Glial cell response to 3,4-(+/-)-methylenedioxymethamphetamine and its metabolites.
Joseph M Herndon, Aram B Cholanians, Serrine S. Lau, Terrence J. Monks
Toxicological sciences : an official journal of the Society of Toxicology March 2014 DOI: 10.1093/toxsci/kft275 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal and in vitro study Peer reviewed |
|---|---|
| Population | Rats (parietal cortex and brain ventricle injections) and primary cultures of embryonic day 18 hippocampal mixed glial and neuronal cells |
| Interventions | MDMA MDA 2 |
| Dose | MDMA 20 mg/kg SC; MDA 20 mg/kg SC; thioether metabolites 10 µM in vitro |
| Duration | Microglial response assessed at various time points up to 7 days after administration |
| Measures | Microglial occupancy status, glial fibrillary acidic protein (GFAP)-positive astrocyte proliferation |
| Topics | MDMA |
| Keywords | 3,4-±-methylenedioxymethamphetamine Metabolites Microglial activation. |
| Key findings | MDMA and MDA activated microglia in rat parietal cortex, with MDMA producing a biphasic response peaking at 12 and 72 hours and MDA a response at 72 hours that subsided by 7 days. Direct intracerebroventricular MDA did not activate microglia, but thioether metabolites of alpha-methyldopamine did, and three such metabolites stimulated astrocyte proliferation in culture at 10 micromolar. The authors argue these findings support a role for thioether metabolites in MDMA/MDA neurotoxicity. |
Abstract
3,4-(±)-Methylenedioxymethamphetamine (MDMA) and 3,4-(±)-methylenedioxyamphetamine (MDA), a primary metabolite of MDMA, are phenylethylamine derivatives that cause serotonergic neurotoxicity. Although several phenylethylamine derivatives activate microglia, little is known about the effects of MDMA on glial cells, and evidence of MDMA-induced microglial activation remains ambiguous. We initially determined microglial occupancy status of the parietal cortex in rats at various time points following a single neurotoxic dose of MDMA (20mg/kg, SC). A biphasic microglial response to MDMA was observed, with peak microglial occupancy occurring 12- and 72-h post-MDMA administration. Because direct injection of MDMA into the brain does not produce neurotoxicity, the glial response to MDMA metabolites was subsequently examined in vivo and in vitro. Rats were treated with MDA (20mg/kg, SC) followed by ex vivo biopsy culture to determine the activation of quiescent microglia. A reactive microglial response was observed 72 h after MDA administration that subsided by 7 days. In contrast, intracerebroventricular (ICV) administration of MDA failed to produce a microglial response. However, thioether metabolites of MDA derived from α-methyldopamine (α-MeDA) elicited a robust microglial response following icv injection. We subsequently determined the direct effects of various MDMA metabolites on primary cultures of E18 hippocampal mixed glial and neuronal cells. 5-(Glutathion-S-yl)-α-MeDA, 2,5-bis-(glutathion-S-yl)-α-MeDA, and 5-(N-acetylcystein-S-yl)-α-MeDA all stimulated the proliferation of glial fibrillary acidic protein-positive astrocytes at a dose of 10 µM. The findings indicate that glial cells are activated in response to MDMA/MDA and support a role for thioether metabolites of α-MeDA in the neurotoxicity.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
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Cites 11
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- Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Journal of Neuroscience August 1, 1988
- Neurotoxicity of MDMA and Related Compounds: Anatomic Studiesa Annals of the New York Academy of Sciences October 1, 1990
- Glutathione and N-Acetylcysteine Conjugates of α-Methyldopamine Produce Serotonergic Neurotoxicity: Possible Role in Methylenedioxyamphetamine-Mediated Neurotoxicity Chemical Research in Toxicology November 19, 1999
- α-Lipoic acid prevents 3,4-methylenedioxy-methamphetamine (MDMA)-induced neurotoxicity Neuroreport November 1, 1999
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