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 degeneratio n of 5-HT neurones that follows administration of 3,4-methylenedioxymethamp hetamine (MDMA or 'ecstasy'). Since there is good evidence that free radica l formation resulting from auto-oxidation of MDMA metabolites is responsibl e for the degeneration we have examined whether clomethiazole is a free rad ical 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 perfus ed through a microdialysis tube implanted in the hippocampus, indicating in creased free radical formation. Clomethiazole (50 mg/kg i.p.) administered 5 min prior and 55 min post MDMA prevented both the acute MDMA-induced hype rthermia and the rise in 2,3- and 2,5-DHBA. However, when the temperature o f the MDMA + clomethiazole treated rats was kept elevated to that of the MD MA 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 t hat free radical formation is inhibited when the acute MDMA-induced hyperth ermia is prevented. Secondly the data further indicate that clomethiazole h as no free radical scavenging activity since the drug produces substantial neuroprotection when MDMA + clomethiazole treated rats are kept hyperthermi c. This conclusion was strengthened by our observation that clomethiazole i s a weak inhibitor (IC50 >1 mM) of lipid peroxidation in synaptosomes when it had been induced by addition of FeCl2 + ascorbic acid. (C) 1999 Elsevier Science Ltd. All rights reserved.