The neurotoxic effects of methylenedioxymethamphetamine (MDMA) and its metabolites on rat brain spheroids in culture.
Rat whole-brain spheroids were used to assess the intrinsic neurotoxicity of methylenedioxy-methamphetamine (MDMA, Ecstasy) and two of its metabolites, dihydroxymethamphetamine (DHMA) and 6-hydroxy-MDMA (6-OH MDMA). Exposure of brain spheroids to MDMA or the metabolite 6-OH MDMA (up to 500 micromol/L) for 5 days in culture did not alter intracellular levels of glutathione (GSH), glial fibrillary acidic protein (GFAP) or serotonin (5-HT). In contrast, exposure to the metabolite DHMA, which can deplete intracellular thiols, significantly increased GSH levels (up to 170% of control) following exposure to 50 and 100 micromol/L DHMA. There was also a significant reduction in the levels of glial fibrillary acidic protein (GFAP) and GSH by DHMA at the highest concentration tested (500 micromol/L) but there was no effect on 5HT. This may constitute a sublethal neurotoxic compensatory response to DHMA in an attempt to replenish depleted intraneural GSH levels following metabolite exposure. Rat whole-brain spheroids may thus be a useful in vitro model to delineate mechanisms and effects of this class of neurotoxin.
Walker
T M
TM
Department of Strategic Toxicological Sciences, GlaxoWellcome, Ware, Herts, UK.
Davenport-Jones
J E
JE
Fox
R M
RM
Atterwill
C K
CK
D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D001927:Brain Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D003846:Deoxyepinephrine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005333:Fetus; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000378:metabolism / Q000633:toxicity*; D018874:Spheroids, Cellular / Q000187:drug effects*
D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D018490:Serotonin Agents; C073631:6-hydroxy-N-methyl-3,4-methylenedioxyamphetamine; C069512:alpha-methylepinine; D012701:Serotonin; D015104:3,4-Methylenedioxyamphetamine; D007770:L-Lactate Dehydrogenase; D005978:Glutathione; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D003846:Deoxyepinephrine