NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease.

Department of Neurology, Columbia University, New York, NY 10032, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 06/2003; 100(10):6145-50. DOI: 10.1073/pnas.0937239100
Source: PubMed

ABSTRACT Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by a loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons, and can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both inflammatory processes and oxidative stress may contribute to MPTP- and PD-related neurodegeneration. However, whether inflammation may cause oxidative damage in MPTP and PD is unknown. Here we show that NADPH-oxidase, the main reactive oxygen species (ROS)-producing enzyme during inflammation, is up-regulated in SNpc of human PD and MPTP mice. These changes coincide with the local production of ROS, microglial activation, and DA neuronal loss seen after MPTP injections. Mutant mice defective in NADPH-oxidase exhibit less SNpc DA neuronal loss and protein oxidation than their WT littermates after MPTP injections. We show that extracellular ROS are a main determinant in inflammation-mediated DA neurotoxicity in the MPTP model of PD. This study supports a critical role for NADPH-oxidase in the pathogenesis of PD and suggests that targeting this enzyme or enhancing extracellular antioxidants may provide novel therapies for PD.

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    ABSTRACT: Parkinson disease (PD) is the third most common neurodegenerative disorder affecting humans. Although it is clear that the etiology of a small number of PD cases is strictly genetic (either dominant or recessive) or purely environmental factors (e.g., pesticides, drug use, viruses, heavy metal exposure), it is likely that most cases arise from a combination of the two risk factors. For this reason, the generation and study of animal models where these interactions can be studied can provide important information regarding the pathophysiology of PD. In this chapter, we examine the mechanisms underlying xenobiotic-induced Parkinsonism using 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine as the model agent. We also examine other environmental agents that have been shown to induce Parkinsonism, including paraquat, lippopolysaccharide, and the highly pathogenic avian influenza virus.
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