Studies on the neuroprotective effect of the enantiomers of AR-A008055, a compound structurally related to clomethiazole, on MDMA ("ecstasy")-induced neurodegeneration in rat brain.
BACKGROUND
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-1-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. [3H]-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 [3H]-paroxetine binding. When rats given the enantiomer plus MDMA were warmed 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)-(-)-AR-A008055 (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)-(-)-AR-A008055 did not involve an attenuating effect on MDMA-induced hyperthermia. The protection afforded by (R)-(+)-AR-A008055, which is not a GABA 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.
Colado
M I
MI
Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain.
O'Shea
E
E
Esteban
B
B
Green
A R
AR
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002719:Chlormethiazole / Q000494:pharmacology; D008297:Male; D008744:Methylamines / Q000494:pharmacology*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010424:Pentobarbital / Q000494:pharmacology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects; D013237:Stereoisomerism; D013844:Thiazoles / Q000494:pharmacology*
C436486:1-(4-methyl-5-thiazolyl)-1-phenylmethylamine; D008744:Methylamines; D018696:Neuroprotective Agents; D011963:Receptors, GABA-A; D013844:Thiazoles; D002719:Chlormethiazole; D010424:Pentobarbital; D018817:N-Methyl-3,4-methylenedioxyamphetamine