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Adverse outcome pathways induced by 3,4‑dimethylmethcathinone and 4‑methylmethcathinone in differentiated human SH‑SY5Y neuronal cells

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dc.contributor.authorSoares, Jorge
dc.contributor.authorCosta, Vera Marisa
dc.contributor.authorGaspar, Helena
dc.contributor.authorSantos, Susana
dc.contributor.authorBastos, Maria de Lourdes
dc.date.accessioned2021-08-23T12:41:05Z
dc.date.available2021-08-23T12:41:05Z
dc.date.issued2020
dc.descriptionJorge Soares acknowledges University of Porto/Faculty of Medicine University of Porto through FSE—Fundo Social Europeu, NORTE2020—Programa Operacional Regional do Norte for his grant (NORTE-08-5369-FSE-000011). This work was supported by the Applied Molecular Biosciences Unit—UCIBIO through UID/MULTI/04378/2019 support with funding from FCT/MCTES through national funds. Centro de Química Estrutural, BioISI—Biosystems and Integrative Sciences Institute, and MARE—Marine and Environmental Sciences Centre, acknowledges the fnancial support of Fundação para a Ciência e Tecnologia—FCT (UIDB/00100/2020, UID/MULTI/04046/2019 and UIDB/04292/2020, respectively). Vera Marisa Costa acknowledges Fundação da Ciência e Tecnologia (FCT) for her grant (SFRH/BPD/110001/2015) that was funded by national funds through FCT—Fundação para a Ciência e a Tecnologia, I.P., under the Norma Transitória—DL57/2016/CP1334/CT0006. The authors wish to thank the Laboratório de Polícia Científca da Polícia Judiciária (LPC-PJ) for providing the smartshop product within the scope of the protocol established between LPC-PJ, FCUL, and FFUP.
dc.description.abstractCathinones (β-keto amphetamines), widely abused in recreational settings, have been shown similar or even worse toxicological profile than classical amphetamines. In the present study, the cytotoxicity of two β-keto amphetamines [3,4-dimethylmethcathinone (3,4-DMMC) and 4-methylmethcathinone (4-MMC)], was evaluated in differentiated dopaminergic SH-SY5Y cells in comparison to methamphetamine (METH). MTT reduction and NR uptake assays revealed that both cathinones and METH induced cytotoxicity in a concentration- and time-dependent manner. Pre-treatment with trolox (antioxidant) partially prevented the cytotoxicity induced by all tested drugs, while N-acetyl-l-cysteine (NAC; antioxidant and glutathione precursor) and GBR 12909 dopamine transporter inhibitor) partially prevented the cytotoxicity induced by cathinones, as evaluated by the MTT reduction assay. Unlike METH, cathinones induced oxidative stress evidenced by the increase on intracellular levels of reactive oxygen species (ROS), and also by the decrease of intracellular glutathione levels. Trolox prevented, partially but significantly, the ROS generation elicited by cathinones, while NAC inhibited it completely. All tested drugs induced mitochondrial dysfunction, since they led to mitochondrial membrane depolarization and to intracellular ATP depletion. Activation of caspase-3, indicative of apoptosis, was seen both for cathinones and METH, and confirmed by annexin V and propidium iodide positive staining. Autophagy was also activated by all drugs tested. Pre-incubation with bafilomycin A1, an inhibitor of the vacuolar H+- ATPase, only protected against the cytotoxicity induced by METH, which indicates dissimilar toxicological pathways for the tested drugs. In conclusion, the mitochondrial impairment and oxidative stress observed for the tested cathinones may be key factors for their neurotoxicity, but different outcome pathways seem to be involved in the adverse effects, when compared to METH.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationSoares J, Costa VM, Gaspar H, Santos S, Bastos ML, Carvalho F, Capela JP. Adverse outcome pathways induced by 3,4-dimethylmethcathinone and 4-methylmethcathinone in differentiated human SH-SY5Y neuronal cells. Arch Toxicol. 2020 Jul;94(7):2481-2503. doi: 10.1007/s00204-020-02761-y.pt_PT
dc.identifier.doi10.1007/s00204-020-02761-ypt_PT
dc.identifier.issn0340-5761
dc.identifier.issn1432-0738
dc.identifier.urihttp://hdl.handle.net/10400.8/6139
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringerpt_PT
dc.relationPoisoning the heart with anticancer drugs: is metabolic bioactivation or aging promotion the link to the cardiotoxicity of anticancer drugs New early putative biomarkers of cardiac damage for an earlier therapeutic approach
dc.relationMarine and Environmental Sciences Centre
dc.relationBiosystems & Integrative Sciences Institute
dc.relationCentro de Química Estrutural
dc.relationApplied Molecular Biosciences Unit
dc.relation.publisherversionhttps ://doi.org/10.1007/s0020 4-020-02761 -ypt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectCathinonespt_PT
dc.subjectMETHpt_PT
dc.subjectToxicological pathwayspt_PT
dc.subjectMitochondrial impairmentpt_PT
dc.subjectOxidative stresspt_PT
dc.subjectSH-SY5Y cellspt_PT
dc.titleAdverse outcome pathways induced by 3,4‑dimethylmethcathinone and 4‑methylmethcathinone in differentiated human SH‑SY5Y neuronal cellspt_PT
dc.typejournal article
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oaire.awardTitlePoisoning the heart with anticancer drugs: is metabolic bioactivation or aging promotion the link to the cardiotoxicity of anticancer drugs New early putative biomarkers of cardiac damage for an earlier therapeutic approach
oaire.awardTitleMarine and Environmental Sciences Centre
oaire.awardTitleBiosystems & Integrative Sciences Institute
oaire.awardTitleCentro de Química Estrutural
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oaire.citation.endPage2503pt_PT
oaire.citation.issue7pt_PT
oaire.citation.startPage2481pt_PT
oaire.citation.titleArchives of Toxicologypt_PT
oaire.citation.volume94pt_PT
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person.familyNameSoares
person.familyNameFreitas Costa
person.familyNameGuerreiro Galla Gaspar
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person.givenNameJorge
person.givenNameVera Marisa
person.givenNameHelena Margarida
person.givenNameMaria de Lourdes
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