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.