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Journal of Neuroscience, Vol 15, 7847-7860, Copyright © 1995 by Society for Neuroscience
Excitotoxic cell death and delayed rescue in human neurons derived from NT2 cells
M Munir, L Lu and P Mcgonigle
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
The excitotoxic response of NT2-N cells, a clonal line of human
teratocarcinoma cells that are terminally differentiated into neuron- like
cells, was examined using several endpoints. A 15 min exposure to glutamate
produced a dose-dependent toxicity with a maximal cell loss of 80-90% in 6
week old cells. The rapidly triggered excitotoxicity induced by glutamate
was blocked by NMDA selective antagonists, was calcium dependent and pH
sensitive and could be mimicked by NMDA but not by non-NMDA agonists, AMPA,
kainate or quisqualate. The non-NMDA agonists however caused toxicity on
prolonged exposure. The NMDA receptor modulators glycine and spermidine
enhanced glutamate-mediated toxicity whereas ifenprodil potently and
completely inhibited toxicity suggesting that the toxic response is
mediated by the NR1/NR2B combination of NMDA subunits. These cells can be
rescued from death up to 1 hr after removal of glutamate by NMDA receptor
blockade, removal of extracellular Ca2+ or lowering of pH. The extent of
rescue is directly related to the time elapsed before intervention.
Blockage of NMDA receptor activity for 1 hr immediately after removal of
glutamate is both necessary and sufficient for complete rescue. Glutamate-
mediated toxicity was not prevented by nitric oxide synthase inhibitors nor
was nitric oxide synthase detected in NT2-N cells indicating that nitric
oxide is not required for glutamate-mediated excitotoxicity. In summary,
NT2-N cells exhibit a robust excitotoxic response and represent a novel
model system in which to study the molecular basis of excitotoxic cell
death.
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