Ecstasy induces apoptosis via 5-HT(2A)-receptor stimulation in cortical neurons.
ABSTRACT 3,4-Methylenedioxymethamphetamine (MDMA or "Ecstasy") is a psychoactive and hallucinogenic drug of abuse. MDMA has been shown to produce neurotoxicity both in animals and humans. MDMA and other amphetamines induce serotonergic and dopaminergic terminal neurotoxicity and also neurodegeneration in areas including the cortex, hippocampus, striatum and thalamus. Herein, we investigated the mechanisms involved in MDMA-induced neurotoxicity to neuronal serum free cultures from rat cortex. The hyperthermic effect produced by MDMA has been shown to be a clinically relevant aspect for the neurotoxic events. Thus, MDMA-induced toxicity to cortical neurons was evaluated both under normothermic (36.5 degrees C) and hyperthermic (40 degrees C) conditions. Our findings showed that MDMA produced neuronal apoptosis, accompanied by activation of caspase 3, in a concentration dependent manner. MDMA neurotoxicity was completely prevented by pre-treatment with a 5-HT(2A)-receptor antibody, which acted as an "irreversible non-competitive antagonist" of this receptor. Furthermore, MDMA depleted intracellular glutathione (GSH) levels in a concentration dependent manner, an effect that was attenuated by Ketanserin, a competitive 5-HT(2A)-receptor antagonist. Accordingly, N-acetylcysteine, an antioxidant and GSH precursor, also reduced MDMA-induced toxicity. Specific inhibitors of the inducible and neuronal nitric oxide synthase (NOS) partially prevented MDMA neurotoxicity, ascertaining the involvement of reactive nitrogen species, in the toxic effect. In conclusion, direct MDMA 5-HT(2A)-receptor stimulation produces intracellular oxidative stress that leads to neuronal apoptosis accompanied by caspase 3 activation.
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ABSTRACT: Amphetamines are a class of psychotropic drugs with high abuse potential, as a result of their stimulant, euphoric, emphathogenic, entactogenic, and hallucinogenic properties. Although most amphetamines are synthetic drugs, of which methamphetamine, amphetamine, and 3,4-methylenedioxymethamphetamine ("ecstasy") represent well-recognized examples, the use of natural related compounds, namely cathinone and ephedrine, has been part of the history of humankind for thousands of years. Resulting from their amphiphilic nature, these drugs can easily cross the blood-brain barrier and elicit their well-known psychotropic effects. In the field of amphetamines' research, there is a general consensus that mitochondrial-dependent pathways can provide a major understanding concerning pathological processes underlying the neurotoxicity of these drugs. These events include alterations on tricarboxylic acid cycle's enzymes functioning, inhibition of mitochondrial electron transport chain's complexes, perturbations of mitochondrial clearance mechanisms, interference with mitochondrial dynamics, as well as oxidative modifications in mitochondrial macromolecules. Additionally, other studies indicate that amphetamines-induced neuronal toxicity is closely regulated by B cell lymphoma 2 superfamily of proteins with consequent activation of caspase-mediated downstream cell death pathway. Understanding the molecular mechanisms at mitochondrial level involved in amphetamines' neurotoxicity can help in defining target pathways or molecules mediating these effects, as well as in developing putative therapeutic approaches to prevent or treat the acute- or long-lasting neuropsychiatric complications seen in human abusers.Archives of Toxicology 03/2015; DOI:10.1007/s00204-015-1478-9 · 5.08 Impact Factor
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ABSTRACT: 3,4-Methylenedioximethamphetamine (MDMA, ecstasy) is a worldwide abused stimulant drug, with persistent neurotoxic effects and high prevalence among adolescents. The massive release of 5-HT from pre-synaptic storage vesicles induced by MDMA followed by monoamine oxidase B (MAO-B) metabolism, significantly increases oxidative stress at the mitochondrial level. l-Carnitine and its ester, acetyl-l-carnitine (ALC), facilitate the transport of long chain free fatty acids across the mitochondrial membrane enhancing neuronal anti-oxidative defense. Here, we show the potential of ALC against the neurotoxic effects of MDMA exposure. Adolescent male Wistar rats were assigned to four groups: control saline solution, isovolumetric to the MDMA solution, administered i.p.; MDMA (4x10 mg/kg MDMA, i.p.); ALC/MDMA (100 mg/kg 30 min of ALC prior to MDMA, i.p.) and ALC (100 mg/kg, i.p.). Rats were killed 2 weeks after exposure and brains were analyzed for lipid peroxidation, carbonyl formation, mitochondrial DNA (mtDNA) deletion and altered expression of the DNA-encoded subunits of the mitochondrial complexes I (NADH dehydrogenase, NDII) and IV (cytochrome c oxidase, COXI) from the respiratory chain. Levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were also assessed. The present work is the first to successfully demonstrate that pretreatment with ALC exerts effective neuroprotection against the MDMA-induced neurotoxicity at the mitochondrial level, reducing carbonyl formation, decreasing mtDNA deletion, improving the expression of the respiratory chain components and preventing the decrease of 5-HT levels in several regions of the rat brain. These results indicate potential benefits of ALC application in the prevention and treatment of neurodegenerative disorders.Neuroscience 11/2008; 158(2):514-23. DOI:10.1016/j.neuroscience.2008.10.041 · 3.33 Impact Factor
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ABSTRACT: Ecstasy (3,4-methylenedioxymethamphetamine; MDMA) has potent CNS stimulant effects. Besides the acute effects of MDMA, such as psychomotor activation, euphoria, decreased appetite, and hyperthermia, long-term damage of dopaminergic and serotonergic nerve terminals in multiple brain areas have also been reported. Although some studies have demonstrated that considerable amounts of MDMA reach the vitreous humor of the eye, and that serious visual consequences can result from MDMA consumption, the toxic effect of MDMA on the retina has not been completely elucidated. Neuropeptide Y (NPY) is present in the CNS, including the retina. The aim of the present study was to evaluate the effect of MDMA on rat retinal neural cell viability and investigate the involvement of 5-HT 2A-receptor (5-HT(2A)) activation. Moreover, the neuroprotective role of NPY on MDMA-induced toxicity was also investigated. MDMA induced necrosis [MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and propidium iodide assays] and apoptosis (immunoreactivity of cleaved caspase-3) in mixed cultures of retinal neural cells (neurons, macroglia and microglia), in a concentration-dependent manner. MDMA-induced toxicity was enhanced at higher temperature (40 degrees C) and was reduced by the 5HT(2A)-receptor antagonist, ketanserin (1 microM). Interestingly, necrotic and apoptotic cell death induced by MDMA was inhibited by NPY (100 nM).Neuroscience 04/2008; 152(1):97-105. DOI:10.1016/j.neuroscience.2007.12.027 · 3.33 Impact Factor