期刊
ACS CHEMICAL NEUROSCIENCE
卷 8, 期 4, 页码 850-859出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.6b00421
关键词
beta-Keto amphetamines; synthetic cathinones; neurotoxicity; oxidative stress; mitochondrial impairment; apoptosis
资金
- European Union (FEDER funds) [POCl/01/0145/FEDER/007728]
- National Funds (FCT/MEC, Fundacao para a Ciencia e Tecnologia and Ministerio da Educacao e Ciencia) [PT2020 UID/MULTI/04378/2013]
- Norte Portugal Regional Operational Programme through the European Regional Development Fund (ERDF) [NORTE-01-0145-FEDER000024]
- Fundacio para a Ciencia e Tecnologia (FCT), Portugal [SFRH/BD/89879/2012]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/89879/2012] Funding Source: FCT
Synthetic cathinones (beta-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-methylenedioxymetlicathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV), with those of 3,4-methylenedioxymethamphetamine (MDMA), using undifferentiated and differentiated SH-SYSY 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 approximate to 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 (Delta psi m) 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 mitochondria] dysfunction play a role in cathinones-induced neuronal damage, ultimately leading to cell death by apoptosis.
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