An in silico and in vitro assessment of the neurotoxicity of mefloquine

El Sharazly, Basma M.; Ahmed, Abrar; Elsheikha, Hany M.; Carter, Wayne G.

Abstract

Mefloquine (MQ) is a quinoline-based anti-malarial drug used for chemoprophylaxis or as treatment in combination with artesunate. Although MQ has clear anti-Plasmodium properties, it can induce neurotoxicity and undesired neuropsychiatric side effects in humans. Hence, this study aimed to characterize the neurotoxicity of MQ using human neuroblastoma SH-SY5Y cells. The effects of MQ on neuronal toxicity and cell viability were investigated over a concentration range of 1-100 µM using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. The influence of MQ on cellular bioenergetics was examined by measuring cellular ATP levels and from the induction of reactive oxygen species (ROS). An in silico approach was used to assess the potential neurotoxicity of MQ mediated via binding to the active sites of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) and then experimentally validated via in vitro enzymatic assays. MQ was cytotoxic to neuronal cells in a concentration and exposure duration dependent manner and induced a significant reduction of viability at concentrations of ≥25 µM after a 24 hour exposure. MQ adversely impacted cellular bioenergetics and significantly depleted ATP production at concentrations ≥1 µM after 24 hours. MQ induced cellular ROS production, which was correlated with the induction of apoptosis, as revealed by flow cytometry. In silico studies suggested that MQ was a dual cholinesterase inhibitor and one with remarkably potent binding to BuChE. Modelling data was supported by in vitro studies which showed that MQ inhibited both human AChE and BuChE enzymes. Collectively, MQ is an antimalarial drug that may induce neurotoxicity by impacting cellular bioenergetics and perturbing the activity of cholinesterases at exposure concentrations relevant to human dosage.

Citation

El Sharazly, B. M., Ahmed, A., Elsheikha, H. M., & Carter, W. G. (2024). An in silico and in vitro assessment of the neurotoxicity of mefloquine. Biomedicines, 12(3), Article 505. https://doi.org/10.3390/biomedicines12030505

• Journal Article Type: Article
• Acceptance Date: Feb 17, 2024
• Online Publication Date: Feb 23, 2024
• Publication Date: Feb 23, 2024
• Deposit Date: Feb 19, 2024
• Publicly Available Date: Feb 19, 2024
• Journal: Biomedicines
• Electronic ISSN: 2227-9059
• Publisher: MDPI
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 3
• Article Number: 505
• DOI: https://doi.org/10.3390/biomedicines12030505
• Keywords: Antimalarial drug; cholinesterase inhibitor; mefloquine; neurotoxicity; redox stress
• Public URL: https://nottingham-repository.worktribe.com/output/31605821
• Publisher URL: https://www.mdpi.com/2227-9059/12/3/505