In vivo evidence against clomethiazole being neuroprotective against MDMA ('ecstasy')-induced degeneration of rat brain 5-HT nerve terminals by a free radical scavenging mechanism.
Clomethiazole is an effective neuroprotective agent against the degeneration of 5-HT neurones that follows administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy'). Since there is good evidence that free radical formation resulting from auto-oxidation of MDMA metabolites is responsible for the degeneration we have examined whether clomethiazole is a free radical scavenger. MDMA (15 mg/kg i.p.) increased the formation of 2,3- and 2,5-dihydroxybenzoic acids (2,3-DHBA and 2,5-DHBA) from salicylic acid perfused through a microdialysis tube implanted in the hippocampus, indicating increased free radical formation. Clomethiazole (50 mg/kg i.p.) administered 5 min prior and 55 min post MDMA prevented both the acute MDMA-induced hyperthermia and the rise in 2,3- and 2,5-DHBA. However, when the temperature of the MDMA + clomethiazole treated rats was kept elevated to that of the MDMA treated rats with a homeothermic blanket there was no inhibition of the MDMA-induced increase in 2,3-DHBA or 2,5-DHBA. These data suggest firstly that free radical formation is inhibited when the acute MDMA-induced hyperthermia is prevented. Secondly the data further indicate that clomethiazole has no free radical scavenging activity since the drug produces substantial neuroprotection when MDMA + clomethiazole treated rats are kept hyperthermic. This conclusion was strengthened by our observation that clomethiazole is a weak inhibitor (IC50 > 1 mM) of lipid peroxidation in synaptosomes when it had been induced by addition of FeCl2 + ascorbic acid.
Colado
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MI
Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, Spain. colado@eucmax.sim.ucm.es
O'Shea
E
E
Esteban
B
B
Granados
R
R
Green
A R
AR
D000818:Animals; D001711:Biotransformation; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D002719:Chlormethiazole / Q000494:pharmacology*; D003342:Corpus Striatum / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005841:Gentisates; D006624:Hippocampus / Q000378:metabolism; D062385:Hydroxybenzoates / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007700:Kinetics; D008297:Male; D017551:Microdialysis; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017374:Paroxetine / Q000493:pharmacokinetics; D051381:Rats; D020156:Salicylic Acid / Q000493:pharmacokinetics; D012701:Serotonin / Q000378:metabolism*
D016166:Free Radical Scavengers; D005841:Gentisates; D062385:Hydroxybenzoates; D018696:Neuroprotective Agents; D002719:Chlormethiazole; D012701:Serotonin; D017374:Paroxetine; D006897:Hydroxyindoleacetic Acid; C009135:2,3-dihydroxybenzoic acid; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D020156:Salicylic Acid; C010925:2,5-dihydroxybenzoic acid