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Nitric oxide and DOPAC-induced cell death: From GSH depletion to mitochondrial energy crisis.
MedLine Citation:
PMID:  21708261     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The molecular mechanisms inherent to cell death associated with Parkinson's disease are not clearly understood. Diverse pathways, sequence of events and models have been explored in several studies. Recently, we have proposed an integrative mechanism, encompassing the interaction of nitric oxide (NO) and a major dopamine metabolite, dihydroxyphenylacetic (DOPAC), leading to a synergistic mitochondrial dysfunction and cell death that may be operative in PD. In this study, we have studied the sequence of events underlying the mechanisms of cell death in PC12 cells exposed to NO and DOPAC in terms of: a) free radical production; b) modulation by glutathione (GSH); c) energetic status and d) outer membrane mitochondria permeability. Using Electron Paramagnetic Resonance (EPR) it is shown the early production of oxygen free radicals followed by a depletion of GSH reflected by an increase of GSSG/GSH ratio in the cells treated with the mixture of NO/DOPAC, as compared with the cells individually exposed to each of the stimulus. Glutathione ethyl ester (GSH-EE) and N-acetylcysteine (NAC) may rescue cells from death, increasing GSH content and preventing ATP loss in cells treated with the mixture DOPAC/NO but failed to exert similar effects in the cells challenged only with NO. The depletion of GSH is accompanied by a decreased activity of mitochondrial complex I. At a later stage, the concerted action of DOPAC and NO include a rise in the ratio Bax/Bcl-2, an observation not evident when cells were exposed only to NO. The results support a free radical-induced pathway leading to cell death involving the concerted action of DOPAC and NO and the critical role of GSH in maintaining a functional mitochondria.
Authors:
Carla Nunes; Rui M Barbosa; Leonor Almeida; João Laranjinha
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-6-24
Journal Detail:
Title:  Molecular and cellular neurosciences     Volume:  -     ISSN:  1095-9327     ISO Abbreviation:  -     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-6-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9100095     Medline TA:  Mol Cell Neurosci     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011. Published by Elsevier Inc.
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