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Journal of Neuroscience, Vol 10, 283-292, Copyright © 1990 by Society for Neuroscience
Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations
RL Michaels and SM Rothman
Department of Biological Chemistry, Washington University School of Medicine, St. Louis, Missouri 63110.
There is now convincing evidence that excessive accumulation of the
excitatory amino acid glutamate (GLU) in the extracellular space is toxic
to central mammalian neurons. However, the role of different GLU receptors
in producing this toxicity has not been adequately ascertained. There is
also no adequate information about the correlation of free intracellular
calcium concentration with eventual excitotoxic death. We have used
cultured rat hippocampal neurons to address these issues. Approximately 75%
of our neurons died after a 20- min GLU exposure. The potent
kainate/quisqualate receptor antagonist 6-
cyano-7-nitroquinoxaline-2,3-dione did not significantly ameliorate the GLU
toxicity, while the selective noncompetitive N-methyl-D-aspartate (NMDA)
antagonist methyl-10,11-dihydro-5-H-dibenzocyclohepten-5,10- imine (MK-801)
blocked the GLU toxicity for periods of at least 2 hr. Interestingly,
kainate was very toxic to the hippocampal neurons, but this toxicity was
markedly attenuated by MK-801. These results suggest that the major
toxicity of GLU is mediated by NMDA receptors and that under some
conditions kainate toxicity reflects nonspecific opening of NMDA channels.
The intracellular calcium concentrations in these neurons at the end of
exposure to GLU and kainate (in the presence and absence of different
antagonists) correlated poorly with eventual survival. Antagonists that
limited the rise in calcium were still ineffective in preventing death.
These results confirm earlier observations that stressed the importance of
NMDA receptors in mediating GLU toxicity. However, they indicate that the
relationship between toxicity and neuronal calcium concentration may be
very complicated. An unexpected finding of these experiments was that MK-
801, unlike competitive antagonists of GLU, elevated intracellular calcium.
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