"Ecstasy"-induced toxicity in SH-SY5Y differentiated cells: role of hyperthermia and metabolites.
Daniel José Barbosa, João Paulo Capela, Renata Silva, Luísa Maria Ferreira, Paula Sério Branco, Eduarda Fernandes, Maria Lourdes Bastos, Félix Carvalho
Archives of Toxicology February 2014 DOI: 10.1007/s00204-013-1147-9 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro experimental study Peer reviewed |
|---|---|
| Population | Cultured SH-SY5Y differentiated cells |
| Interventions | MDMA α-methyldopamine N-methyl-α-methyldopamine N-acetyl-cysteine |
| Topics | MDMA |
| Key findings | MDMA metabolites, particularly glutathione and N-acetyl-cysteine conjugates, were more toxic to SH-SY5Y differentiated cells than MDMA itself. Hyperthermia increased the toxicity of catechol metabolites but not glutathione conjugates, while N-acetyl-cysteine conjugates were more toxic at normal temperature. The authors conclude that reactive metabolites and hyperthermia play a major role in MDMA neurotoxicity. |
Abstract
3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a recreational hallucinogenic drug of abuse known to elicit neurotoxic properties. Hepatic formation of neurotoxic metabolites is thought to play a major role in MDMA-related neurotoxicity, though the mechanisms involved are still unclear. Here, we studied the neurotoxicity mechanisms and stability of MDMA and 6 of its major human metabolites, namely α-methyldopamine (α-MeDA) and N-methyl-α-methyldopamine (N-Me-α-MeDA) and their correspondent glutathione (GSH) and N-acetyl-cysteine (NAC) conjugates, under normothermic (37 °C) or hyperthermic conditions (40 °C), using cultured SH-SY5Y differentiated cells. We showed that MDMA metabolites exhibited toxicity to SH-SY5Y differentiated cells, being the GSH and NAC conjugates more toxic than their catecholic precursors and MDMA. Furthermore, whereas the toxicity of the catechol metabolites was potentiated by hyperthermia, NAC-conjugated metabolites revealed higher toxicity under normothermia and GSH-conjugated metabolites-induced toxicity was temperature-independent. Moreover, a time-dependent decrease in extracellular concentration of MDMA metabolites was observed, which was potentiated by hyperthermia. The antioxidant NAC significantly protected against the neurotoxic effects of MDMA metabolites. MDMA metabolites increased intracellular glutathione levels, though depletion in thiol content was observed in MDMA-exposed cells. Finally, the neurotoxic effects induced by the MDMA metabolite N-Me-α-MeDA involved caspase 3 activation. In conclusion, this study evaluated the stability of MDMA metabolites in vitro, and demonstrated that the catechol MDMA metabolites and their GSH and NAC conjugates, rather than MDMA itself, exhibited neurotoxic actions in SH-SY5Y differentiated cells, which were differently affected by hyperthermia, thus highlighting a major role for reactive metabolites and hyperthermia in MDMA's neurotoxicity.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 7
- Para-Halogenation of Amphetamine and Methcathinone Increases the Mitochondrial Toxicity in Undifferentiated and Differentiated SH-SY5Y Cells International Journal of Molecular Sciences April 18, 2020
- Ecstasy metabolites and monoamine neurotransmitters upshift the Na+/K+ ATPase activity in mouse brain synaptosomes. Archives of Toxicology December 2022
- Amphetamine-related drugs neurotoxicity in humans and in experimental animals: Main mechanisms. Progress in Neurobiology August 2017
- Involvement of autophagy upregulation in 3,4-methylenedioxymethamphetamine ('ecstasy')-induced serotonergic neurotoxicity. Neurotoxicology January 2016
- Modeling chronic brain exposure to amphetamines using primary rat neuronal cortical cultures. Neuroscience September 26, 2014
and 2 more in the library
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and 35 more in the library