Intranigral transplantation in Parkinsonian Monkeys

多巴胺分泌异位胎儿腹侧中脑（FVM）组织移植到纹状体，提供突触 移植物和宿主之间的连接已被证明可以改善帕金森症，但有引起延迟的风险。 运动障碍我们已经证明，分泌多巴的人视网膜色素上皮细胞纹状体移植物 不引起移植物和宿主之间突触连接的hRPEC改善帕金森症， 导致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 帕金森病患者运动障碍风险降低的功能恢复和基底神经节神经生理学恢复 疾病（PD）。我们建议将FVM移植物与hPVPEC移植物移植到SN和HPVPEC移植物中的效果进行比较。 纹状体，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 用左旋多巴治疗以诱导药物诱导的运动障碍，并使用行为测试组定期测试 (BBT)评估帕金森综合征和药物诱发的运动障碍。在特定目标1（SA 1）中，一组偏侧帕金森病患者 (HP)大鼠将接受FVM移植到SN和纹状体中 移植到单独的纹状体和另外的对照组。在SA2中，一组HP大鼠将接受黑质和纹状体 另一组HP大鼠将接受hRPEC移植物进入纹状体，而另一组HP大鼠将接受hRPEC移植物进入纹状体。这两个小组将 与对照组相比。基底神经节神经元活动的微电极记录，BBT的差异 评分和免疫组织化学将是结果测量。为了进一步描述基底神经节神经生理学， 运动障碍和评估双重移植对复杂运动行为和疾病进展的影响，我们建议 在MPTP处理的猴中测试多巴胺能双重移植的改善质量。在SA3中，双边 帕金森病猴“准备”有药物诱导的运动障碍，将接受多巴胺能双重移植的FVM 或hRPEC，并用慢性左旋多巴暴露定期激发，以评估 药物引起的运动障碍这些研究将测试两个独立但相关的关于突触连接的问题 以及黑质和纹状体多巴胺能神经元移植物在调节药物诱导的神经元凋亡中的作用 运动障碍拟议的研究将更好地描述PD和药物诱导的运动障碍的病理生理学， 潜在地使我们接近完全恢复PD中黑质纹状体多巴胺能通路的理想。

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 substantianigra (SN) and the striatum may provide better recovery of function and restoration of basal ganglia neurophysiologywith 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 imrnunohistochernistry 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.