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MDMA-induced neurotoxicity of serotonin neurons involves autophagy and rilmenidine is protective against its

Linda D Mercer1, Gavin C Higgins1, Chew L Lau1

  • 1Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria 3010, Australia.

Neurochemistry International
|January 26, 2017
PubMed

Insights

3,4-methylenedioxymethamphetamine (MDMA) neurotoxicity in serotonin (5-HT) neurons involves autophagy induction. The drug rilmenidine demonstrated neuroprotective effects against MDMA-induced damage in this specific neuronal population.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Pharmacology

Background:

  • 3,4-methylenedioxymethamphetamine (MDMA) is known to be toxic to biogenic amine neurons, particularly serotonin (5-HT) neurons in the primate brain.
  • MDMA causes damage to 5-HT axons and nerve fibers, characterized by intracytoplasmic inclusions and mitochondrially-mediated oxidative stress.

Purpose of the Study:

  • To investigate the hypothesis that MDMA activates autophagy, a cellular degradation mechanism.
  • To explore the mechanisms underlying MDMA neurotoxicity and autophagy recruitment in 5-HT neurons.
  • To evaluate the potential neuroprotective effects of rilmenidine against MDMA-induced neurotoxicity.

Main Methods:

  • Primary cultures of ventral pons from embryonic murine brain, enriched in 5-HT neurons, were utilized.
  • Cell viability, 5-HT uptake, and autophagosome formation (LC3) were assessed after MDMA treatment.
  • Immunocytochemistry and Hoechst labeling were employed to evaluate neuronal damage and autophagy markers.

Main Results:

  • MDMA reduced cell viability and inhibited [3H]5-HT uptake in a concentration-dependent manner.
  • MDMA induced 5-HT neuron damage, including neuritic blebbing and nuclear fragmentation, and triggered autophagy with abundant LC3-positive puncta.
  • Rilmenidine (1 μM) significantly protected 5-HT neurons against MDMA-induced injury, preserving 5-HT arbors.

Conclusions:

  • MDMA-induced neurotoxicity in 5-HT neurons is mediated by the induction of autophagy.
  • Rilmenidine exhibits neuroprotective properties against MDMA's toxic effects, suggesting its potential therapeutic value for MDMA-related pathologies.
Keywords:
MDMANeuroprotectionProgrammed cell deathRilmenidineSerotonin neuronmTOR-independent autophagy

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