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 used to investigate the NMDA antagonistic effects of the glycineB antagonist 5,7-DCKA and the competitive antagonist CGP 37849. Extracellular field potential recording from area CA1 of hippocampal slices was used to investigate their effects on the induction of LTP and hypoxia/hypoglycaemia-induced suppression of fEPSPs. Additionally, memantine and (+)MK-801 were tested in the later model. 5,7-DCKA inhibited NMDA-induced plateau currents (IC50=0.24+/-0.02 microM) with around nine times higher potency than against peak (IC50=2.14+/-0.17 microM). In contrast, CGP 37849 slowed the onset of NMDA-induced currents considerably and antagonized currents at the time point when the peak component occurred in control responses (IC50=0.18+/-0.01 microM) with around seven times higher potency than against plateau (IC50=1.26+/-0.19 microM). Both 5,7-DCKA and CGP 37849 inhibited the induction of LTP (IC50s=2.53+/-0.13 and 0.37+/-0.04 microM respectively) with potencies close to those inhibiting peak currents in patch clamp studies. 5,7-DCKA and CGP 37849 also blocked the hypoxia/hypoglycaemia-induced suppression of fEPSPs but CGP 37849 (EC50=4.3+/-0.33 microM) was far less potent than against the induction of LTP whilst 5,7-DCKA (EC50=1.47+/-0.04 microM) had similar potency in these two models. Memantine and (+)MK-801 also blocked hypoxia/hypoglycaemia-induced suppression of fEPSPs with EC50s of 14.1+/-0.52 and 0.53+/-0.02 microM respectively. 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 (IC50 LTP over EC50 hypoxia/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 severe model of hypoxia/hypoglycaemia, glycineB site antagonists and moderate affinity channel blockers exhibit a better therapeutic index than competitive antagonists and high affinity channel blockers. It is likely that in milder forms of pathology the observed differences in therapeutic indices remain the same but the absolute values are expected to be higher.
Frankiewicz
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Dept. of Pharmacology, Merz and Co., Frankfurt am Main, Germany.
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Parsons
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D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015687:Cell Hypoxia; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000502:physiology
D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C064539:2-amino-4-methyl-5-phosphono-3-pentenoic acid; D015763:2-Amino-5-phosphonovalerate; D007736:Kynurenic Acid; D005947:Glucose; C066192:5,7-dichlorokynurenic acid