NMDA RECEPTOR AS THERAPEUTIC TARGET FOR PARKINSON?S DISEASE

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 这项研究的目的是在体内证实阻断NR2D型NMDA受体在帕金森病动物模型6-羟基多巴胺损伤大鼠中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，而底核是帕金森病中过度活跃的结构。阻断NR2D受体可使该核团的活动正常化。为了验证这一假设，我们计划进行三个实验：(1)用我们最好的NR2D选择性拮抗剂建立抑制丘脑下丘脑神经元中天然NR2D受体的量效曲线。这一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有率作为给药剂量的函数。(2)用免疫组织化学方法检测正常大鼠和6-羟基多巴胺处理的大鼠脑内NR2D蛋白的分布，以证实NR2D受体在帕金森病动物模型中的存在。(3)观察选择性阻断基底节区NR2D受体改变6-OHDA损毁动物运动行为的能力。该项目已经完成，成果的出版工作正在筹备之中。

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.