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

D. C. Wu, Peter Teismann, K. Tieu, M. Vila, V. Jackson-Lewis, H. Ischiropoulos, S. Przedborski

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Abstract

Parkinson's disease (PD) is a neuroclegenerative disorder of uncertain pathogenesis characterized by a loss of substantia nigra pars compacta (SNpc) clopaminergic (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.

Original languageEnglish
Pages (from-to)6145-6150
Number of pages5
JournalPNAS
Volume100
Issue number10
Early online date29 Apr 2003
DOIs
Publication statusPublished - 13 May 2003

Keywords

  • microglial activation
  • alpha-synuclein
  • MPTP toxicity
  • mouse model
  • synthase
  • mice
  • neurotoxicity
  • neurons
  • neurodegeneration
  • peroxynitrite

Cite this

Wu, D. C., Teismann, P., Tieu, K., Vila, M., Jackson-Lewis, V., Ischiropoulos, H., & Przedborski, S. (2003). NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. PNAS, 100(10), 6145-6150. https://doi.org/10.1073/pnas.0937239100