Intranigral transplantation in Parkinsonian Monkeys

描述(申请人提供)：多巴胺分泌异位胎儿腹中脑(FVM)组织移植到纹状体，提供移植物和宿主之间的突触连接，已被证明改善帕金森氏症，但有导致迟发性残疾障碍的风险。我们已经证明，分泌多巴的人视网膜色素上皮细胞(HRPEC)纹状体移植物不会导致移植物和宿主之间的突触连接，可以在不引起运动障碍的情况下改善帕金森综合症。在帕金森病(PD)患者中，黑质(SN)和纹状体的双多巴胺能移植可以提供更好的功能恢复和基底节神经生理学的恢复，并降低运动障碍的风险。我们建议比较fvm移植物和hPvPEC移植物移植到黑质和纹状体的效果，并评估这种移植物对药物诱导的帕金森病动物模型运动障碍的影响。所有动物都将接受左旋多巴治疗，以诱导药物诱导的运动障碍，并定期使用行为测试组(BBT)进行测试，以评估帕金森症和药物诱导的运动障碍。在特定目标1(SA1)中，一组偏侧帕金森病(HP)大鼠将接受FVM移植到黑质和纹状体，并与仅接受FVM移植到纹状体的HP大鼠和另外的对照组进行比较。在SA2中，一组HP大鼠将接受黑质和纹状体hRPEC移植，而另一组HP大鼠将hRPEC移植到纹状体。这两组将与对照组进行比较。微电极记录基底节的神经元活动、BBT评分的差异和免疫组织化学将是结果衡量标准。为了进一步描述运动障碍时的基底节神经生理学，并评估双重移植对复杂的运动行为和疾病进展的影响，我们建议在MPTP治疗的猴子身上测试多巴胺能双重移植的改善质量。在SA3实验中，双侧帕金森病猴子接受FVM或hRPEC的多巴胺能双重移植，并定期接受长期左旋多巴暴露，以评估药物诱导的运动障碍的神经生理学相关性。这些研究将测试两个独立但相互关联的问题，涉及宿主和移植物之间的突触连接，以及黑质和纹状体双侧多巴胺能移植物在调节药物诱导的运动障碍中的作用。所提出的研究将更好地描述帕金森病和药物诱导的运动障碍的病理生理机制，并有可能使我们更接近完全恢复帕金森病患者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.