MPP+-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress

Ya-Ching Hsieh, Ross B Mounsey, Peter Teismann

Research output: Contribution to journalArticle

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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.
Original languageEnglish
Pages (from-to)157-167
Number of pages11
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume384
Issue number2
Early online date12 Jun 2011
DOIs
Publication statusPublished - Aug 2011

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Cyclooxygenase 2
Dopamine
Oxidative Stress
Apoptosis
Parkinson Disease
Reactive Oxygen Species
Cyclooxygenase 2 Inhibitors
1-Methyl-4-phenylpyridinium
Dopamine Agents
Ibuprofen
Dopaminergic Neurons
Reserpine
Neurotoxins
Neurons

Keywords

  • 1-Methyl-4-phenylpyridinium
  • Animals
  • Apoptosis
  • Cell Survival
  • Cells, Cultured
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Dopamine
  • Dopaminergic Neurons
  • Immunohistochemistry
  • Mesencephalon
  • Oxidative Stress
  • Parkinson Disease
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species

Cite this

MPP+-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress. / Hsieh, Ya-Ching; Mounsey, Ross B; Teismann, Peter.

In: Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 384, No. 2, 08.2011, p. 157-167.

Research output: Contribution to journalArticle

Hsieh, Ya-Ching ; Mounsey, Ross B ; Teismann, Peter. / MPP+-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress. In: Naunyn-Schmiedeberg's Archives of Pharmacology. 2011 ; Vol. 384, No. 2. pp. 157-167.
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AB - 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.

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