STUDIES OF NMDA-MEDIATED AND NON-NMDA-MEDIATED NEUROTOXICITY IN CULTURED NEURONS

The neurotoxic effects of various glutamate agonists were studied usin g whole fetal rat brain cultures. The results showed that L-glutamate (L-glu) and N-methyl-D-aspartate (NMDA) were the most potent agonists for inducing neurotoxicity, producing significant toxicity at 0.10 and 0.01 mM concentrations, respectively. Kainic acid (KA) and quisqualic acid (QA) also produced neurotoxicity, but only at a relatively high concentration (1.0 mM). No other glutamate agonist tested produced neu rotoxicity in the cultures following brief incubations. The effects of each agonist were found to be Ca2+ dependent, and the selective NMDA Ca2+ channel agonist, 0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne hydrogen maleate (MK-801), blocked the toxicity produced by all the glutamate agonists. Thus, the results of this study found little or n o evidence for a direct non-NMDA receptor mediated neurotoxicity. Thes e results suggest that the neurotoxicity produced by the non-NMDA agon ists may be due to one of the following mechanisms: (i) non-specific b inding of non-NMDA agonists to NMDA receptor; (ii) release of L-glu vi a non-NMDA agonists induced depolarization of cell membrane and subseq uent activation of NMDA receptor by released L-glu; (iii) inhibition o f L-glu uptake by non-NMDA agonists resulting in activation of L-glu r eceptors including NMDA receptors. Copyright (C) 1996 Elsevier Science Ltd.