MDMA-induced neurotoxicity of serotonin neurons involves autophagy and rilmenidine is protective against its pathobiology.
Linda D Mercer, Gavin C Higgins, Chew L Lau, Andrew J Lawrence, Philip M Beart
Neurochemistry International May 2017 DOI: 10.1016/j.neuint.2017.01.010 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro cell culture study Peer reviewed |
|---|---|
| Population | Embryonic murine ventral pons cell culture enriched in serotonin (5-HT) neurons |
| Interventions | MDMA Rilmenidine Rapamycin Hydrogen peroxide |
| Dose | MDMA 100 μM–1 mM; rilmenidine 1 μM |
| Duration | Up to 72 h |
| Measures | cell viability assay, [3H]5-HT uptake, Western immunoblotting for LC3, immunocytochemistry for 5-HT, Hoechst labelling, confocal microscopy |
| Topics | MDMA Serotonin |
| Keywords | Neuroprotection Programmed cell death Rilmenidine Serotonin neuron Mtor-independent autophagy |
| Key points | MDMA reduced viability of cultured serotonin neurons in a concentration- and time-dependent manner and induced autophagy, marked by LC3-positive puncta within these neurons; rilmenidine (1 μM) protected against MDMA-induced injury and preserved serotonin arbours. The authors propose that autophagy induction contributes to MDMA neurotoxicity in serotonin neurons and that rilmenidine may be a potential treatment for its pathobiology in sustained usage. |
Abstract
Toxicity of 3,4-methylenedioxymethamphetamine (MDMA) towards biogenic amine neurons is well documented and in primate brain predominantly affects serotonin (5-HT) neurons. MDMA induces damage of 5-HT axons and nerve fibres and intracytoplasmic inclusions. Whilst its pathobiology involves mitochondrially-mediated oxidative stress, we hypothesised MDMA possessed the capacity to activate autophagy, a proteostatic mechanism for degradation of cellular debris. We established a culture of ventral pons from embryonic murine brain enriched in 5-HT neurons to explore mechanisms of MDMA neurotoxicity and recruitment of autophagy, and evaluated possible neuroprotective actions of the clinically approved agent rilmenidine. MDMA (100 μM-1 mM) reduced cell viability, like rapamycin (RM) and hydrogen peroxide (H2O2), in a concentration- and time-dependent manner. Immunocytochemistry revealed dieback of 5-HT arbour: MDMA-induced injury was slower than for RM and H2O2, neuritic blebbing occurred at 48 and 72 h and Hoechst labelling revealed nuclear fragmentation with 100 μM MDMA. MDMA effected concentration-dependent inhibition of [3H]5-HT uptake with 500 μM MDMA totally blocking transport. Western immunoblotting for microtubule associated protein light chain 3 (LC3) revealed autophagosome formation after treatment with MDMA. Confocal analyses and immunocytochemistry for 5-HT, Hoechst and LC3 confirmed MDMA induced autophagy with abundant LC3-positive puncta within 5-HT neurons. Rilmenidine (1 μM) protected against MDMA-induced injury and image analysis showed full preservation of 5-HT arbours. MDMA had no effect on GABA neurons, indicating specificity of action at 5-HT neurons. MDMA-induced neurotoxicity involves autophagy induction in 5-HT neurons, and rilmenidine via beneficial actions against toxic intracellular events represents a potential treatment for its pathobiology in sustained usage.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
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and 8 more in the library