The role of microglia in paraquat-induced dopaminergic neurotoxicity

Xue Fei Wu, Michelle L. Block, Wei Zhang, Liya Qin, Belinda Wilson, Wan Qin Zhang, Bellina Veronesi, Jau Shyong Hong

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

Abstract

The herbicide paraquat (PQ) has been implicated as a potential risk factor for the development of Parkinson's disease. In this study, PQ (0.5-1 μM) was shown to be selectively toxic to dopaminergic (DA) neurons through the activation of microglial NADPH oxidase and the generation of superoxide. Neuron-glia cultures exposed to PQ exhibited a decrease in DA uptake and a decline in the number of tyrosine hydroxylase-immunoreactive cells. The selectivity of PQ for DA neurons was confirmed when PQ failed to alter γ-aminobutyric acid uptake in neuron-glia cultures. Microglia-depleted cultures exposed to 1 μM PQ failed to demonstrate a reduction in DA uptake, identifying microglia as the critical cell type mediating PQ neurotoxicity. Neuron-glia cultures treated with PQ failed to generate tumor necrosis factor-α and nitric oxide. However, microglia-enriched cultures exposed to PQ produced extracellular superoxide, supporting the notion that microglia are a source of PQ-derived oxidative stress. Neuron-glia cultures from NADPH oxidase-deficient (PHOX-/-) mice, which lack the functional catalytic subunit of NADPH oxidase and are unable to produce the respiratory burst, failed to show neurotoxicity in response to PQ, in contrast to PHOX +/+ mice. Here we report a novel mechanism of PQ-induced oxidative stress, where at lower doses, the indirect insult generated from microglial NADPH oxidase is the essential factor mediating DA neurotoxicity.

Original languageEnglish (US)
Pages (from-to)654-661
Number of pages8
JournalAntioxidants and Redox Signaling
Volume7
Issue number5-6
DOIs
StatePublished - May 2005

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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