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Titolo:
Serotonergic neurotoxicity of 3,4-(+/-) -methylenedioxyamphetamine and 3,4-(+/-)-methylendioxymethamphetamine (ecstasy) is potentiated by inhibition of gamma-glutamyl transpeptidase
Autore:
Bai, FJ; Jones, DC; Lau, SS; Monks, TJ;
Indirizzi:
Univ Texas, Coll Pharm, Ctr Cellular & Mol Toxicol, Austin, TX 78712 USA Univ Texas Austin TX USA 78712 llular & Mol Toxicol, Austin, TX 78712 USA
Titolo Testata:
CHEMICAL RESEARCH IN TOXICOLOGY
fascicolo: 7, volume: 14, anno: 2001,
pagine: 863 - 870
SICI:
0893-228X(200107)14:7<863:SNO3-A>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
BLOOD-BRAIN-BARRIER; CARRIER-MEDIATED TRANSPORT; MDMA ECSTASY; RAT-BRAIN; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; MONOAMINERGIC SYSTEMS; OXIDATIVE METABOLITES; ANTITUMOR AGENT; COMPLEX-I; GLUTATHIONE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
41
Recensione:
Indirizzi per estratti:
Indirizzo: Monks, TJ Univ Texas, Coll Pharm, Ctr Cellular & Mol Toxicol, Austin, TX 78712 USA Univ Texas Austin TX USA 78712 ol Toxicol, Austin, TX 78712 USA
Citazione:
F.J. Bai et al., "Serotonergic neurotoxicity of 3,4-(+/-) -methylenedioxyamphetamine and 3,4-(+/-)-methylendioxymethamphetamine (ecstasy) is potentiated by inhibition of gamma-glutamyl transpeptidase", CHEM RES T, 14(7), 2001, pp. 863-870

Abstract

Reactive metabolites play an important role in 3,4-(+/-)-methylenedioxyamphetamine (MDA) and 3,4-(+/-)-methylenedioxymethamphetamine (MDMA; ecstasy)-mediated serotonergic neurotoxicity, although the specific identity of suchmetabolites remains unclear. 5-(Glutathion-S-yl)-alpha -methyldopamine (5-GSyl-alpha -MeDA) is a serotonergic neurotoxicant found in the bile of MDA-treated rats. The brain uptake of 5-GSyl-alpha -MeDA is decreased by glutathione (GSH), but sharply increases in animals pretreated with acivicin, an inhibitor of gamma -glutamyl transpeptidase (gamma -GT) suggesting competition between intact 5-GSyl-alpha -MeDA and GSH for the putative GSH transporter. gamma -GT is enriched in blood-brain barrier endothelial cells and is the only enzyme known to cleave the gamma -glutamyl bond of GSH. We now show that pretreatment of rats with acivicin (18 mg/kg, ip) inhibits brain microvessel endothelial gamma -GT activity by 60%, and potentiates MDA- and MDMA-mediated depletions in serotonin (5-HT) and 5-hydroxylindole acidic acid(6-HIAA) concentrations in brain regions enriched in 5-HT nerve terminal axons (striatum, cortex, hippocampus, and hypothalamus). In addition, glial fibrillary acidic protein (GFAP) expression increases in the striatum of acivicin and MDA (10 mg/kg) treated rats, but remains unchanged in animals treated with just MDA (10 mg/kg). Inhibition of endothelial cell gamma -GT atthe blood-brain barrier likely enhances the uptake into brain of thioethermetabolites of MDA and MDMA, such as 5-(glutathion-S-yl)-alpha -MeDA and 2,5-bis-(glutathion-S-yl)-alpha -MeDA, by increasing the pool of thioether conjugates available for uptake via the intact GSH transporter. The data indicate that thioether metabolites of MDA and MDMA contribute to the serotonergic neurotoxicity observed following peripheral administration of these drugs.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/01/20 alle ore 12:18:00