[WITHDRAWN] Overexpression of superoxide dismutase or glutathione peroxidase protects against the paraquat + maneb-induced Parkinson disease phenotype.
Oxidative stress has been implicated in the pathogenesis of Parkinson disease based on its role in the cascade of biochemical changes that lead to dopaminergic neuronal death. This study analyzed the role of oxidative stress as a mechanism of the dopaminergic neurotoxicity produced by the combined paraquat and maneb model of the Parkinson disease phenotype. Transgenic mice overexpressing either Cu,Zn superoxide dismutase or intracellular glutathione peroxidase and non-transgenic mice were exposed to saline, paraquat, or the combination of paraquat + maneb twice a week for 9 weeks. Non-transgenic mice chronically exposed to paraquat + maneb exhibited significant reductions in locomotor activity, levels of striatal dopamine and metabolites, and dopaminergic neurons in the substantia nigra pars compacta. In contrast, no corresponding effects were observed in either Cu,Zn superoxide dismutase or glutathione peroxidase transgenic mice. Similarly, the increase in levels of lipid hydroperoxides in the midbrain and striatum of paraquat + maneb-treated non-transgenic mice was not detected in either Cu,Zn superoxide dismutase or glutathione peroxidase transgenic mice. To begin to determine critical pathways of paraquat + maneb neurotoxicity, the functions of cell death-inducing and protective mechanisms were analyzed. Even a single injection of paraquat + maneb in the non-transgenic treated group modulated several key pro- and anti-apoptotic proteins, including Bax, Bad, Bcl-xL, and upstream stress-induced cascade. Collectively, these findings support the assertion that protective mechanisms against paraquat + maneb-induced neurodegeneration could involve modulation of the level of reactive oxygen species and alterations of the functions of specific signaling cascades.
Thiruchelvam
Mona
M
Department of Biochemistry, and Environmental and Occupational Health Sciences Institute, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA.
Prokopenko
Olga
O
Cory-Slechta
Deborah A
DA
Richfield
Eric K
EK
Buckley
Brian
B
Mirochnitchenko
Oleg
O
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001835:Body Weight; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D005659:Fungicides, Industrial / Q000494:pharmacology; D005979:Glutathione Peroxidase / Q000096:biosynthesis*; D006540:Herbicides / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007150:Immunohistochemistry; D050356:Lipid Metabolism; D015227:Lipid Peroxidation; D008344:Maneb / Q000494:pharmacology*; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012701:Serotonin; D015398:Signal Transduction; D013378:Substantia Nigra / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051020:bcl-X Protein
C494812:Bcl2l1 protein, mouse; D005659:Fungicides, Industrial; D006540:Herbicides; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D008344:Maneb; D012701:Serotonin; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D014446:Tyrosine 3-Monooxygenase; D013482:Superoxide Dismutase; D010269:Paraquat; D004298:Dopamine