Intranigral transplantation in Parkinsonian Monkeys

描述（由申请人提供）：多巴胺分泌异位胎儿腹侧中脑（FVM）组织移植到纹状体中，在移植物和宿主之间提供突触连接，已显示可改善帕金森综合征，但有引起延迟性失能性运动障碍的风险。我们已经表明，多巴分泌纹状体移植的人视网膜色素上皮细胞（hRPEC），不引起移植物和宿主之间的突触连接改善帕金森氏症，而不引起运动障碍。双多巴胺能移植到黑质（SN）和纹状体可能会提供更好的功能恢复和基底神经节神经生理学的恢复，降低帕金森病（PD）的运动障碍的风险。我们建议将FVM移植物与hPVPEC移植物移植到SN和纹状体中的效果进行比较，并评估这种移植物对PD动物模型中药物诱导的运动障碍的影响。所有动物将接受左旋多巴处理以诱导药物诱导的运动障碍，并使用行为测试组合（BBT）定期进行测试，以评估帕金森症和药物诱导的运动障碍。在具体目标1（SA 1）中，一组偏侧帕金森病（HP）大鼠将接受FVM移植到SN和纹状体中，并与接受FVM移植到单独纹状体中的HP大鼠和另外的对照组进行比较。在SA2中，一组HP大鼠将接受hRPEC的黑质和纹状体移植物，而另一组HP大鼠将接受hRPEC单独移植到纹状体中。将这2组与对照组进行比较。基底神经节神经元活动的微电极记录、BBT评分的差异和免疫组织化学将作为结局指标。为了进一步描述运动障碍期间的基底神经节神经生理学，并评估双重移植物对复杂运动行为和疾病进展的影响，我们建议在MPTP治疗的猴中测试多巴胺能双重移植物的改善质量。在SA3中，“致敏”具有药物诱导的运动障碍的双侧帕金森病猴将接受FVM或hRPEC的多巴胺能双重移植物，并定期用慢性左旋多巴暴露激发以评估药物诱导的运动障碍的神经生理学相关性。这些研究将测试2个独立但相关的问题，即宿主与移植物之间的突触连接以及双黑质和纹状体多巴胺能移植物在调节药物诱导的运动障碍中的作用。拟议的研究将更好地描绘PD和药物诱导的运动障碍的病理生理学，并可能使我们接近完全恢复PD的黑质纹状体多巴胺能通路的理想。

DESCRIPTION (provided by applicant): Dopamine secreting heterotopic fetal ventral mesencephalic (FVM) tissue grafts into the striatum that provide synaptic connectivity between the graft and the host have been shown to improve parkinsonism but at the risk of causing delayed disabling dyskinesias. We have shown that dopa secreting striatal grafts of human retinal pigment epithelial cells (hRPEC) that do not cause synaptic connectivity between the graft and the host ameliorate parkinsonism without causing dyskinesias. Dual dopaminergic grafts into the substantia nigra (SN) and the striatum may provide better recovery of function and restoration of basal ganglia neurophysiology with reduced risk for dyskinesias in Parkinson's disease (PD). We propose to compare the effects of transplanting FVM grafts versus hPvPEC grafts into the SN and the striatum and to assess the effects of such grafts on drug induced dyskinesias in animal models of PD. All animals will be treated with levodopa to induce drug induced dyskinesias and periodically tested using a behavioral battery of tests (BBT) to assess parkinsonism and drug induced dyskinesias. In specific aim 1 (SA1), one group of hemiparkinsonian (HP) rats will receive FVM transplants into the SN and into the striatum and compared to HP rats that receive FVM grafts into the striatum alone and additional control groups. In SA2, a group of HP rats will receive nigral and striatal grafts of hRPEC while another group of HP rats will receive hRPEC grafts into the striatum alone. These 2 groups will be compared to controls. Microelectrode recordings of neuronal activity from the basal ganglia, differences in BBT scores and immunohistochemistry will be outcome measures. To further delineate basal ganglia neurophysiology during dyskinesias and to assess the effects of dual grafts on complex motor behavior and disease progression, we propose to test the ameliorative qualities of dopaminergic dual transplants in the MPTP treated monkey. In SA3, bilaterally parkinsonian monkeys "primed" to have drug induced dyskinesias will receive dopaminergic dual grafts of either FVM or hRPEC and periodically challenged with chronic levodopa exposure to assess the neurophysiological correlates of drug induced dyskinesias. These studies will test 2 separate but linked questions regarding synaptic connectivity between the host and the graft and the role of dual nigral and striatal dopaminergic grafts in modulating drug induced dyskinesias. Proposed studies will better delineate the pathophysiology of PD and drug induced dyskinesias and potentially bring us close to the ideal of complete restoration of the nigrostriatal dopaminergic pathway in PD.