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

Author(s)

dos Santos, Laisa Aliandro ; dos Santos, Gabriela Salles ; Borges Fernandes, Gustavo Ariel ; Correa, Michelle Fidelis ; de Faria Almeida, Carolina Aparecida ; Fernandes, Liliam ; Marcourakis, Tania ; Fernandes, Joao Paulo S. ; Tamborelli Garcia, Raphael Caio

• Document type: Journal article
• Source: NEUROTOXICITY RESEARCH; v. 40, n. 6, p. 11-pg., 2022-11-07.

Abstract

Excessive levels of dopamine in the synaptic cleft, induced by cocaine for example, activates dopaminergic receptors, mainly D1R, D2R, and D3R 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 (H3R) ligands, are also dopaminergic receptor ligands, mainly D2R and D3R. 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 mu M 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 mu M. When incubated with 2.5 mM cocaine (lethal concentration 50) for 48h, 10 mu M of each LINS compound, metoclopramide (D2R antagonist) and haloperidol (D2R/D3R 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. (AU)

• FAPESP's process: 17/21834-8 - Exposure to ketamine, ethanol and ketamine-ethanol combination: neurotoxicity evaluation in SH-SY5Y neural cells
• Grantee: Raphael Caio Tamborelli Garcia
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/23139-2 - Synthesis and biological evaluation of the LINS01 series as procognitive agents: a multitarget approach
• Grantee: Michelle Fidelis Corrêa
• Support Opportunities: Scholarships in Brazil - Doctorate