title: MPP(+)-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress.
abstract: Accumulating evidence suggests that endogenous dopamine may act as a neurotoxin and thereby participate in the pathophysiology of Parkinson's disease (PD). Cyclooxygenase-2 (COX-2) has been implicated in the pathogenesis of PD due to its ability to generate reactive oxygen species (ROS). Inhibition of COX-2 leads to neuroprotection by preventing the formation of dopamine-quinone. In this study, we examined whether dopamine mediates 1-methyl-4-phenylpyridinium (MPP(+))-induced toxicity in primary ventral mesencephalic (VM) neurons, an in vitro model of PD, and if so, whether the protective effects of COX-2 inhibitors on dopamine mediated MPP(+)-induced VM neurotoxicity and VM dopaminergic cell apoptosis result from the reduction of ROS. Reserpine, a dopamine-depleting agent, significantly reduced VM neurotoxicity induced by MPP(+), whereas dopamine had an additive effect on MPP(+)-induced VM neurotoxicity and VM dopaminergic cell apoptosis. However, inhibition of COX-2 by a selective COX-2 inhibitor (DFU) or ibuprofen significantly attenuated MPP(+)-induced VM cell toxicity and VM dopaminergic cell apoptosis, which was accompanied by a decrease in ROS production in VM dopaminergic neurons. These results suggest that dopamine itself mediates MPP(+)-induced VM neurotoxicity and VM dopaminergic cell apoptosis in the presence of COX-2.
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, Scotland, UK.
authors.forename: Ya-Ching
authors.initials: YC
authors.lastname: Hsieh
authors.forename: Ross B
authors.initials: RB
authors.lastname: Mounsey
authors.forename: Peter
authors.initials: P
authors.lastname: Teismann
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D007150:Immunohistochemistry; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D017382:Reactive Oxygen Species; D051546:Cyclooxygenase 2; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine