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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该项目中的研究的目的是在帕金森氏病动物模型（6-OH-多巴胺剂量的大鼠）中，在体内确认NR2D型NMDA受体的封锁作用的潜在反帕金森氏症。 这些药物最有可能通过阻断丘脑下核中的NR2D受体（在帕金森氏病过度活跃的结构）中起作用。 NR2D受体阻滞可以使该核中的活性正常化。 为了检验这一假设，计划了三个实验：（1）我们将建立抑制我们最好的NR2D-Sepalsection拮抗剂中丘脑神经元中含有天然NR2D的NR2D 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组合将使我们能够估计受体占用率是施用剂量的函数。 （2）我们将使用6-OH-多巴巴胺治疗的正常大鼠和大鼠中的免疫组织化学确定NR2D蛋白分布，以确认这种帕金森氏病动物模型中存在NR2D受体。 （3）我们将评估基底神经元中含NR2D受体的选择性阻断的能力，以改变6- OHDA丧失的动物中运动行为。