期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 47, 期 7, 页码 1049-1056出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2009.07.013
关键词
Cyclooxygenase; DNA; MPTP; Neurodegeneration; Nitric oxide; Oxidative damage; Parkinson disease; Free radicals
资金
- NIH/NINDS [RO1 NS38586, NS42269, R21NS062180, NS064191, P01 ES016732, P50NS38370, P50 NS38377, P01NS11766-27A2, P50NS38367]
- U.S. Department of Defense [W81XWH-08-1-0522, W81XWH-08-1-0465, DAMD 17-03-1]
- Parkinson Disease Foundation (New York, NY, USA)
- Thomas Hartman Foundation
- European Commission
- La Caixa Foundation (Spain)
- Fondo de Investigacion Sanitaria (Instituto de Salud Carlos III, Spain)
DNA damage is a proposed pathogenic factor in neurodegenerative disorders such as Parkinson disease. To probe the underpinning mechanism of such neuronal perturbation, we sought to produce an experimental model of DNA damage. We thus first assessed DNA damage by in situ nick translation and emulsion autoradiography in the mouse brain after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4x20 mg/kg, ip, every 2 h), a neurotoxin known to produce a model of Parkinson disease. Here we show that DNA strand breaks occur in vivo in this mouse model of Parkinson disease with kinetics and a topography that parallel the degeneration of substantia nigra neurons, as assessed by FluoroJade labeling. Previously, nitric oxide synthase and cyclooxygenase-2 (Cox-2) were found to modulate MPTP-induced dopaminergic neuronal death. We thus assessed the contribution of these enzymes to DNA damage in mice lacking neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), or Cox-2. We found that the lack of Cox-2 and nNOS activities but not of iNOS activity attenuated MPTP-related DNA damage. We also found that not only nuclear, but also mitochondrial, DNA is a target for the MPTP insult. These results suggest that the loss of genomic integrity can be triggered by the concerted actions of nNOS and Cox-2 and provide further support to the view that DNA damage may contribute to the neurodegenerative process in Parkinson disease. (C) 2009 Elsevier Inc. All rights reserved.
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