Glutamate (Glu), the major excitatory neurotransmitter in the nervous
system, is toxic to neurons when it accumulates at high concentrations
in the extracellular space. Even though Glu is a mixed agonist, capab
le of activating N-methyl-D-aspartate (NMDA) receptors and non-NMDA re
ceptors, in many preparations Glu neurotoxicity is prevented by select
ive blockade of NMDA receptors. In cultures of hippocampal neurons, tr
eatment with 500 mu M Glu for 30 min killed more than 90% of the neuro
ns. The simultaneous addition of the selective NMDA agonist yl-10,11-d
ihydro-5-H-dibenzocyclohepten-5,10-imine (MK-801) reduced the cell los
s to less than 30%. However, when Glu was combined with either diazoxi
de or cyclothiazide, two thiazides which dramatically diminish rapid G
lu desensitization, MK-801 was no longer very protective and neuronal
loss exceeded 80%. However, the non-NMDA antagonist 6-cyano-7-nitroqui
noxaline-2,3-dione (CNQX), in combination with MK-801, was able to pre
vent most Glu neurotoxicity in the presence of these thiazides. These
experiments show that there are circumstances under which Glu neurotox
icity is produced by overactivation of non-NMDA receptors. Our observa
tions offer a possible explanation for the recent finding that blockad
e of non-NMDA receptors is much more beneficial than NMDA receptor blo
ckade in protecting the brain in some in vivo models of global ischemi
a.