Autophagy activation is involved in 3,4-methylenedioxymethamphetamine ('ecstasy')--induced neurotoxicity in cultured cortical neurons.
I-Hsun Li, Kuo-Hsing Ma, Shao-Ju Weng, Shiang-Suo Huang, Chang-Min Liang, Yuahn-Sieh Huang
PLoS One December 31, 2014 DOI: 10.1371/journal.pone.0116565 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro experimental study Peer reviewed |
|---|---|
| Population | Cultured rat cortical neurons |
| Interventions | MDMA 3-methyladenine rapamycin bafilomycin A1 |
| Measures | monodansylcadaverine (MDC) staining, LC3B immunofluorescence, western blot for LC3B-I/LC3B-II, neurite damage assessment, neuronal death assessment |
| Topics | MDMA |
| Keywords | Neurons Cells, cultured Animals Rats, sprague-dawley 3,4-methylenedioxyamphetamine Adenine Neurotoxins Signal transduction Cell survival Amp-activated protein kinases Autophagy-related protein-1 homolog |
| Citations | 40 |
| Key findings | MDMA exposure induced autophagy in cultured rat cortical neurons, and excessive autophagosome accumulation contributed to MDMA-induced neurite damage and neuronal death. Inhibiting autophagy with 3-methyladenine reduced this toxicity, while enhancing autophagy with rapamycin or blocking clearance with bafilomycin A1 worsened it. The authors suggest the AMPK/ULK1 signaling pathway may mediate MDMA-induced autophagy activation. |
Abstract
Autophagic (type II) cell death, characterized by the massive accumulation of autophagic vacuoles in the cytoplasm of cells, has been suggested to play pathogenetic roles in cerebral ischemia, brain trauma, and neurodegenerative disorders. 3,4-Methylenedioxymethamphetamine (MDMA or ecstasy) is an illicit drug causing long-term neurotoxicity in the brain. Apoptotic (type I) and necrotic (type III) cell death have been implicated in MDMA-induced neurotoxicity, while the role of autophagy in MDMA-elicited neurotoxicity has not been investigated. The present study aimed to evaluate the occurrence and contribution of autophagy to neurotoxicity in cultured rat cortical neurons challenged with MDMA. Autophagy activation was monitored by expression of microtubule-associated protein 1 light chain 3 (LC3; an autophagic marker) using immunofluorescence and western blot analysis. Here, we demonstrate that MDMA exposure induced monodansylcadaverine (MDC)- and LC3B-densely stained autophagosome formation and increased conversion of LC3B-I to LC3B-II, coinciding with the neurodegenerative phase of MDMA challenge. Autophagy inhibitor 3-methyladenine (3-MA) pretreatment significantly attenuated MDMA-induced autophagosome accumulation, LC3B-II expression, and ameliorated MDMA-triggered neurite damage and neuronal death. In contrast, enhanced autophagy flux by rapamycin or impaired autophagosome clearance by bafilomycin A1 led to more autophagosome accumulation in neurons and aggravated neurite degeneration, indicating that excessive autophagosome accumulation contributes to MDMA-induced neurotoxicity. Furthermore, MDMA induced phosphorylation of AMP-activated protein kinase (AMPK) and its downstream unc-51-like kinase 1 (ULK1), suggesting the AMPK/ULK1 signaling pathway might be involved in MDMA-induced autophagy activation.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 10
- Evaluation of Cytotoxic, Necrotic, Apoptotic, and Autophagic Effects of Methamphetamine and 3,4-Methylenedioxymethamphetamine on U-87 MG (Glial) and B104-1–1 (Neuronal) Cell Lines Neurotoxicity Research October 1, 2022
- MDMA (3,4-methylenedioxy-methamphetamine) Drug Addiction Mechanisms in the Brain April 8, 2024
- Glutathione as a Potential Neuroprotectant Against MDMA-Induced Oxidative Stress, Neuroinflammation, and Apoptosis in the Rat Brain. Neurochemical Research May 6, 2026
- Role of Microglia in 3, 4 Methylenedioxymethamphetamine (MDMA) -Induced Neurotoxicity: A Mini Review ASM Science Journal November 17, 2023
- Lysosomal Dysfunction and Autophagy Blockade Contribute to MDMA-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells. Chemical Research in Toxicology April 20, 2020
and 5 more in the library
Cites 6
- (±)3,4-Methylenedioxymethamphetamine (‘Ecstasy’)-Induced Serotonin Neurotoxicity: Studies in Animals Neuropsychobiology 2000
- Neurotoxicity of Methamphetamine and 3,4-methylenedioxymethamphetamine Life Science July 24, 2013
- Neurotoxicity of Ecstasy (MDMA): An Overview Current Pharmaceutical Biotechnology June 27, 2010
- MDMA (Ecstasy) Annals of Clinical Psychiatry 2007
- Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview Molecular Neurobiology June 1, 2009
and 1 more in the library