Synergistic dopaminergic neurotoxicity of MPTP and inflammogen lipopolysaccharide: relevance to the etiology of Parkinson's disease
- 15 August 2003
- journal article
- Published by Wiley in The FASEB Journal
- Vol. 17 (13), 1-25
- https://doi.org/10.1096/fj.03-0203fje
Abstract
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.Keywords
This publication has 61 references indexed in Scilit:
- Role of Microglia in Inflammation-Mediated Neurodegenerative Diseases: Mechanisms and Strategies for Therapeutic InterventionThe Journal of pharmacology and experimental therapeutics, 2003
- Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: Implications for Parkinson's diseaseThe FASEB Journal, 2002
- ETIOLOGY AND PATHOGENESIS OF PARKINSON'S DISEASEAnnual Review of Neuroscience, 1999
- Diphenyleneiodonium, an NAD(P)H Oxidase Inhibitor, also Potently Inhibits Mitochondrial Reactive Oxygen Species ProductionBiochemical and Biophysical Research Communications, 1998
- Postencephalitic parkinsonism - a reviewJournal of Neural Transmission, 1998
- Elevated reactive oxygen species and antioxidant enzyme activities in animal and cellular models of Parkinson's diseaseBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1997
- Inhibition of Neuronal Nitric Oxide Synthase by 7‐Nitroindazole Protects Against MPTP‐Induced Neurotoxicity in MiceJournal of Neurochemistry, 1995
- 1-Methyl-4-phenylpyridinium (MPP+) induces NADH-dependent superoxide formation and enhances NADH-dependent lipid peroxidation in bovine heart submitochondrial particlesBiochemical and Biophysical Research Communications, 1990
- Neurology: Predicting Parkinson's diseaseNature, 1985
- I. MPTP neurotoxicity: An overview and characterization of phases of toxicityLife Sciences, 1985