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Titolo:
Studies on the neuroprotective effect of the enantiomers of AR-A008055, a compound structurally related to clomethiazole, on MDMA ("ecstasy")-inducedneurodegeneration in rat brain
Autore:
Colado, MI; OShea, E; Esteban, B; Green, AR;
Indirizzi:
AstraZeneca R&D Charnwood, Loughborough LE11 5RH, Leics, England AstraZeneca R&D Charnwood Loughborough Leics England LE11 5RH cs, England Univ Complutense, Fac Med, Dept Farmacol, E-28040 Madrid, Spain Univ Complutense Madrid Spain E-28040 pt Farmacol, E-28040 Madrid, Spain De Montfort Univ, Sch Pharm, Pharmacol Res Grp, Leicester LE1 9BH, Leics, England De Montfort Univ Leicester Leics England LE1 9BH LE1 9BH, Leics, England
Titolo Testata:
PSYCHOPHARMACOLOGY
fascicolo: 1, volume: 157, anno: 2001,
pagine: 82 - 88
Fonte:
ISI
Lingua:
ENG
Soggetto:
GAMMA-AMINOBUTYRIC ACID; ACUTE ISCHEMIC STROKE; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; SEROTONERGIC TOXICITY; P-CHLOROAMPHETAMINE; FOREBRAIN ISCHEMIA; GABA(A) RECEPTORS; CHLORMETHIAZOLE; DIZOCILPINE; PHARMACOLOGY;
Keywords:
3,4-methylenedioxymethamphetamine; GABA; ecstasy; neurodegeneration; 5-hydroxytryptamine; hyperthermia; neuroprotection; clomethiazole; AR-A008055;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
28
Recensione:
Indirizzi per estratti:
Indirizzo: Green, AR AstraZeneca R&D Charnwood, Bakewell Rd, Loughborough LE11 5RH, Leics, England AstraZeneca R&D Charnwood Bakewell Rd Loughborough Leics England LE11 5RH
Citazione:
M.I. Colado et al., "Studies on the neuroprotective effect of the enantiomers of AR-A008055, a compound structurally related to clomethiazole, on MDMA ("ecstasy")-inducedneurodegeneration in rat brain", PSYCHOPHAR, 157(1), 2001, pp. 82-88

Abstract

Rationale: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") administration produces neurotoxic degeneration of 5-HT nerve endings in several regions of rat brain. Administration of the GABAmimetic drug clomethiazole protects against this damage. Objective: We wished to see whether the enantiomers of AR-A008055 (1-4-methyl-5-thiazolyl-l-phenyl-methylamine), a compound structurally related to clomethiazole, were also neuroprotective against MDMA-induced degeneration. Methods: (R)-(+)-AR-A008055 or (S)-(-)AR-A008055 (100 mg/kg IP) was injected 5 min prior to and 55 min after MDMA (15 mg/kg IP) administration to Dark Agouti rats. Rectal temperature was measured during this time and the concentration of 5-HT and 5-HIAA measured in hippocampus, cortex and striatum 7 days later. [H-3]-Paroxetine binding was also measured in cortex. Results: Both enantiomers abolished the acute MDMA-induced hyperthermia and attenuated the subsequent neurotoxic loss of 5-HT, 5-HIAA and [H-3]-paroxetine binding. When rats given the enantiomer plus MDMA werewarmed to keep their rectal temperature elevated to near that of animals given only MDMA, the neuroprotective effect of (S)-(-)-AR-A008055 was still seen, while the effect of (R)-(+)-AR-A008055 was abolished. Protection was also seen when (S)-(-)-ARA008055 (50 mg/kg) was given, a dose which produced only a modest attenuation of MDMA-induced hyperthermia. Conclusions: The current data suggest that a major proportion of the neuroprotective action of (S)-(-)-ARA008055 did not involve an attenuating effect on MDMA-induced hyperthermia. The protection afforded by (R)-(+)-AR-A008055, which is not aGABA agonist, appears to be solely due to its action on body temperature, strengthening the contention that abolishing the acute MDMA-induced hypothermia can produce neuroprotection. Since (S)-(-)-AR-A008055 has a similar pharmacology to clomethiazole, these data suggest that drugs which increase GABAA receptor channel opening are neuroprotective against MDMA-induced damage.

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Documento generato il 25/01/20 alle ore 03:43:07