The Role of NADPH Oxidase 1–Derived Reactive Oxygen Species in Paraquat-Mediated Dopaminergic Cell Death
- 1 September 2009
- journal article
- research article
- Published by Mary Ann Liebert Inc in Antioxidants and Redox Signaling
- Vol. 11 (9), 2105-2118
- https://doi.org/10.1089/ars.2009.2459
Abstract
Oxidative stress is the common downstream effect of a variety of environmental neurotoxins that are strongly implicated in the pathogenesis of Parkinson's disease. We demonstrate here that the activation of NADPH oxidase 1 (Nox1), a specialized superoxide-generating enzyme complex, plays a key role in the oxidative stress and subsequent dopaminergic cell death elicited by paraquat. Paraquat increased the expression of Nox1 in a concentration-dependent manner in rat dopaminergic N27 cells. Rac1, a key component necessary for Nox1-mediated superoxide generation, also was activated by paraquat. Paraquat-induced reactive oxygen species generation and dopaminergic cell death were significantly reduced after pretreatment with apocynin, a putative NADPH oxidase inhibitor, and Nox1 knockdown with siRNA. Male C57BL/6 mice received intraperitoneal (IP) injections of paraquat (10 mg/kg) once every 3 days and showed increased Nox1 levels in the substantia nigra as well as a 35% reduction in tyrosine hydroxylase–positive dopaminergic neurons 5 days after the last injection. Preadministration of apocynin (200 mg/kg, IP) led to a significant decrease in dopaminergic neuronal loss. Our results suggest that Nox1-generated superoxide is implicated in the oxidative stress elicited by paraquat in DA cells, and it can serve as a novel target for pharmacologic intervention. Antioxid. Redox Signal. 11, 2105–2118.Keywords
This publication has 60 references indexed in Scilit:
- Mitochondria Are a Major Source of Paraquat-induced Reactive Oxygen Species Production in the BrainOnline Journal of Public Health Informatics, 2007
- Microglial activation as a priming event leading to paraquat-induced dopaminergic cell degenerationNeurobiology of Disease, 2007
- A pivotal role of matrix metalloproteinase‐3 activity in dopaminergic neuronal degeneration via microglial activationThe FASEB Journal, 2006
- Link between Mitochondria and NADPH Oxidase 1 Isozyme for the Sustained Production of Reactive Oxygen Species and Cell DeathOnline Journal of Public Health Informatics, 2006
- NADPH Oxidases of the Brain: Distribution, Regulation, and FunctionAntioxidants and Redox Signaling, 2006
- Nox1-dependent Reactive Oxygen Generation Is Regulated by Rac1Online Journal of Public Health Informatics, 2006
- NOX1/NADPH oxidase negatively regulates nerve growth factor-induced neurite outgrowthFree Radical Biology & Medicine, 2006
- Involvement of Rac1 in Activation of Multicomponent Nox1- and Nox3-Based NADPH OxidasesMolecular and Cellular Biology, 2006
- Pesticides and Parkinson’s Disease—Is There a Link?Environmental Health Perspectives, 2006
- Environmental risk factors and Parkinson's diseaseNeurology, 1997