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.

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。 该项目的目的是测试代谢性谷氨酸受体5（MGLUR5）拮抗剂在MPTP处理的帕金森氏病模型中的抗帕金森氏症和神经保护作用。基于有前途的啮齿动物研究，显示了MPPTP处理或MGLUR5敲除小鼠的MGLUR5介导的中脑多巴胺能神经元神经保护的证据，我们进行了一系列旨在测试MGLUR5拮抗剂的神经药物特性的实验。使用行为研究，功能性脑成像（使用多巴胺转运蛋白配体-18F-FECNT进行PET成像）和验尸后免疫细胞化学，我们的发现为NigroStriatal多巴胺能在MPTP培养的蒙基中的nigrostriatal dopropties oproption oprotient of Mggroptient of Mgg of Mgg the the of MMG的神经保护提供了明确的证据MGLUR5帕金森氏病的拮抗剂。 在另一系列正在进行的实验中，我们目前正在评估单独使用MGLUR5拮抗剂或与MPTP处理的Parkinsonian猴子中的A2A拮抗剂的症状性反帕金森疗法。尽管这些研究尚未完成，但我们有一些证据表明，在经MPTP处理的猴子中，系统地给予MGLUR5拮抗剂具有显着的反帕金森氏症。实验正在进行中，以评估这些动物中MGLUR5和A2A拮抗剂的潜在协同作用，如PD大鼠模型最近所示。 这些令人兴奋的发现应该为帕金森氏病中新型的反帕金森和神经保护疗法的发展提供有力的临床前证据。