Supramolecular Complexes of Plant Neurotoxin Veratridine with Cyclodextrins and Their Antidote-like Effect on Neuro-2a Cell Viability.

Laura A Uribe,Sandra Leonardo,Alex Fragoso,Thorbjørn Terndrup Nielsen,Mònica Campàs,Casper Steinmann

doi:10.3390/pharmaceutics14030598

Laura A Uribe, Sandra Leonardo + Show 4 more

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https://doi.org/10.3390/pharmaceutics14030598

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Abstract

Veratridine (VTD) is a plant neurotoxin that acts by blocking the voltage-gated sodium channels (VGSC) of cell membranes. Symptoms of VTD intoxication include intense nausea, hypotension, arrhythmia, and loss of consciousness. The treatment for the intoxication is mainly focused on treating the symptoms, meaning there is no specific antidote against VTD. In this pursuit, we were interested in studying the molecular interactions of VTD with cyclodextrins (CDs). CDs are supramolecular macrocycles with the ability to form host–guest inclusion complexes (ICs) inside their hydrophobic cavity. Since VTD is a lipid-soluble alkaloid, we hypothesized that it could form stable inclusion complexes with different types of CDs, resulting in changes to its physicochemical properties. In this investigation, we studied the interaction of VTD with β-CD, γ-CD and sulfobutyl ether β-CD (SBCD) by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) spectroscopy. Docking and molecular dynamics studies confirmed the most stable configuration for the inclusion complexes. Finally, with an interest in understanding the effects of the VTD/CD molecular interactions, we performed cell-based assays (CBAs) on Neuro-2a cells. Our findings reveal that the use of different amounts of CDs has an antidote-like concentration-dependent effect on the cells, significantly increasing cell viability and thus opening opportunities for novel research on applications of CDs and VTD.

Highlights

Veratridine (VTD) is a lipid-soluble alkaloid neurotoxin derived from Veratrum plants, which belong to the lily family
We studied the complexation between native β- and γ-cyclodextrin (β-CD and γ-CD) and the anionic derivative sulfobutyl β-cyclodextrin (SBCD) with the neurotoxin VTD for the first time (Figure 1)
From the obtained thermogram it is possible to characterize the stoichiometry of the complex (n), the equilibrium constant (Keq ), the enthalpy (∆H), and entropy (∆S) changes, which are related to the Gibbs free energy (∆G)

Summary

Introduction

Veratridine (VTD) is a lipid-soluble alkaloid neurotoxin derived from Veratrum plants, which belong to the lily family. It has been used in the past as a drug against arterial hypertension, its pharmacological use was stopped due to the secondary effects of intoxication. VTD is used as a research tool, given that it acts by targeting the voltage-gated sodium channels (VGSCs) of cell membranes, producing a persistent. An important use of VTD in research is enhancing the specificity of neuroblastoma (Neuro-2a) cell-based assays (CBAs) used for the detection, evaluation of toxicity, and study of the mechanisms of VGSC toxins [2]. The alteration in VGSC caused by VTD produces symptoms such as intense retching, bradycardia, hypotension, arrhythmia, loss of consciousness, and seizures. The treatment for VTD poisoning is mainly focused on relieving the symptoms using drugs

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