Neurotoxicity Assessment of 1-[(2,3-Dihydro-1-Benzofuran-2-yl)Methyl]Piperazine (LINS01 Series) Derivatives and their Protective Effect on Cocaine-Induced Neurotoxicity Model in SH-SY5Y Cell Culture.

Autor: Dos Santos LA; Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil., Dos Santos GS; Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil., Fernandes GAB; Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil., Corrêa MF; Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil.; Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil., de Faria Almeida CA; Department of Food and Drugs, School of Pharmaceutical Sciences, Federal University of Alfenas, Alfenas, Minas Gerais, Brazil., Fernandes L; Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil., Marcourakis T; Departament of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil., Fernandes JPS; Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil., Garcia RCT; Department of Pharmaceutical Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo, Diadema, São Paulo, Brazil. raphael.garcia@unifesp.br.
Jazyk: angličtina
Zdroj: Neurotoxicity research [Neurotox Res] 2022 Dec; Vol. 40 (6), pp. 1653-1663. Date of Electronic Publication: 2022 Nov 07.
DOI: 10.1007/s12640-022-00601-8
Abstrakt: Excessive levels of dopamine in the synaptic cleft, induced by cocaine for example, activates dopaminergic receptors, mainly D 1 R, D 2 R, and D 3 R subtypes, contributing to neurotoxic effects. New synthetic 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine derivatives (the LINS01 compounds), designed as histaminergic receptor (H 3 R) ligands, are also dopaminergic receptor ligands, mainly D 2 R and D 3 R. This study aims to evaluate the neurotoxicity of these new synthetic LINS01 compounds (LINS01003, LINS01004, LINS01011, and LINS01018), as well as to investigate their protective potential on a cocaine model of dopamine-induced neurotoxicity using SH-SY5Y cell line culture. Neurotoxicity was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and automated cell counting with fluorescent dyes (acridyl orange and propidium iodide) assays. Concentration-response curves (CRCs) were performed for all LINS compounds and cocaine using MTT assay. The results show that LINS series did not decrease cell viability after 48h of exposure-except for 100 µM LINS01018, which was discontinued from the study. Likewise, MTT, LDH, and fluorescent dyes staining showed no difference is cell viability for LINS compounds at 10 µM. When incubated with 2.5 mM cocaine (lethal concentration 50) for 48h, 10 µM of each LINS compound, metoclopramide (D 2 R antagonist) and haloperidol (D 2 R/D 3 R antagonist), ameliorated cocaine-induced neurotoxicity. However, only metoclopramide, haloperidol, and LINS01011 compound significantly decreased LDH released in the culture medium, suggesting that this new synthetic compound presents a more robust effect. This preliminary in vitro neurotoxicity study suggests that LINS01 compounds are not neurotoxic, and that they play a promising role in preventing cocaine-induced neurotoxicity.
(© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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