title: Blockade of metabotropic glutamate receptor 5 protects against DNA damage in a rotenone-induced Parkinson's disease model.
abstract: Glutamate excitotoxicity contributes to the development of Parkinson's disease (PD) and pharmacological blockade of metabotropic glutamate receptor 5 (mGluR5) has beneficial anti-akinetic effects in animal models of PD; however, the mechanism by which these antagonists alleviate PD symptoms is largely unknown. In our study, the effects of mGluR5 inhibition on DNA damage were investigated in a rotenone-induced model of PD. We first found that the selective mGluR5 antagonist, 2-methyl-6- (phenylethynyl) pyridine, prevented rotenone-induced DNA damage in MN9D dopaminergic neurons through a mechanism involving the downregulation of intracellular calcium release which was associated with a reduction in endoplasmic reticulum stress and reactive oxygen species (ROS)-related mitochondrial dysfunction. Interestingly, the ROS-related mitochondrial dysfunction was accompanied by an increase in expression of the antioxidant protein, Trx2. Treatment of cells with the calcium chelating agent 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid or the ROS scavenger N-acetyl-L-cysteine, also reduced rotenone-induced DNA damage, while transfection of a dominant-negative form of Trx2 increased it. In addition, mGluR5 inhibition altered the expression profiles of proteins involved in DNA repair activity. Specifically, the expression of phosphorylated ERK (p-ERK) and CREB, as well as APE1 and Rad51 were elevated after rotenone stimulation and were subsequently downregulated following blockade of mGluR5. These findings were confirmed in vivo in a rotenone-induced rat model of PD. Inhibition of mGluR5 protected against neurotoxicity by mitigating oxidative stress-related DNA damage associated with 8-hydroxy-2'-deoxyguanosine production and also reduced p-ERK activity and Trx2 expression. These findings provide a novel link between mGluR5 and DNA damage in a model of PD, and reveal a potential mechanism by which mGluR5 mediates DNA damage in neurodegenerative diseases.
authors.affiliation: Department of Neurobiology, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, Beijing 100069, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Xia
authors.affiliation: Department of Neurobiology, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, Beijing 100069, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, Beijing 100069, China.
authors.forename: Shu Ting
authors.initials: ST
authors.lastname: Wang
authors.affiliation: Department of Neurobiology, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, Beijing 100069, China.
authors.forename: Li
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Neurobiology, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, Beijing 100069, China.
authors.forename: Hui Min
authors.initials: HM
authors.lastname: Yang
authors.affiliation: Department of Neurobiology, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, Beijing 100069, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA 02129.
authors.forename: Rachit
authors.initials: R
authors.lastname: Bakshi
authors.affiliation: Department of Neurobiology, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, Beijing 100069, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Neurobiology, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disease of the Ministry of Education, Capital Medical University, Beijing 100069, China. Electronic address: hzhang@ccmu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D020552:Comet Assay; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D012402:Rotenone / Q000633:toxicity; D014475:Uncoupling Agents / Q000633:toxicity
chemical_list: C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D014475:Uncoupling Agents; D012402:Rotenone
keywords: 8-OHdG, [Ca(2+)]i; DNA damage; ER; ERK; Metabotropic glutamate receptor 5; PD; Trx2