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Titolo:
Characterization of the anticonvulsant and neuroprotectant BIIR 561 CL in vitro: effects on native and recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors
Autore:
Weiser, T; Iizuka, M; Nishimura, S; Akiba, I; Barsoumian, E; Zhou, M; Steinhauser, C; Brenner, M; Palluk, R; Wienrich, M;
Indirizzi:
Boehringer Ingelheim Pharma KG, D-55218 Ingelheim, Germany Boehringer Ingelheim Pharma KG Ingelheim Germany D-55218 elheim, Germany Boehringer Ingelheim Co Ltd, Kawanishi, Japan Boehringer Ingelheim Co LtdKawanishi Japan im Co Ltd, Kawanishi, Japan
Titolo Testata:
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
fascicolo: 4-5, volume: 362, anno: 2000,
pagine: 419 - 426
SICI:
0028-1298(200011)362:4-5<419:COTAAN>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
RAT CORTICAL-NEURONS; METHYL-D-ASPARTATE; SODIUM-CHANNELS; GLUTAMATE RECEPTORS; CEREBRAL-ISCHEMIA; EXTRACELLULAR PH; DESENSITIZATION; ANTAGONISM; GYKI-52466; NBQX;
Keywords:
AMPA receptor; patch clamp; non-competitive blocker; human glutamate receptor; cortical neuron; nucleated outside-out patch;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
26
Recensione:
Indirizzi per estratti:
Indirizzo: Weiser, T Boehringer Ingelheim Pharma KG, D-55218 Ingelheim, Germany Boehringer Ingelheim Pharma KG Ingelheim Germany D-55218 rmany
Citazione:
T. Weiser et al., "Characterization of the anticonvulsant and neuroprotectant BIIR 561 CL in vitro: effects on native and recombinant alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors", N-S ARCH PH, 362(4-5), 2000, pp. 419-426

Abstract

BIIR 561 CL is a novel blocker of AMPA receptors and voltage-dependent sodium channels. In this study we further describe the effects of BIIR 561 CL on AMPA receptor-mediated membrane currents in rodent. neurons, as well as in cells expressing recombinant human GluR1/2 receptors in more detail. BIIR 561 CL suppressed responses to kainate in neuronal cultures from rat cortex with an IC50 of 9.8 muM. Similar effects were observed using acutelydissociated neurons from the CA1 region of rat hippocampus (IC50=9.5 muM). Inhibition of kainate responses by BIIR 561 CL was prevented by preapplication of GYKI 53655, suggesting that both non-competitive inhibitors bind toa common site of the receptor. The effect of 10 muM BIIR 561 CL on kainate-induced currents was dependenton extracellular pH, with more pronounced block (84.1%) under acidic conditions (pH(extern)=6.4), compared to only 30.1% at a pH(extern) of 8.4. Thus, it can be hypothesized that BIIR 561 CL inhibits AMPA receptors in ischaemic brain regions more effectively than in healthy tissue. BIIR 561 CL inhibited responses to 1 mM glutamate in cells expressing recombinant human GluR1/2 receptors with similar potency, as compared to kainate responses in rat neurons (IC50=17.3 muM). The reference compound NBQX hadan IC50 of 25.2 nM. None of the two compounds affected the glutamate-induced receptor desensitization sit any tested concentration. The block by BIIR561 CL was not use-dependent and had fast on- and off-kinetics (tau (on)=6.8 s; tau (off)=1.3 s in hGluR1/2 receptors With 30 muM BIIR 561 CL). Thus, BIIR 561 CL can be anticipated to have a promising profile for the treatment of neurological disorders like brain ischaemia and head trauma.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/03/20 alle ore 01:52:17