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Titolo:
COMPARISON OF THE UPTAKE OF [H-3] GABAPENTIN WITH THE UPTAKE OF L-[H-3]-LEUCINE INTO RAT-BRAIN SYNAPTOSOMES
Autore:
THURLOW RJ; HILL DR; WOODRUFF GN;
Indirizzi:
PFIZER LTD,CENT RES,DEPT DISCOVERY BIOL SANDWICH CT13 9NJ KENT ENGLAND PARKE DAVIS NEUROSCI RES CTR CAMBRIDGE CB2 2QB ENGLAND
Titolo Testata:
British Journal of Pharmacology
fascicolo: 3, volume: 118, anno: 1996,
pagine: 449 - 456
SICI:
0007-1188(1996)118:3<449:COTUO[>2.0.ZU;2-8
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMINO-ACID-TRANSPORT; CEREBRAL-CORTEX; H-3 GABAPENTIN; SLICES; TRYPTOPHAN; PHENYLALANINE; INHIBITORS; HISTIDINE; KINETICS; SYSTEMS;
Keywords:
GABAPENTIN; LARGE NEUTRAL AMINO ACID UPTAKE; SYSTEM-L; RAT BRAIN; SYNAPTOSOMES;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
33
Recensione:
Indirizzi per estratti:
Citazione:
R.J. Thurlow et al., "COMPARISON OF THE UPTAKE OF [H-3] GABAPENTIN WITH THE UPTAKE OF L-[H-3]-LEUCINE INTO RAT-BRAIN SYNAPTOSOMES", British Journal of Pharmacology, 118(3), 1996, pp. 449-456

Abstract

1 Gabapentin is a novel anticonvulsant with an unknown mechanism of action. Homogenate binding studies described elsewhere have suggested that [H-3]-gabapentin binds to a site in brain similar to the large neutral amino acid (LNAA) uptake site, termed system-L. 2 This study describes an investigation into the uptake of [H-3]-gabapentin into a crude synaptosomal preparation from cerebral cortex of rat brain. Characterization studies showed that [H-3]-gabapentin is taken up into synaptosomes by a system that is similar to that responsible for the uptake of L-[H-3]leucine. This system is sodium-independent, temperature-sensitive and requires ATP for function. 3 Kinetic studies of [H-3]-gabapentin uptake produced a Michaelis constant (K-M=160 mu M) Similar to that observed for L-[H-3]-leucine (K-M=110.3 mu M). V-max values were 837.1 pmol mg(-1) protein min(-1) and 2.192 nmol mg(-1) protein min(-1) respectively. 4 Gabapentin and L-leucine mutually inhibit their uptake. Lineweaver-Burke plots of these data demonstrate that inhibition occurs by a competitive mechanism. Further to this the Dixon transformation of the data illustrates that these two substrates share a common uptake site by the similarity between their calculated K-i, and K-M values (gabapentin inhibition of L-[H-3]-leucine uptake: K-i=160 mu M; L-leucine inhibition of [H-3]-gabapentin uptake: K-i=262 mu M). 5 Studies into the effect of gabapentin, the system-A-specific ligand 2-(-)-endoamino-bicycloheptane-2-carboxylic acid (BCH), and the system-A-specific ligand alpha-(methyl-amino)-isobutyric acid (MeAIB), on the initial rate of uptake of [H-3]-glycine, L-[H-3]-glutamate, L-[H-3]-glutamine,and L-[H-3]-leucine were performed. At 100 mu M, gabapentin significantly inhibited initial rate of uptake of [H-3]-glycine (29%), L-[H-3]-glutamate (22%) and L-[H-3]-leucine (40%). 6 Gabapentin is taken up into synaptosomes by a system similar to system-L, responsible for the uptake of large neutral amino acids. Gabapentin will also inhibit the uptake of certain excitatory amino acids in this synaptosomal preparation. The implications of these findings for the mechanism of action forgabapentin are unclear. The data presented here may suggest an intracellular site for mechanism of action for this compound. Similarly changes in levels of amino acid pools may be involved in the mechanism of gabapentin's anticonvulsant action.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/01/21 alle ore 07:17:57