TY - JOUR
T1 - Blockade of metabotropic glutamate receptors inhibits cognition and neurodegeneration in an MPTP-induced Parkinson's disease rat model
AU - Hsieh, Ming Hong
AU - Ho, Shih Chun
AU - Yeh, Kuei Ying
AU - Pawlak, Cornelius Rainer
AU - Chang, Hung Ming
AU - Ho, Ying Jui
AU - Lai, Te Jen
AU - Wu, Fu Ying
PY - 2012/7
Y1 - 2012/7
N2 - 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.
AB - 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.
KW - Cognition
KW - Dementia
KW - Metabotropic glutamate receptor
KW - MPEP
KW - Parkinson's disease
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U2 - 10.1016/j.pbb.2012.03.022
DO - 10.1016/j.pbb.2012.03.022
M3 - Article
C2 - 22487770
AN - SCOPUS:84859804848
VL - 102
SP - 64
EP - 71
JO - Pharmacology, Biochemistry and Behavior
JF - Pharmacology, Biochemistry and Behavior
SN - 0091-3057
IS - 1
ER -