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Titolo:
Differential effects of NMDA-receptor antagonists on long-term potentiation and hypoxic/hypoglycaemic excitotoxicity in hippocampal slices
Autore:
Frankiewicz, T; Pilc, A; Parsons, CG;
Indirizzi:
Merz & Co, Dept Pharmacol, D-60318 Frankfurt, Germany Merz & Co Frankfurt Germany D-60318 harmacol, D-60318 Frankfurt, Germany Polish Acad Sci, Inst Pharmacol, Dept Neurobiol, PL-31343 Krakow, Poland Polish Acad Sci Krakow Poland PL-31343 eurobiol, PL-31343 Krakow, Poland
Titolo Testata:
NEUROPHARMACOLOGY
fascicolo: 4, volume: 39, anno: 2000,
pagine: 631 - 642
SICI:
0028-3908(2000)39:4<631:DEONAO>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
D-ASPARTATE RECEPTOR; TRANSIENT GLOBAL-ISCHEMIA; GLYCINE SITE; SPREADING DEPRESSION; RAT-BRAIN; ANTICONVULSANT MK-801; GLUTAMATE ANTAGONISTS; CULTURED NEURONS; QUINOLINIC ACID; NUCLEUS BASALIS;
Keywords:
LTP; excitotoxicity; patch clamp; memantine; (+)-MK-801; 5,7-DCKA; CGP 37849;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
57
Recensione:
Indirizzi per estratti:
Indirizzo: Parsons, CG Merz & Co, Dept Pharmacol, Eckenheimer Landstr 100-104, D-60318 Frankfurt,Germany Merz & Co Eckenheimer Landstr 100-104 Frankfurt Germany D-60318
Citazione:
T. Frankiewicz et al., "Differential effects of NMDA-receptor antagonists on long-term potentiation and hypoxic/hypoglycaemic excitotoxicity in hippocampal slices", NEUROPHARM, 39(4), 2000, pp. 631-642

Abstract

Whole-cell patch clamp recording from cultured hippocampal neurones was used to investigate the NMDA antagonistic effects of the glycine, antagonist 5,7-DCKA and the competitive antagonist CGP 37849. Extracellular field potential recording from area CA1 of hippocampal slices was used to investigatetheir 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 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-inducedcurrents considerably and antagonized currents at the time point when the peak component occurred in control responses (IC50=0.18+/-0.01 mu M) with around 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 inhibiting peak currents in patch clamp studies. 5,7-DCKA and CGP 37849 alsoblocked the hypoxia/hypoglycaemia-induced suppression of fEPSPs but CGP 37849 (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 two models. Memantine and (+)MK-801 also blocked hypoxia/hypoglycaemia-induced suppression of fEPSPs with EC(50)s of 14.1+/-0.52 and 0.53+/-0.02 mu M respectively. Whereas memantine blocked this effect with similar potency aswe previously reported for LTP, (+)MK-801 was four time less potent in this model. The calculated relative therapeutic indices (ICS, 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, glycine, 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. (C) 2000 Elsevier Science Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 09/07/20 alle ore 17:54:31