کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8268669 | 1534954 | 2015 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Blockade of metabotropic glutamate receptor 5 protects against DNA damage in a rotenone-induced Parkinson's disease model
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کلمات کلیدی
TRX2MMPPhospho-histone H2AXmGluR5MPEPDHPGERK8-OHdGγ-H2AX2-methyl-6-(phenylethynyl)pyridine - 2-متیل-6- (فنیلئتینیل) پیریدینDMSO - DMSOMAPK - MAPKROS - ROS[Ca2+]i - [Ca2 +] iDNA damage - آسیبDNABAPTA - بیایپیتیایParkinson’s disease - بیماری پارکینسونtyrosine hydroxylase - تیروزین هیدروکسیلازDimethylsulfoxide - دیمتیل سولفواکسیدendoplasmic reticulum - شبکه آندوپلاسمی Mitochondrial membrane potential - پتانسیل غشای میتوکندریmitogen-activated protein kinase - پروتئین کیناز فعال با mitogenIntracellular calcium - کلسیم داخل سلولیextracellular signal-regulated kinase - کیناز تنظیم شده سیگنال خارج سلولیReactive oxygen species - گونههای فعال اکسیژنmetabotropic glutamate receptor 5 - گیرنده گلوتامات metabotropic 5
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
پیش نمایش صفحه اول مقاله
![عکس صفحه اول مقاله: Blockade of metabotropic glutamate receptor 5 protects against DNA damage in a rotenone-induced Parkinson's disease model Blockade of metabotropic glutamate receptor 5 protects against DNA damage in a rotenone-induced Parkinson's disease model](/preview/png/8268669.png)
چکیده انگلیسی
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-2â²-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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Free Radical Biology and Medicine - Volume 89, December 2015, Pages 567-580
Journal: Free Radical Biology and Medicine - Volume 89, December 2015, Pages 567-580
نویسندگان
Ning Xia, Qian Zhang, Shu Ting Wang, Li Gu, Hui Min Yang, Li Liu, Rachit Bakshi, Hui Yang, Hong Zhang,