AbstractA large body of evidence exists to demonstrate that excitatory amino acids (EAA) and their receptors are involved in the pathophysiological mechanisms linking several acute brain insults, such as cerebral ischemia, to neuronal degeneration and death. Accordingly, the use of EAA receptor antagonists can be beneficial in attenuating or preventing the neuronal irreversible damage subsequent to various neuropathological syndromes. We have investigated the effect of 15 min of simulated ischemic conditions, i. e., oxygen/glucose deprivation, on hippocampal slices preparation measuring, as neurotoxicity indexes, both the amino acids efflux in the incubation medium, detected by HPLC, and the inhibition of protein synthesis, evaluated as3H‐Leucine incorporation into proteins. Accumulation of neurotransmitter amino acids was measured in the medium during the “ischemic” period. Glutamate increased 30‐fold over the basal level while aspartate was sevenfold and GABA 12‐fold higher than in normal conditions. After a reoxygenation period of 30 min, the rate of protein synthesis of hippocampal slices subjected to “ischemia” was reduced to 35–50% of controls. The non‐competitive NMDA antagonist MK‐801 (100 μM) and the competitive NMDA antagonist CGP 39551 (100–250 μM) as well as the non‐NMDA receptor antagonist NBQX (100 μM) and AP3 (300 μM) were unable to counteract the metabolic impairment when they were present alone in the incubation fluid during simulated “ischemia.” An incomplete, but highly significant (p<0.001), protection from protein synthesis impairment was achieved in the presence of an equimolar concentration (100 μM) of MK‐801 and NBQX. A similar protective effect could be reproduced using 100 μM NBQX in concomitance with a high Mg++(20 μM) voltage‐dependent block of the NMDA receptor‐associated channel but not exposing the slices to a NBQX (100 μM) and CGP 39551 (100–250 μM) mixture. The recovery of protein synthesis in the presence of the MK‐801/NBQX effective combination was not paralleled by a detectable decrease in the amount of amino acids released in the incubation medium during the “ischemic” period. Taken together, the present data allow new insights into neurotoxicity‐mediating mechanisms, suggesting that multiple additive processes are involved and that antagonists acting at different sites on excitatory amino acid receptor subtype can show diffe