The neurotoxic effects of methylenedioxymethamphetamine (MDMA) and its metabolites on rat brain spheroids in culture |
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Authors: | T.M. Walker J.E. Davenport-Jones R.M. Fox C.K. Atterwill |
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Affiliation: | (1) Department of Strategic Toxicological Sciences, GlaxoWellcome, Ware, Herts, UK;(2) Department of Biosciences, University of Hertfordshire, Hatfield, Herts, UK;(3) Roche Discovery, Department of Preclinical Drug Safety, Welwyn Garden City, Herts, UK |
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Abstract: | Rat whole-brain spheroids were used to assess the intrinsic neurotoxicity of methylenedioxymethamphetamine (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 mol/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 mol/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 mol/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. |
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Keywords: | brain culture glutathione MDMA neurotoxicity spheroids |
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