NMDA RECEPTOR AS THERAPEUTIC TARGET FOR PARKINSON?S DISEASE

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 该项目研究的目的是在帕金森病动物模型（6-OH-多巴胺损伤的大鼠）中体内证实阻断 NR2D 型 NMDA 受体的潜在抗帕金森病作用。 这些药物最有可能通过阻断丘脑底核中的 NR2D 受体发挥作用，丘脑底核是一种在帕金森病中过度活跃的结构。 NR2D 受体阻断可能会使该细胞核的活性正常化。 为了检验这一假设，计划进行三个实验：（1）建立我们最好的 NR2D 选择性拮抗剂抑制底丘脑神经元中含有天然 NR2D 的 NMDA 受体的浓度效应曲线。 这些数据与体内药代动力学数据的结合将使我们能够估计受体占用率作为给药剂量的函数。 (2)利用免疫组织化学法测定正常大鼠和6-OH-多巴胺处理的大鼠中NR2D蛋白的分布，以证实该帕金森病动物模型中存在NR2D受体。 (3) 评估选择性阻断基底神经节神经元中含有 NR2D 的受体改变 6-OHDA 损伤动物运动行为的能力。 该项目已完成，正在准备发布结果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal of the studies in this project is to obtain in vivo confirmation of the potential antiparkinsonian effects of blockade of NR2D-type NMDA receptors in an animal model of Parkinson's disease, the 6-OH-dopamine-lesioned rat. These agents are most likely to work by blocking NR2D receptors in the subthalamic nucleus, a structure which is overactive in Parkinson's disease. NR2D receptor blockade may act to normalize the activity in this nucleus. To test this hypothesis, three experiments were planned: (1) To establish the concentration-effect curve for inhibition of native NR2D-containing NMDA receptors in subthalamic neurons by our best NR2D-selective antagonist. The combination of this data with in vivo pharmacokinetic data will allow us to estimate receptor occupancy as a function of administered dose. (2) To determine the NR2D protein distribution using immunohistochemistry in normal rats and rats treated with 6-OH-dopamine to confirm that NR2D receptors are present in this animal model of Parkinson's disease. (3) To evaluate the ability of selective blockade of NR2D-containing receptors in basal ganglia neurons to alter motor behavior in 6-OHDA-lesioned animals. This project was completed and publications of results are in preparation.