Studies on the neuroprotective effect of the enantiomers of AR-A008055, a compound structurally related to clomethiazole, on MDMA ("ecstasy")-inducedneurodegeneration in rat brain

Rationale: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") administrati on produces neurotoxic degeneration of 5-HT nerve endings in several region s of rat brain. Administration of the GABAmimetic drug clomethiazole protec ts against this damage. Objective: We wished to see whether the enantiomers of AR-A008055 (1-4-methyl-5-thiazolyl-l-phenyl-methylamine), a compound st ructurally related to clomethiazole, were also neuroprotective against MDMA -induced degeneration. Methods: (R)-(+)-AR-A008055 or (S)-(-)AR-A008055 (10 0 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 measu red in cortex. Results: Both enantiomers abolished the acute MDMA-induced h yperthermia and attenuated the subsequent neurotoxic loss of 5-HT, 5-HIAA a nd [H-3]-paroxetine binding. When rats given the enantiomer plus MDMA were warmed to keep their rectal temperature elevated to near that of animals gi ven only MDMA, the neuroprotective effect of (S)-(-)-AR-A008055 was still s een, while the effect of (R)-(+)-AR-A008055 was abolished. Protection was a lso seen when (S)-(-)-ARA008055 (50 mg/kg) was given, a dose which produced only a modest attenuation of MDMA-induced hyperthermia. Conclusions: The c urrent data suggest that a major proportion of the neuroprotective action o f (S)-(-)-ARA008055 did not involve an attenuating effect on MDMA-induced h yperthermia. The protection afforded by (R)-(+)-AR-A008055, which is not a GABA agonist, appears to be solely due to its action on body temperature, s trengthening the contention that abolishing the acute MDMA-induced hypother mia can produce neuroprotection. Since (S)-(-)-AR-A008055 has a similar pha rmacology to clomethiazole, these data suggest that drugs which increase GA BAA receptor channel opening are neuroprotective against MDMA-induced damag e.