Intranigral Transplantation in Parkinsonian Monkeys

帕金森病猴的黑质内移植

• 批准号: 6540522
• 负责人: THYAGARAJAN SUBRAMANIAN
• 金额: $ 34.36万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540522
• 关键词: Parkinson's disease; Primates; amphetamines; apomorphine; dopamine; embryo /fetus tissue transplantation; laboratory rat; levodopa; magnetic resonance imaging; methylphenyltetrahydropyridine; microdialysis; nervous system disorder therapy; nervous system transplantation; neuropharmacology; nonhuman therapy evaluation; substantia nigra

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.

描述：（改编自研究者摘要）：最近的调查 表明黑质 (SN) 中的多巴胺能 (DArgic) 神经元 不仅在纹状体内的轴突末端分泌多巴胺，而且 也通过它们在 SN 网状部 (SNr) 内的树突，并且损失 SNr 中的多巴胺可能在帕金森病的发展中发挥作用 灵长类动物。作为推论，黑质和纹状体多巴胺的恢复 与帕金森病相比，输入可能会更好地恢复帕金森病的功能 仅恢复纹状体中的多巴胺输入。因此，PI 提议检查联合 DArgic 胎儿腹侧中脑的影响 (FVM) 细胞移植到 1-甲基-4-苯基-1 的 SN 和纹状体中， 2, 3, 6-四氢吡啶 (MPTP) 治疗的偏帕金森病 (HP) 猴和 将结果与单独纹状体或 SN 中的 FVM 移植进行比较。动物 将由不了解该类型的调查人员定期评估 使用行为测试组（BBT）进行移植。所有动物都会 颈动脉内注射MPTP以引起稳定的HP状态并 口服左旋多巴进行短暂治疗，以验证对 DArgic 治疗的反应 在随机分为 4 个相等的组 (1-4) 之前。微电极记录 神经元活动和磁共振成像（MRI）将用于指导 所有移植程序。在具体目标 1 (SA 1) 中，第 1 组动物将 同时接受纹状体和 SN 的 FVM 移植，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 SN 中，第 4 组动物将接受“对照”胎儿组织 移植到SN。定期 BBT 评估和免疫化学评估 第 1-4 组之间比较的移植动物的数量将用于测试 假设纹状体和黑质 FVM 移植相结合可以改善 帕金森病的程度比纹状体 FVM 或黑质 FVM 移植更大 独自的。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 和底丘脑移植 核（STN）并进行比较。这个实验将检验以下假设： 纹状体 FVM 移植将改变两个 SNr 的神经元放电模式 在 STN 中，黑质 FVM 移植会改变神经元放电 仅 SNr 中的模式。在 SA 3 中，将测量体内多巴胺水平 在从 SN 和黑质 FVM 移植之前和之后使用微透析 第 3 组和第 4 组动物中的 STN。这个实验将检验假设 黑质 FVM 移植可以恢复 SN 中的多巴胺含量，但不能恢复 影响 STN 中的多巴胺含量。这3个实验将客观 除了评估将 DArgic 输入恢复到 SN 之外的作用 恢复纹状体的 DArgic 输入以改善帕金森病行为 灵长类动物中的迹象，将有助于理解 SNr 在 灵长类帕金森病的病理生理学。