The role of microglia in paraquat-induced dopaminergic neurotoxicity

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

Research output: Contribution to journalArticle

112 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Paraquat
Microglia
Neurons
NADPH Oxidase
Neuroglia
Oxidative stress
Dopaminergic Neurons
Superoxides
Oxidative Stress
Aminobutyrates
Respiratory Burst
Poisons
Tyrosine 3-Monooxygenase
Herbicides
Parkinson Disease
Catalytic Domain
Nitric Oxide
Tumor Necrosis Factor-alpha
Chemical activation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Wu, X. F., Block, M., Zhang, W., Qin, L., Wilson, B., Zhang, W. Q., ... Hong, J. S. (2005). The role of microglia in paraquat-induced dopaminergic neurotoxicity. Antioxidants and Redox Signaling, 7(5-6), 654-661. https://doi.org/10.1089/ars.2005.7.654

The role of microglia in paraquat-induced dopaminergic neurotoxicity. / Wu, Xue Fei; Block, Michelle; Zhang, Wei; Qin, Liya; Wilson, Belinda; Zhang, Wan Qin; Veronesi, Bellina; Hong, Jau Shyong.

In: Antioxidants and Redox Signaling, Vol. 7, No. 5-6, 05.2005, p. 654-661.

Research output: Contribution to journalArticle

Wu, XF, Block, M, Zhang, W, Qin, L, Wilson, B, Zhang, WQ, Veronesi, B & Hong, JS 2005, 'The role of microglia in paraquat-induced dopaminergic neurotoxicity', Antioxidants and Redox Signaling, vol. 7, no. 5-6, pp. 654-661. https://doi.org/10.1089/ars.2005.7.654
Wu, Xue Fei ; Block, Michelle ; Zhang, Wei ; Qin, Liya ; Wilson, Belinda ; Zhang, Wan Qin ; Veronesi, Bellina ; Hong, Jau Shyong. / The role of microglia in paraquat-induced dopaminergic neurotoxicity. In: Antioxidants and Redox Signaling. 2005 ; Vol. 7, No. 5-6. pp. 654-661.
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