Antagonism of non-NMDA receptors augments the neuroprotective effect of NMDA receptor blockade in cortical cultures subjected to prolonged deprivation of oxygen and glucose

A 30-60 min period of oxygen and glucose deprivation induced widespread degeneration of cultured murine neocortical neurons. Neuronal degeneration could be blocked by adding the selective NMDA antagonist MK-801 to the bathing medium; however, if the deprivation period was prolonged to 90-105 min, the neuroprotective effect of MK-801 was overcome. The non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) at 1-100 μM concentrations also failed to protect neurons against this prolonged insult, but te combination of CNQX with either MK-801 or d-APV produced marked neuroprotection. This synergistic actuon of CNQX was not due to enhanced blockage of NMDA receptors, as it was not mimicked by combining MK-801 with d-APV or 7-chlorokynurenate. These observations support the idea that combined NMDA and non-NMDA receptor blockade may have value in ameliorating the neuronal loss associated with prolonged ischemic insults in vivo.