Neurotoxicity of "ecstasy" and its metabolites in human dopaminergic differentiated SH-SY5Y cells.
Patrícia Silva Ferreira, Tiago Bernandes Nogueira, Vera Marisa Costa, Paula Sério Branco, Luísa Maria Ferreira, Eduarda Fernandes, Maria Lourdes Bastos, Andreas Meisel, Félix Carvalho, João Paulo Capela
Toxicology Letters February 4, 2013 DOI: 10.1016/j.toxlet.2012.11.015 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro cell study Peer reviewed |
|---|---|
| Population | Human dopaminergic SH-SY5Y cells differentiated with retinoic acid and 12-O-tetradecanoyl-phorbol-13-acetate |
| Interventions | MDMA α-methyldopamine (α-MeDA) N-methyl-α-methyldopamine (N-Me-α-MeDA) N-acetylcysteine (NAC) tiron GBR 12909 buthionine sulfoximine (BSO) |
| Duration | Up to 48 h |
| Topics | MDMA |
| Key points | MDMA catechol metabolites α-methyldopamine and N-methyl-α-methyldopamine were neurotoxic to differentiated human dopaminergic SH-SY5Y cells in a concentration- and time-dependent manner, causing caspase 3-independent cell death, whereas MDMA itself did not show such concentration- and time-dependent death. N-acetylcysteine strongly protected against metabolite toxicity, and glutathione synthesis inhibition modified these effects, indicating differential toxic mechanisms. |
Abstract
"Ecstasy" (3,4-methylenedioxymethamphetamine or MDMA) is a widely abused recreational drug, reported to produce neurotoxic effects, both in laboratory animals and in humans. MDMA metabolites can be major contributors for MDMA neurotoxicity. This work studied the neurotoxicity of MDMA and its catechol metabolites, α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA) in human dopaminergic SH-SY5Y cells differentiated with retinoic acid and 12-O-tetradecanoyl-phorbol-13-acetate. Differentiation led to SH-SY5Y neurons with higher ability to accumulate dopamine and higher resistance towards dopamine neurotoxicity. MDMA catechol metabolites were neurotoxic to SH-SY5Y neurons, leading to caspase 3-independent cell death in a concentration- and time-dependent manner. MDMA did not show a concentration- and time-dependent death. Pre-treatment with the antioxidant and glutathione precursor, N-acetylcysteine (NAC), resulted in strong protection against the MDMA metabolites' neurotoxicity. Neither the superoxide radical scavenger, tiron, nor the inhibitor of the dopamine (DA) transporter, GBR 12909, prevented the metabolites' toxicity. Cells exposed to α-MeDA showed an increase in intracellular glutathione (GSH) levels, which, at the 48 h time-point, was not dependent in the activity increase of γ-glutamylcysteine synthetase (γ-GCS), revealing a possible transient effect. Importantly, pre-treatment with buthionine sulfoximine (BSO), an inhibitor of γ-GCS, prevented α-MeDA induced increase in GSH levels, but did not augment this metabolite cytotoxicity. Even so, BSO pre-treatment abolished NAC protective effects against α-MeDA neurotoxicity, which were, at least partially, due to GSH de novo synthesis. Inversely, pre-treatment of cells with BSO augmented N-Me-α-MeDA-induced neurotoxicity, but only slightly affected NAC neuroprotection. In conclusion, MDMA catechol metabolites promote differential toxic effects to differentiated dopaminergic human SH-SY5Y cells.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 7
- A review on the mitochondrial toxicity of “ecstasy” (3,4-methylenedioxymethamphetamine, MDMA) Current Research in Toxicology May 27, 2022
- Ecstasy metabolites and monoamine neurotransmitters upshift the Na+/K+ ATPase activity in mouse brain synaptosomes. Archives of Toxicology December 2022
- Lysosomal Dysfunction and Autophagy Blockade Contribute to MDMA-Induced Neurotoxicity in SH-SY5Y Neuroblastoma Cells. Chemical Research in Toxicology April 20, 2020
- Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms. Progress in Neurobiology August 2017
- Non-Serotonergic Neurotoxicity by MDMA (Ecstasy) in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells. PLoS One November 18, 2016
and 2 more in the library
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