Synergistic dopaminergic neurotoxicity of MPTP and inflammogen lipopolysaccharide: relevance to the etiology of Parkinson's disease.
Parkinson's disease (PD) is a profound movement disorder resulting from progressive degeneration of the nigrostriatal dopaminergic pathway. Although its etiology remains unknown, increasing evidence suggests the involvement of multiple factors such as environmental toxins and genetic susceptibilities in the pathogenesis of PD. In this study using mesencephalic neuron-glia cultures as an in vitro PD model, we demonstrated that the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 0.1-0.5 microM) and an inflammogen lipopolysaccharide (LPS, 0.5 ng/ml) synergistically induced a progressive and selective degeneration of dopaminergic neurons. The synergistic neurotoxicity was observed when both agents were applied either simultaneously or in tandem. The synergistic neurotoxicity was more prominent when lower doses of both agents were applied for a longer period of time. Mechanistically, microglial NADPH oxidase-mediated generation of reactive oxygen species played a pivotal role in the synergistic neurotoxicity: MPTP and LPS synergistically stimulated the NADPH oxidase-mediated release of superoxide free radical; pharmacological inhibition and genetic inactivation of NADPH oxidase prevented superoxide production and the synergistic neurotoxicity. Additionally, inhibition of nitric oxide synthase afforded significant neuroprotection, suggesting the involvement of nitric oxide in the synergistic neurotoxicity. This study lends strong support for a multifactorial etiology of PD and provides clues for therapeutic interventions.
Gao
Hui-Ming
HM
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. gao@niehs.nih.gov
Liu
Bin
B
Zhang
Wanqin
W
Hong
Jau-Shyong
JS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D018920:Coculture Techniques; D004298:Dopamine / Q000032:analysis; D004357:Drug Synergism; D005609:Free Radicals / Q000378:metabolism; D018836:Inflammation Mediators / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity*; D051379:Mice; D017628:Microglia / Q000201:enzymology; D008959:Models, Neurological; D019255:NADPH Oxidases / Q000502:physiology; D009410:Nerve Degeneration / Q000139:chemically induced; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010302:Parkinson Disease, Secondary / Q000209:etiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D005609:Free Radicals; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D013481:Superoxides; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D019255:NADPH Oxidases; D004298:Dopamine