GLUTAMATE RECEPTORS: TARGETS FOR PARKINSON?S DISEASE PHARMACOTHERAPY

谷氨酸受体：帕金森病药物治疗的靶点

• 批准号: 7958216
• 负责人: Yoland Smith
• 金额: $ 5.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958216
• 关键词: Animals; Antiparkinson Agents; Autopsy; Behavioral; Brain imaging; Computer Retrieval of Information on Scientific Projects Database; Development; Dose; Funding; Glutamate Receptor; Grant; Injection of therapeutic agent; Institution; Knockout Mice; Lead; Ligands; Macaca mulatta; Mediating; Midbrain structure; Modeling; Monkeys; Parkinson Disease; Parkinsonian Disorders; Pharmacotherapy; Positron-Emission Tomography; Primates; Property; Rattus; Research; Research Personnel; Resources; Rodent; Series; Source; System; Testing; United States National Institutes of Health; base; dopamine transporter; dopaminergic neuron; immunocytochemistry; metabotropic glutamate receptor 5; neuroprotection; novel; pre-clinical; research study

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 purpose of this project is to test the antiparkinsonian efficacy and neuroprotective effects of metabotropic glutamate receptor 5 (mGluR5) antagonist in the MPTP-treated monkey model of Parkinson's disease. Based on promising rodent studies showing evidence for mGluR5-mediated neuroprotection of midbrain dopaminergic neurons in MPTP-treated or mGluR5 knock out mice, we undertook a series of experiments aimed at testing the neuroprotective properties of the mGluR5 antagonist, MTEP, in rhesus monkeys treated chronically with low doses of MPTP. Using a combination of behavioral studies, functional brain imaging (PET imaging using the dopamine transporter ligand-18F-FECNT) and postmortem immunocytochemistry, our recent findings provided clear evidence for significant neuroprotection of the nigrostriatal dopaminergic system in MPTP-treated monkeys that received daily injection of mGluR5 antagonist, suggesting the potential neuroprotective properties of mGluR5 antagonist in Parkinson's disease. In another series of ongoing experiments, we are currently assessing the symptomatic antiparkinsonian efficacy of mGluR5 antagonist alone or in combination with A2A antagonist in MPTP-treated parkinsonian monkeys. Although these studies are not yet completed, we have some evidence that systemic administration of mGluR5 antagonist in MPTP-treated monkeys has significant antiparkinsonian effects. Experiments are in progress to assess the potential synergistic effects of mGluR5 and A2A antagonist in these animals, as recently shown in rat models of PD. These exciting findings should lead to strong preclinical evidence for the development of novel antiparkinsonian and neuroprotective therapies in Parkinson's disease.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 本课题旨在研究代谢型谷氨酸受体5（mGluR 5）拮抗剂对MPTP治疗的猴帕金森病模型的抗帕金森病疗效和神经保护作用。基于有希望的啮齿动物研究显示MPTP治疗或mGluR 5敲除小鼠中脑多巴胺能神经元的mGluR 5介导的神经保护的证据，我们进行了一系列实验，旨在测试mGluR 5拮抗剂MTEP在长期接受低剂量MPTP治疗的恒河猴中的神经保护特性。结合行为学研究，脑功能成像（PET成像使用多巴胺转运蛋白配体-18F-FECNT）和死后免疫细胞化学，我们最近的研究结果提供了明确的证据，证明每日注射mGluR 5拮抗剂的MPTP治疗猴的黑质纹状体多巴胺能系统具有显著的神经保护作用，表明mGluR 5拮抗剂在帕金森病中具有潜在的神经保护作用。 在另一系列正在进行的实验中，我们目前正在评估MPTP治疗的帕金森病猴中单独使用mGluR 5拮抗剂或与A2 A拮抗剂联合使用的症状性抗帕金森病疗效。虽然这些研究尚未完成，但我们有一些证据表明，在MPTP治疗的猴中全身给予mGluR 5拮抗剂具有显著的抗帕金森病作用。正在进行实验以评估mGluR 5和A2 A拮抗剂在这些动物中的潜在协同作用，如最近在PD大鼠模型中所示。 这些令人兴奋的发现将为帕金森病新型抗帕金森病和神经保护疗法的开发提供强有力的临床前证据。