthermore, a correlation analysis revealed a number of inverse relationships between the rate of DA neuron survival and sensorimotor performances, e.g., for skilled forelimb use. DA grafts placed into the NAc induced a partial recovery in drug-induced rotation tests but failed to restore any of the other sensorimotor behaviors tested. Taken together, these data have important implications both for a better understanding of the complex functional graft-host interactions as well as for the further optimization of clinical neural transplantation strategies in neurodegenerative diseases.
胎儿多巴胺能（DA）移植的功能恢复能力受许多关键参数的控制，包括移植位置、DA神经元的存活情况以及移植技术。此外，对于一些移植帕金森病（PD）患者中观察到的功能恢复不完全是由于DA神经元“存活过多”还是“存活过少”，目前仍存在争议。在此，我们在PD大鼠模型中研究了两个植入部位，即伏隔核（NAc）和尾状核 - 壳核单元（CPU），以及CPU内两种不同的移植物分布，即在CPU中分别注射两个0.75微升移植物（CPU - 2）与六个0.25微升移植物（CPU - 6）。移植物取自胚胎第14天大鼠的腹侧中脑，并通过一系列复杂的感觉运动行为测试评估长期功能结果。数据显示，与CPU - 2移植组动物相比，CPU - 6移植组动物的前肢踏步、平衡行为和熟练的前肢抓握行为恢复得更好，尽管两组中存活的多巴胺能神经元数量和多巴胺释放情况相似。此外，相关性分析揭示了DA神经元存活率与感觉运动表现之间存在一些负相关关系，例如熟练前肢使用方面。植入NAc的DA移植物在药物诱导的旋转试验中诱导了部分恢复，但未能恢复所测试的任何其他感觉运动行为。综上所述，这些数据对于更好地理解复杂的移植物 - 宿主功能相互作用以及进一步优化神经退行性疾病的临床神经移植策略具有重要意义。
