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Structure-cytotoxicity relationship profile of 13 synthetic cathinones in differentiated human SH-SY5Y neuronal cells
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Advisor(s)
Abstract(s)
Synthetic 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.
Description
Jorge 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.
Keywords
Synthetic cathinones Classical amphetamines Cytotoxicity SH-SY5Y cells Structure-toxicity relationship
Citation
Soares, 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.2019.08.009
Publisher
Elsevier