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

Proceedings of the National Academy of Sciences of the United States of America - Tập 100 Số 10 - Trang 6145-6150 - 2003
Du‐Chu Wu1, Peter Teismann1, Kim Tieu1, Miquel Vila1, Vernice Jackson‐Lewis1, Harry Ischiropoulos1,2, Serge Przedborski1
1Departments of Neurology and Pathology and Center for Neurobiology and Behavior, Columbia University, New York, NY 10032; and Stokes Research Institute, Department of Pediatrics, Children's Hospital of Philadelphia, and Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
2School of Medicine, Philadelphia, PA 19104

Tóm tắt

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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Proceedings of the National Academy of Sciences of the United States of America

Tập 100 Số 10

6145-6150

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