Journal
BRAIN RESEARCH
Volume 1167, Issue -, Pages 129-139Publisher
ELSEVIER
DOI: 10.1016/j.brainres.2007.06.046
Keywords
paraquat; NADPH oxidase; apocynin; microglia; cytotoxicity; ROS; Parkinson's disease
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Funding
- NIA NIH HHS [P01 AG018357, P01 AG018357-05] Funding Source: Medline
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Excess production of reactive oxygen species (ROS) is an important mechanism underlying the pathogenesis of a number of neurodegenerative diseases including Parkinson's disease (PD) which is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. Exposure to paraquat, an herbicide with structure similar to the dopaminergic neurotoxin, 1-methyl-4-phenylpyridinium (MPP+), has been shown to produce PD-like symptoms. Despite previous focus on the dopaminergic neurons and signaling pathways involved in their cell death, recent studies have implicated microglial cells as a major producer of ROS for damaging neighboring neurons. In this study, we examined the source of ROS and the underlying signaling pathway for paraquat-induced cytotoxicity to BV-2 microglial cells. Paraquat-induced ROS production (including superoxide anions) in BV-2 cells was accompanied by translocation of the p67(phox) CYtOSOliC subunit of NADPH oxidase to the membrane. Paraquat-induced ROS production was inhibited by NADPH oxidase inhibitors, apocynin and diphenylene iodonium (DPI), but not the xanthine/xanthine oxidase inhibitor, allopurinol. Apocynin and DPI also rescued cells from paraquat-induced toxicity. The inhibitors for protein kinase C delta (PKC delta) or extracellular signal-regulated kinases (ERK1/2) could partially attenuate paraquat-induced ROS production and cell death. Rottlerin, a selective PKC delta inhibitor, also inhibited paraquat-induced translocation of p67(phox). Taken together, this study demonstrates the involvement of ROS from NADPH oxidase in mediating paraquat cytotoxicity in BV-2 microglial cells and this process is mediated through PKC delta- and ERK-dependent pathways. (c) 2007 Elsevier B.V. All rights reserved.
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