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Structure-cytotoxicity relationship profile of 13 synthetic cathinones 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.contributor.authorCarvalho, Félix
dc.contributor.authorCapela, João Paulo
dc.date.accessioned2020-08-19T13:54:14Z
dc.date.available2020-08-19T13:54:14Z
dc.date.issued2019
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 received financial support from the European Union (FEDER funds POCI/01/0145/FEDER/007728) and National Funds (FCT/MEC, Fundação para a Ciência e a Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/MULTI/04378/2013 (UCIBIO), UID/MULTI/00612/2013 (CQB), UID/MAR/04292/2013 (MARE) and UID/Multi/04046/2013 (BioISI). Also supported by the project NORTE-01-0145-FEDER000024, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement (DESignBIOtecHealth—New Technologies for three Health Challenges of Modern Societies: Diabetes, Drug Abuse and Kidney Diseases), through the European Regional Development Fund (ERDF). Vera Marisa Costa acknowledges Fundação da Ciência e Tecnologia (FCT) for her grant (SFRH/BPD/110001/2015). The authors wish to thank the Laboratório de Polícia Científica da Polícia Judiciária (LPC-PJ) for providing the smartshop products within the scope of the protocol established between LPC-PJ, FCUL and FFUP.pt_PT
dc.description.abstractSynthetic cathinones also known as β-keto amphetamines are a new group of recreational designer drugs. We aimed to evaluate the cytotoxic potential of thirteen cathinones lacking the methylenedioxy ring and establish a putative structure-toxicity profile using differentiated SH-SY5Y cells, as well as to compare their toxicity to that of amphetamine (AMPH) and methamphetamine (METH). Cytotoxicity assays [mitochondrial 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) reduction and lysosomal neutral red (NR) uptake] performed after a 24-h or a 48-h exposure revealed for all tested drugs a concentration-dependent toxicity. The rank order regarding the concentration that promoted 50 % of toxicity, at 24 h exposure, by the MTT assay was: 3,4-dimethylmethcathinone (3,4-DMMC)>METH > mephedrone ≈ α-pyrrolidinopentiophenone > AMPH ≈ methedrone > pentedrone > buphedrone ≈ flephedrone>α-pyrrolidinobutiophenone > methcathinone ≈ N-ethylcathinone>α-pyrrolidinopropiophenone>N,N-dimethylcathinone ≈ amfepramone. Apoptotic cell death signs were seen for all studied cathinones. 3,4-DMMC, methcathinone and pentedrone triggered autophagy activation, as well as increased reactive oxygen species production, and N-acetyl-L-cysteine (NAC) totally prevented that rise. Importantly, NAC was also able to prevent the cytotoxicity promoted by 6 tested drugs, ruling for an involvement of oxidative stress in the toxic events observed. The increased lipophilic chain on the alpha carbon, the presence and the high steric volume occupied by the substituents on the aromatic ring, and the substitution of the pyrrolidine ring by its secondary amine analogue have proved to be key points for the cytotoxicity profile of these cathinones. The structure-toxicity relationship established herein may enlighten future human relevant mechanistic studies, and future clinical approaches on intoxications.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationSoares, J., Costa, V. M., Gaspar, H., Santos, S., Bastos, M.L., Carvalho, F., & Capela, J. P. (2019). Structure-cytotoxicity relationship profile of 13 synthetic cathinones in differentiated human SH-SY5Y neuronal cells. Neurotoxicology, 75, 158–173. https://doi.org/10.1016/j.neuro.2019.08.009pt_PT
dc.identifier.doi10.1016/j.neuro.2019.08.009pt_PT
dc.identifier.issn0161-813X
dc.identifier.urihttp://hdl.handle.net/10400.8/5102
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationPOCI/01/0145/FEDER/007728pt_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.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectSynthetic cathinonespt_PT
dc.subjectClassical amphetaminespt_PT
dc.subjectCytotoxicitypt_PT
dc.subjectSH-SY5Y cellspt_PT
dc.subjectStructure-toxicity relationshippt_PT
dc.titleStructure-cytotoxicity relationship profile of 13 synthetic cathinones in differentiated human SH-SY5Y neuronal cellspt_PT
dc.typejournal article
dspace.entity.typePublication
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.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F04378%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F00612%2F2013/PT
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oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F110001%2F2015/PT
oaire.citation.endPage173pt_PT
oaire.citation.startPage158pt_PT
oaire.citation.titleNeuroToxicologypt_PT
oaire.citation.volume75pt_PT
oaire.fundingStream5876
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person.familyNameGuerreiro Galla Gaspar
person.givenNameHelena Margarida
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