ARE NMDA OR AMPA KAINATE RECEPTOR ANTAGONISTS MORE EFFICACIOUS IN THEDELAYED TREATMENT OF EXCITOTOXIC NEURONAL INJURY

At which time-point and to what extent do N-methyl-D-aspartate (NMDA) receptors, lpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AM PA)/kainate receptors and L-type voltage-sensitive Ca2+ channels (VSCC ) contribute to glutamate-induced neuronal injury? To address this que stion, we induced glutamate neurotoxicity in two neuronal culture syst ems, chick telencephalic neurons and rat hippocampal neurons, and test ed selective antagonists for their neuroprotective activity when admin istered either during the excitotoxic insult (acute treatment) or duri ng the recovery period (posttreatment). In cultured chick telencephali c neurons exposed to 1 mM L-glutamate for 60 min, both the NMDA recept or antagonist dizocilpine (MK-801; 0.1 mu M) and the AMPA/kainate rece ptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1 mu M) co mpletely blocked glutamate-induced neuronal injury when applied concom itantly with glutamate. If the antagonists were applied during the rec overy period, dizocilpine at concentrations up to 10 mu M only moderat ely increased cell viability, whereas CNQX showed a neuroprotective ac tivity comparable to that observed in the case of the acute treatment. In cultured rat hippocampal neurons, excitotoxic injury was induced b y a 30-min exposure to 1 mM glutamate. Treatment with dizocilpine duri ng the glutamate exposure could rescue the hippocampal neurons from th e excitotoxic insult, whereas acute treatment with the AMPA/kainate re ceptor antagonist roxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline(NBQX) o r the L-type VSCC blocker nimodipine showed no protection. In contrast , all three drugs showed neuroprotective activity when applied 30, 60 or 120 min after the glutamate exposure. Surprisingly, when the onset of the treatment was delayed for even 240 min, only NBQX and nimodipin e led to a reduction in excitotoxic neuronal injury. We conclude that activation of AMPA/kainate receptors and L-type VSCC is critically inv olved in a late stage of glutamate neurotoxicity, thereby allowing pha rmacological intervention at a time when blockade of NMDA receptors be comes less efficacious.