Blockade of metabotropic glutamate receptors inhibits cognition and neurodegeneration in an MPTP-induced Parkinson's disease rat model

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• 作者：Ming-Hong Hsieh^a ; ^b ; Shih-Chun Ho^c ; Kuei-Ying Yeh^d ; Cornelius Rainer Pawlak^e ; ^f ; Hung-Ming Chang^g ; Ying-Jui Ho^b ; ^c ; ^{yjho@csmu.edu.tw} ; ^{joshuayjho@yahoo.com.tw} ; Te-Jen Lai^a ; ^b ; ^{ltj3123@ms2.hinet.net} ; ^{tejenlai@hotmail.com} ; Fu-Ying Wu^h
• 关键词：Parkinson's disease ; Dementia ; Metabotropic glutamate receptor ; MPEP ; Cognition
• 刊名：Pharmacology Biochemistry and Behavior
• 出版年：2012
• 期刊代码：219_00913057
• 类别：med
• 出版时间：July, 2012
• 卷：102
• 期：1
• 页码：64-71
• 文件大小：1286 K

摘要

Hyperactivity of the glutamatergic system is involved in excitotoxicity and neurodegeneration in Parkinson's disease (PD). Metabotropic glutamate receptor subtype 5 (mGluR5) modulates glutamatergic transmission and thus has been proposed as a potential target for neuroprotective drugs. The aim of this study was to determine the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), an mGluR5 antagonist, on working memory, object recognition, and neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were stereotaxically injected with MPTP into the substantia nigra pars compacta (SNc). Starting 1 day after lesioning (day 1), the rats were treated daily with MPEP (2 mg/kg/day, i.p.) for 14 days and rats underwent a T-maze test on days 8-10 and an object recognition test on days 12-14. MPTP-lesioned rats showed impairments of working memory in the T-maze test and of recognition function in the object recognition test and both effects were prevented by MPEP treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area were all inhibited by MPEP treatment. These data provide support for a role of mGluR5s in the pathophysiology of PD and suggest that MPEP is a promising pharmacological tool for the development of new treatments for dementia associated with PD.