NMDA RECEPTOR AS THERAPEUTIC TARGET FOR PARKINSON?S DISEASE

NMDA 受体作为帕金森病的治疗靶点

• 批准号: 8172433
• 负责人: Stella M Papa
• 金额: $ 4.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172433
• 关键词: Animal Model; Animals; Antiparkinson Agents; Basal Ganglia; Behavior; Cell Nucleus; Computer Retrieval of Information on Scientific Projects Database; Data; Dopamine; Dose; Drug Kinetics; Funding; Goals; Grant; Immunohistochemistry; Institution; Lesion; Motor; N-Methyl-D-Aspartate Receptors; Neurons; Parkinson Disease; Rattus; Research; Research Personnel; Resources; Source; Structure; Structure of subthalamic nucleus; Testing; United States National Institutes of Health; Work; in vivo; protein distribution; receptor; research study; therapeutic target

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 are planned: (1) We will 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 these data with in vivo pharmacokinetic data will allow us to estimate receptor occupancy as a function of administered dose. (2) We will 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) We will evaluate the ability of selective blockade of NR2D-containing receptors in basal ganglia neurons to alter motor behavior in 6-OHDA-lesioned animals.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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)我们将建立我们最好的NR2D选择性拮抗剂对丘脑下丘脑神经元中含有NR2D的天然NMDA受体的抑制浓度-效应曲线。将这些数据与体内药代动力学数据相结合，将使我们能够估计受体占有率作为给药剂量的函数。(2)我们将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)我们将评估选择性阻断6-OHDA损毁动物基底节神经元中含NR2D受体改变运动行为的能力。