Neurotoxicity mechanisms of thioether ecstasy metabolites.
J P Capela, Carla Macedo, P S Branco, L M Ferreira, Ana M. Lobo, Eduarda Fernandes, Fernando Remião, Maria L Bastos, Ulrich Dirnagl, Andreas Meisel, F Carvalho
Neuroscience June 8, 2007 DOI: 10.1016/j.neuroscience.2007.03.028 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rat cortical neuronal cultures |
| Duration | 6 h exposure |
| Topics | MDMA |
| Key findings | Thioether MDMA metabolites are stronger neurotoxins than their parent catechols and MDMA, inducing delayed neuronal death via oxidative stress, which is prevented by NAC. |
Abstract
3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy"), is a widely abused, psychoactive recreational drug that is known to induce neurotoxic effects. Human and rat hepatic metabolism of MDMA involves N-demethylation to 3,4-methylenedioxyamphetamine (MDA), which is also a drug of abuse. MDMA and MDA are O-demethylenated to N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA) and alpha-methyldopamine (alpha-MeDA), respectively, which are both catechols that can undergo oxidation to the corresponding ortho-quinones. Ortho-quinones may be conjugated with glutathione (GSH) to form glutathionyl adducts, which can be transported into the brain and metabolized to the correspondent N-acetylcysteine (NAC) adducts. In this study we evaluated the neurotoxicity of nine MDMA metabolites, obtained by synthesis: N-Me-alpha-MeDA, alpha-MeDA and their correspondent GSH and NAC adducts. The studies were conducted in rat cortical neuronal cultures, for a 6 h of exposure period, under normal (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Our findings show that thioether MDMA metabolites are strong neurotoxins, significantly more than their correspondent parent catechols. On the other hand, N-Me-alpha-MeDA and alpha-MeDA are more neurotoxic than MDMA. GSH and NAC conjugates of N-Me-alpha-MeDA and alpha-MeDA induced a concentration dependent delayed neuronal death, accompanied by activation of caspase 3, which occurred earlier in hyperthermic conditions. Furthermore, thioether MDMA metabolites time-dependently increased the production of reactive species, concentration-dependently depleted intracellular GSH and increased protein bound quinones. Finally, thioether MDMA metabolites induced neuronal death and oxidative stress was prevented by NAC, an antioxidant and GSH precursor. This study provides new insights into the neurotoxicity mechanisms of thioether MDMA metabolites and highlights their importance in "ecstasy" neurotoxicity.
Comparable studies
Other experimental studies on MDMA, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| Oxytocin-dependent reopening of a social reward learning critical period with MDMA | 2019 | Experimental study | |
| Effects of certain hallucinogenic amphetamine analogs on the release of [3H]-serotonin from rat brain synaptosomes Rat whole brain synaptosomes | 1982 | Experimental study |
Citations in the library
Cited by 37
- Pro‐oxidant effects of Ecstasy and its metabolites in mouse brain synaptosomes British Journal of Pharmacology April 21, 2011
- Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences due to polymorphisms and drug–drug interactions Critical Reviews in Toxicology October 3, 2012
- Enzymatic–nonenzymatic cellular antioxidant defense systems response and immunohistochemical detection of MDMA, VMAT2, HSP70, and apoptosis as biomarkers for MDMA (Ecstasy) neurotoxicity Journal of Neuroscience Research October 1, 2009
- Microglial and astroglial activation by 3,4‐methylenedioxymethamphetamine (MDMA) in mice depends on S(+) enantiomer and is associated with an increase in body temperature and motility Journal of Neurochemistry October 20, 2012
- Enantioselectivity in the Methylation of the Catecholic Phase I Metabolites of Methylenedioxy Designer Drugs and Their Capability To Inhibit Catechol-O-methyltransferase-Catalyzed Dopamine 3-Methylation Chemical Research in Toxicology May 22, 2009
and 32 more in the library
Cites 28
- Positron emission tomographic evidence of toxic effect of MDMA (“Ecstasy”) on brain serotonin neurons in human beings The Lancet October 1, 1998
- Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Journal of Pharmacology and Experimental Therapeutics 1987
- Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat Journal of Neuroscience July 1, 1998
- Altered Serotonin Innervation Patterns in the Forebrain of Monkeys Treated with (±)3,4-Methylenedioxymethamphetamine Seven Years Previously: Factors Influencing Abnormal Recovery Journal of Neuroscience June 15, 1999
- Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or Ecstasy Journal of Psychopharmacology 2005
and 23 more in the library