Intranigral Transplantation in Parkinsonian Monkeys

描述：(改编自《调查员摘要》)：近期调查 黑质(SN)内的多巴胺(DA)能神经元 不仅在纹状体内的轴突终末分泌多巴胺，而且 也通过它们在SN网状部(SNR)内的树突和 SNR中的多巴胺可能在帕金森病的发生中起作用 灵长类动物。作为必然结果，黑质和纹状体多巴胺的恢复 在帕金森氏病患者中，输入可能会产生更好的功能恢复 仅在纹状体中恢复多巴胺输入。因此，PI 建议检查联合DAG对胎儿腹侧中脑的影响 1-甲基-4-苯基-1-甲基-4-苯基-1，2，4-二甲基-4-苯基-1，4，4，6-二甲基-4-苯基-1，4，6-二甲基-4-苯基-1，4，4，6-二甲基-4-苯基-1，2，4，4-二甲基-4-苯基-1，4，4-二甲基-4-苯基-1，4，4，4-二甲基-4-苯基-1，4，4，4-二甲基-4-苯基-1，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4，4， 2，3，6-四氢吡啶(MPTP)治疗偏侧帕金森病(HP)猴和 将结果与仅在纹状体或黑质内进行FVM移植进行比较。动物 将由调查人员定期评估，调查人员对 使用行为测试组合(BBT)进行移植。所有的动物都会 颈动脉内注射MPTP可使幽门螺杆菌状态稳定并 口服左旋多巴以验证对多巴胺能治疗的反应性 随机分为4组(1-4)。微电极记录 将使用神经元活动和磁共振成像(MRI)来指导 所有的移植程序。在特定目标1(SA 1)中，第1组动物将 接受FVM同时移植到纹状体和SN，第2组 动物将接受纹状体FVM移植，第3组动物将接受FVM 移植到黑质和第4组动物体内的胎儿组织将会是“对照”的 移植到SN中。定期BBT评估和免疫化学评估 在1-4组之间比较的移植动物将被用来测试 纹状体和黑质FVM联合移植改善症状的假说 帕金森病的程度比纹状体FVM或黑质FVM移植更严重 独自一人。在SA 2中，将在组织之前和之后获得神经元记录 所有4组动物的SNR和丘脑下部移植 细胞核(STN)，并进行比较。这个实验将检验这样一种假设 纹状体FVM移植将改变双侧SNR的神经元放电模式 在STN，黑质FVM移植将改变神经元放电 仅限SNR中的模式。在SA 3中，将在体内测量多巴胺水平 黑质FVM移植前后的微透析术 第3组和第4组动物的STN。这项实验将检验这一假设 黑质FVM移植恢复了黑质中的多巴胺含量，但不能 影响STN中的多巴胺含量。这三个实验将客观地 评估恢复SN的DA能输入的作用 恢复纹状体内DA能传入改善帕金森病行为 在灵长类动物中的标志，将有助于理解SNR在 灵长类帕金森综合征的病理生理学。

DESCRIPTION: (Adapted from the Investigator's Abstract): Recent investigations indicate that dopaminergic (DArgic) neurons in the substantia nigra (SN) secrete dopamine not only in their axonal terminals within the striatum but also via their dendrites within the SN pars reticulata (SNr) and that loss of dopamine in the SNr may have a role in the development of parkinsonism in primates. As a corollary, restoration of both nigral and striatal dopamine inputs may produce better recovery of function in Parkinson's disease than restoration of dopamine inputs in the striatum alone. Therefore, the PI proposes to examine the effects of combined DArgic fetal ventral mesencephalic (FVM) cell transplantation into the SN and the striatum in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated hemiparkinsonian (HP) monkeys and compare the results with FVM transplants in the striatum or SN alone. Animals will be periodically assessed by investigators blinded to the type of transplantation using a behavioral battery of tests (BBT). All animals will be treated with intracarotid MPTP injections to cause a stable HP state and briefly treated with oral levodopa to verify responsiveness to DArgic therapy prior to randomization into 4 equal groups (1-4). Microelectrode recordings of neuronal activity and magnetic resonance imaging (MRI) will be used to guide all transplantation procedures. In specific aim 1 (SA 1), group 1 animals will receive simultaneous FVM transplants into both striatum and the SN, group 2 animals will receive striatal FVM transplants, group 3 animals will receive FVM transplants into the SN and group 4 animals will receive "control" fetal tissue transplants into the SN. Periodic BBT assessments and immunochemical assessment of the transplanted animals compared across groups 1-4 will be used to test the hypothesis that combined striatal and nigral FVM transplants ameliorates parkinsonism to a greater extent than striatal FVM or nigral FVM transplants alone. In SA 2, neuronal recordings will be obtained before and after tissue transplantation from all 4 groups of animals from the SNr and the subthalamic nucleus (STN) and compared. This experiment will examine the hypothesis that striatal FVM transplantation will alter neuronal discharge patterns in both SNr and in the STN, while nigral FVM transplantation will alter neuronal discharge patterns in the SNr only. In SA 3, dopamine levels will be measured in vivo using microdialysis before and after nigral FVM transplantation from the SN and STN in group 3 and group 4 animals. This experiment will test the hypothesis that nigral FVM transplants restore dopamine content in the SN but do not effect dopamine content in the STN. These 3 experiments will objectively evaluate the role of restoring DArgic inputs into the SN in addition to restoring DArgic inputs into the striatum to ameliorate parkinsonian behavioral signs in primates and will help to understand the role of SNr in the pathophysiology of primate parkinsonism.