HTDP-2, a new synthetic compound, inhibits glutamate release through reduction of voltage-dependent Ca²âº influx in rat cerebral cortex nerve terminals.
Pharmacology
; 88(1-2): 26-32, 2011.
Article
en En
| MEDLINE
| ID: mdl-21720189
ABSTRACT
AIM:
The present study was aimed at investigating the effect of trans-6-(4-chlorobutyl)-5-hydroxy-4-(phenylthio)-1-tosyl-5,6-dihydropyridine-2(1H)-one (HTDP-2), a novel synthetic compound, on the release of endogenous glutamate in rat cerebrocortical nerve terminals (synaptosomes) and exploring the possible mechanism.METHODS:
The release of glutamate was evoked by the K⺠channel blocker 4-aminopyridine (4-AP) and measured by an on-line enzyme-coupled fluorimetric assay. We also used a membrane potential-sensitive dye to assay nerve terminal excitability and depolarization, and a Ca²âº indicator, Fura-2-acetoxymethyl ester, to monitor cytosolic Ca²âº concentrations ([Ca²âº](c)).RESULTS:
HTDP-2 inhibited the release of glutamate evoked by 4-AP in a concentration-dependent manner. Inhibition of glutamate release by HTDP-2 was prevented by the chelating intraterminal Ca²âº ions, and by the vesicular transporter inhibitor bafilomycin A1, but was insensitive to the glutamate transporter inhibitor DL-threo-ß-benzyloxyaspartate. HTDP-2 did not alter the resting synaptosomal membrane potential or 4-AP-mediated depolarization whereas it decreased the 4-AP-induced increase in [Ca²âº](c). Furthermore, the inhibitory effect of HTDP-2 on the evoked glutamate release was abolished by the N-, and P/Q-type Ca²âº channel blocker ω-conotoxin MVIIC, but not by the ryanodine receptor blocker dantrolene, or the mitochondrial Naâº/Ca²âº exchanger blocker CGP37157.CONCLUSION:
Based on these results, we suggest that, in rat cerebrocortical nerve terminals, HTDP-2 decreases voltage-dependent Ca²âº channel activity and, in so doing, inhibits the evoked glutamate release.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piridonas
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Compuestos de Tosilo
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Bloqueadores de los Canales de Calcio
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Canales de Calcio
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Corteza Cerebral
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Fármacos Neuroprotectores
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Ácido Glutámico
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Pharmacology
Año:
2011
Tipo del documento:
Article