Mitochondrial uncoupling agents antagonize rotenone actions in rat substantia nigra dopamine neurons

Yan Na Wu, Adam C. Munhall, Steven Johnson

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Mild uncoupling of oxidative phosphorylation has been reported to reduce generation of reactive oxygen species (ROS) and therefore may be neuroprotective. We reported previously that the mitochondrial poison rotenone enhanced currents evoked by N-methyl-d-aspartate (NMDA) by a ROS-dependent mechanism in rat midbrain dopamine neurons. Thus, rotenone, which produces a model of Parkinson's disease in rodents, may increase the risk of dopamine neuron excitotoxicity. The purpose of this study was to test the hypothesis that oxidative phosphorylation uncoupling agents would antagonize the effect of rotenone on NMDA current. We used patch pipettes to record whole-cell currents under voltage-clamp (- 60 mV) in substantia nigra dopamine neurons in slices of rat brain. Rotenone, NMDA and uncoupling agents were added to the brain slice superfusate. Inward currents evoked by NMDA (30 μM) more than doubled in amplitude after slices were superfused for 30 min with 100 nM rotenone. Continuous superfusion with the uncoupling agent carbonyl cyanide-p- trifluoromethoxy-phenylhydrazone (1-3 nM) or 2,4-dinitrophenol (100 nM) significantly antagonized and delayed the ability of rotenone to potentiate NMDA currents. Coenzyme Q 10 (1-10 nM), which has been reported to facilitate uncoupling protein activity, also antagonized this action of rotenone. These results suggest that mild uncoupling of oxidative phosphorylation may protect dopamine neurons against injury from mitochondrial poisons such as rotenone.

Original languageEnglish (US)
Pages (from-to)86-93
Number of pages8
JournalBrain Research
Volume1395
DOIs
StatePublished - Jun 13 2011

Fingerprint

Uncoupling Agents
Rotenone
Dopaminergic Neurons
Substantia Nigra
Aspartic Acid
Oxidative Phosphorylation
Poisons
Reactive Oxygen Species
2,4-Dinitrophenol
Ubiquinone
Brain
Mesencephalon
Parkinson Disease
Rodentia

Keywords

  • 2,4-dinitrophenol
  • Coenzyme Q
  • Dopamine neuron
  • FCCP
  • N-methyl-D-aspartate
  • Uncoupling agent

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

Mitochondrial uncoupling agents antagonize rotenone actions in rat substantia nigra dopamine neurons. / Wu, Yan Na; Munhall, Adam C.; Johnson, Steven.

In: Brain Research, Vol. 1395, 13.06.2011, p. 86-93.

Research output: Contribution to journalArticle

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