Differential effects of NMDA-receptor antagonists on long-term potentiation and hypoxic/hypoglycaemic excitotoxicity in hippocampal slices

Whole-cell patch clamp recording from cultured hippocampal neurones was use d to investigate the NMDA antagonistic effects of the glycine, antagonist 5 ,7-DCKA and the competitive antagonist CGP 37849. Extracellular field poten tial recording from area CA1 of hippocampal slices was used to investigate their effects on the induction of LTP and hypoxia/hypoglycaemia-induced sup pression of fEPSPs. Additionally, memantine and (+)MK-801 were tested in th e later model. 5,7-DCKA inhibited NMDA-induced plateau currents (IC50=0.24/-0.02 mu M) with around nine times higher potency than against peak (IC50= 2.14+/-0.17 mu M). In contrast, CGP 37849 slowed the onset of NMDA-induced currents considerably and antagonized currents at the time point when the p eak component occurred in control responses (IC50=0.18+/-0.01 mu M) with ar ound seven times higher potency than against plateau (IC50=1.26+/-0.19 mu M ). Both 5,7-DCKA and CGP 37849 inhibited the induction of LTP (IC(50)s=2.53 +/-0.13 and 0.37+/-0.04 mu M respectively) with potencies close to those in hibiting peak currents in patch clamp studies. 5,7-DCKA and CGP 37849 also blocked the hypoxia/hypoglycaemia-induced suppression of fEPSPs but CGP 378 49 (EC50=4.3+/-0.33 mu M) was far less potent than against the induction of LTP whilst 5,7-DCKA (EC50=1.47+/-0.04 mu M) had similar potency in these t wo models. Memantine and (+)MK-801 also blocked hypoxia/hypoglycaemia-induc ed suppression of fEPSPs with EC(50)s of 14.1+/-0.52 and 0.53+/-0.02 mu M r espectively. Whereas memantine blocked this effect with similar potency as we previously reported for LTP, (+)MK-801 was four time less potent in this model. The calculated relative therapeutic indices (ICS, LTP over EC50 hyp oxia/hypoglycaemia) for 5,7-DCKA, CGP 37849, memantine and (+)MK-801 were 1 .72, 0.09, 0.82 and 0.24 respectively. These results show that even in a se vere model of hypoxia/hypoglycaemia, glycine, site antagonists and moderate affinity channel blockers exhibit a better therapeutic index than competit ive antagonists and high affinity channel blockers. It is likely that in mi lder forms of pathology the observed differences in therapeutic indices rem ain the same but the absolute values are expected to be higher. (C) 2000 El sevier Science Ltd. All rights reserved.