title: Neurotoxicity of β-Keto Amphetamines: Deathly Mechanisms Elicited by Methylone and MDPV in Human Dopaminergic SH-SY5Y Cells.
abstract: Synthetic cathinones (β-keto amphetamines) act as potent CNS stimulants similarly to classical amphetamines, which raise concerns about their potential neurotoxic effects. The present in vitro study aimed to explore and compare the mechanisms underlying the neurotoxicity of two commonly abused cathinone derivatives, 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV), with those of 3,4-methylenedioxymethamphetamine (MDMA), using undifferentiated and differentiated SH-SY5Y cells. Following a 24 h exposure period, methylone and MDPV induced loss of cell viability in a concentration-dependent manner, in the following order of potency: MDPV ≈ MDMA > methylone. Dopaminergic differentiated cells evidenced higher sensitivity to the neurotoxic effects of both cathinones and MDMA than the undifferentiated ones, but this effect was not inhibited by the DAT inhibitor GBR 12909. Intracellular oxidative stress mediated by methylone and MDPV was demonstrated by the increase in reactive oxygen and nitrogen species (ROS and RNS) production, depletion of intracellular reduced glutathione and increased oxidized glutathione levels. All three drugs elicited mitochondrial impairment, characterized by the mitochondrial membrane potential (Δψm) dissipation and intracellular ATP depletion. Apoptosis was found to be a common mechanism of cell death induced by methylone and MDPV, with evident chromatin condensation and formation of pyknotic nuclei, and activation of caspases 3, 8, and 9. In conclusion, the present data shows that oxidative stress and mitochondrial dysfunction play a role in cathinones-induced neuronal damage, ultimately leading to cell death by apoptosis.
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto , 4050-313 Porto, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Valente
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto , 4050-313 Porto, Portugal.
authors.forename: Maria de Lourdes
authors.initials: ML
authors.lastname: Bastos
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Applied Chemistry, Faculty of Pharmacy, University of Porto , 4050-313 Porto, Portugal.
authors.forename: Eduarda
authors.initials: E
authors.lastname: Fernandes
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto , 4050-313 Porto, Portugal.
authors.forename: Félix
authors.initials: F
authors.lastname: Carvalho
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto , 4050-313 Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Guedes de Pinho
authors.affiliation: UCIBIO-REQUIMTE, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto , 4050-313 Porto, Portugal.|FP-ENAS, CEBIMED, Fundação Ensino e Cultura Fernando Pessoa , 4249-004 Porto, Portugal.
authors.forename: Márcia
authors.identifier: 0000-0001-9884-4751
authors.initials: M
authors.lastname: Carvalho
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D052117:Benzodioxoles / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D059290:Dopaminergic Neurons / Q000187:drug effects*; D006801:Humans; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D011759:Pyrrolidines / Q000633:toxicity*; D000094982:Synthetic Cathinone
chemical_list: D052117:Benzodioxoles; D000697:Central Nervous System Stimulants; D011759:Pyrrolidines; D008694:Methamphetamine; C400939:methylone; D000094982:Synthetic Cathinone
keywords: apoptosis; mitochondrial impairment; neurotoxicity; oxidative stress; synthetic cathinones; β-Keto amphetamines