Selective blockade of non-NMDA receptors does not block rapidly triggered glutamate-induced neuronal death

The quinoxalinedione, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), has been introduced as a relatively selective antagonist of non-N-methyl-D-aspartate (non-NMDA) glutamate receptors. We studied the ability of CNQX to block excitatory amino acid-induced neurotoxicity in murine cortical cell cultures. 100 microM CNQX blocked the acute neuronal swelling induced by 500 microM kainate, but it also attenuated the swelling and degeneration induced by 500 microM NMDA. Addition of 1 mM glycine to the CNQX eliminated antagonism of NMDA toxicity, while preserving antagonism of the neuronal degeneration induced by kainate or AMPA. This selective non-NMDA antagonist combination of CNQX plus glycine substantially attenuated the acute neuronal swelling induced by brief exposure to 500 microM glutamate, but had little effect on subsequent late degeneration, supporting the conclusion that rapidly triggered glutamate-induced cortical neuronal death is predominantly mediated by NMDA receptors.