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Titolo:
Stereoselective neuroprotection by novel 2,3-benzodiazepine noncompetitiveAMPA antagonists against non-NMDA receptor-mediated excitotoxicity in primary rat hippocampal cultures
Autore:
May, PC; Robison, PM; Fuson, KS;
Indirizzi:
Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA Eli Lilly & CoIndianapolis IN USA 46285 Labs, Indianapolis, IN 46285 USA
Titolo Testata:
NEUROSCIENCE LETTERS
fascicolo: 3, volume: 262, anno: 1999,
pagine: 219 - 221
SICI:
0304-3940(19990312)262:3<219:SNBN2N>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
GLUTAMATE RECEPTORS; PHARMACOLOGY; GYKI-53655; PROTECTS;
Keywords:
LY300164; LY303070; GYKI 52466; kainate; alpha-amino-3-hydroxy-5-methyl-isoxazolepropionate/kainic acid-receptor; excitotoxicity; rat hippocampal culture;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
17
Recensione:
Indirizzi per estratti:
Indirizzo: May, PC Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA Eli Lilly & Co Indianapolis IN USA 46285 dianapolis, IN 46285 USA
Citazione:
P.C. May et al., "Stereoselective neuroprotection by novel 2,3-benzodiazepine noncompetitiveAMPA antagonists against non-NMDA receptor-mediated excitotoxicity in primary rat hippocampal cultures", NEUROSCI L, 262(3), 1999, pp. 219-221

Abstract

Glutamate excitotoxicity has been implicated in a variety of acute and chronic neurodegenerative diseases but early phase clinical trials with competitive antagonists at both N-methyl-D-aspartate (NMDA)-receptors and alpha-amino-3-hydroxy-5-methylisoxazotepropionate (AMPA) receptors have been disappointing. A family of atypical 2,3 benzodiazepines, exemplified by GYK1 52466, have been described recently which function as non-competitive AMPA-receptor antagonists. We have investigated the neuroprotective efficacy of LY303070 and LY300164, two analogs of GYKI-52466, in an embryonic rat hippocampal culture model of non-NMDA receptor-mediated excitotoxicity using kainicacid (KA) as an agonist at the AMPA/KA receptor. Overnight treatment with 500 mu M KA resulted in prominent neuronal excitotoxicity as assessed by lactate dehydrogenase efflux. LY300164 and LY303070 attenuated KA-excitotoxicity in a dose-dependent manner with IC(50)s Of 4 and 2 mu M, respectively. In contrast, their stereoisomers, LY300165 and LY303071 showed no neuroprotection at concentrations up to 25 mu M. In addition, AMPA-mediated excitotoxicity in cyclothiazide pre-treated cultures was also completely blocked byLY303070. Finally, neuroprotection by this class of 2,3 benzodiazepines was not influenced by antagonism of the classical benzodiazepine receptor. LY303070 and LY300164 represent novel non-competitive AMPA-receptor antagonists which may offer unique advantages in the clinic over competitive AMPA-receptor antagonists. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/04/20 alle ore 01:52:02