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Journal of Neuroscience, Vol 15, 6377-6388, Copyright © 1995 by Society for Neuroscience
Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate
LL Dugan, SL Sensi, LM Canzoniero, SD Handran, SM Rothman, TS Lin, MP Goldberg and DW Choi
Center for the Study of Nervous System Injury, Washington University Medical School, St. Louis, Missouri 63130, USA.
Increasing evidence suggests that glutamate neurotoxicity is partly
mediated by reactive oxygen species, formed as a consequence of several
processes, including arachidonic acid metabolism and nitric oxide
production. Here we used an oxidation-sensitive indicator, dihydrorhodamine
123, in combination with confocal microscopy, to examine the hypothesis
that electron transport by neuronal mitochondria may be an important source
of glutamate-induced reactive oxygen species (ROS). Exposure to NMDA, but
not kainate, ionomycin, or elevated potassium stimulated oxygen radical
production in cultured murine cortical neurons, demonstrated by oxidation
of nonfluorescent dihydrorhodamine 123 to fluorescent rhodamine 123.
Electron paramagnetic resonance spectroscopy studies using 5,5-dimethyl-1-
pyrroline-N-oxide (DMPO) as a radical-trapping agent, also showed
production of ROS by cortical neurons after NMDA but not kainate exposure.
NMDA-induced ROS production depended on extracellular Ca2+, and was not
affected by inhibitors of nitric oxide synthase or arachidonic acid
metabolism. The increased production of ROS was blocked by inhibitors of
mitochondrial electron transport, rotenone or antimycin, and mimicked by
the electron transport uncoupler, carbonyl cyanide
p-trifluoromethoxyphenylhydrazone. These data support the possibility that
NMDA receptor-mediated, Ca(2+)-dependent uncoupling of neuronal
mitochondrial electron transport may contribute to the oxidative stress
initiated by glutamate exposure.
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