Intranigral transplantation in Parkinsonian Monkeys

多巴胺分泌异位胎儿腹侧中脑(FVM)组织移植到提供突触的纹状体 移植物和宿主之间的连通性已被证明可以改善帕金森症，但存在导致延迟的风险 使运动障碍失灵。我们已经证明了分泌多巴的人视网膜色素上皮细胞的纹状体移植物 不引起移植物和宿主之间突触连接的(HRPEC)改善帕金森综合征 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 帕金森病患者功能恢复和基底节神经生理学恢复与运动障碍风险降低 疾病(PD)。我们建议比较将FVM移植物和hPvPEC移植物移植到SN和 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。所有动物都会 用左旋多巴治疗药物引起的运动障碍，并定期使用一组行为测试进行测试 (BBT)评估帕金森症和药物引起的运动障碍。在特定目标1(SA1)中，一组偏侧帕金森病患者 (HP)大鼠将接受FVM移植到黑质和纹状体，并与接受FVM的HP大鼠进行比较 单独移植到纹状体和附加对照组。在SA2中，一组HP大鼠将接受黑质和纹状体 另一组大鼠仅接受hRPEC纹状体内移植。这两个小组将 被比作对照。基底神经节神经元活动的微电极记录，BBT差异 评分和免疫组织化学将作为结果衡量标准。以进一步描述基底节的神经生理学 运动障碍和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处理的猴身上测试多巴胺能双重移植的改善效果。在SA3中，双边 帕金森病猴子将接受任何一种FVM的多巴胺能双重移植 或hRPEC，并定期接受左旋多巴慢性暴露，以评估神经生理学相关性 药物引起的运动障碍。这些研究将测试两个关于突触连接的独立但相互关联的问题 宿主和移植物之间的关系以及黑质和纹状体双侧多巴胺能移植物在药物诱导中的调节作用 运动障碍。拟议的研究将更好地描述帕金森病和药物引起的运动障碍的病理生理学和 这可能使我们更接近帕金森病患者黑质纹状体多巴胺能通路完全恢复的理想。

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.