The role of microglia in paraquat-induced dopaminergic neurotoxicity.
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 microM) 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 gamma-aminobutyric acid uptake in neuron-glia cultures. Microglia-depleted cultures exposed to 1 microM 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-alpha 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 PQinduced oxidative stress, where at lower doses, the indirect insult generated from microglial NADPH oxidase is the essential factor mediating DA neurotoxicity.
Wu
Xue-Fei
XF
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Block
Michelle L
ML
Zhang
Wei
W
Qin
Liya
L
Wilson
Belinda
B
Zhang
Wan-Qin
WQ
Veronesi
Bellina
B
Hong
Jau-Shyong
JS
D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D010269:Paraquat / Q000633:toxicity*; D051381:Rats; D013379:Substrate Specificity; D013481:Superoxides / Q000378:metabolism
D013481:Superoxides; D019255:NADPH Oxidases; D010269:Paraquat; D004298:Dopamine