Antiepileptic Drug Tiagabine Does Not Directly Target Key Cardiac Ion Channels Kv11.1, Nav1.5 and Cav1.2.

Magdalena Kowalska,Alicja Nowaczyk,Łukasz Fijałkowski,Jacek Nowaczyk,Kinga Sałat,Monika Kubacka,Grzegorz Grześk

doi:10.3390/molecules26123522

Abstract

Tiagabine is an antiepileptic drug used for the treatment of partial seizures in humans. Recently, this drug has been found useful in several non-epileptic conditions, including anxiety, chronic pain and sleep disorders. Since tachycardia—an impairment of cardiac rhythm due to cardiac ion channel dysfunction—is one of the most commonly reported non-neurological adverse effects of this drug, in the present paper we have undertaken pharmacological and numerical studies to assess a potential cardiovascular risk associated with the use of tiagabine. A chemical interaction of tiagabine with a model of human voltage-gated ion channels (VGICs) is described using the molecular docking method. The obtained in silico results imply that the adverse effects reported so far in the clinical cardiological of tiagabine could not be directly attributed to its interactions with VGICs. This is also confirmed by the results from the isolated organ studies (i.e., calcium entry blocking properties test) and in vivo (electrocardiogram study) assays of the present research. It was found that tachycardia and other tiagabine-induced cardiac complications are not due to a direct effect of this drug on ventricular depolarization and repolarization.

Highlights

Epidemiological studies have consistently shown that people with epilepsy have a higher prevalence of structural cardiac disease than those without it [1]
The functioning of neurons, muscles and cardiac myocytes is based on action potentials (APs) generated by transmutational ion currents mediated mainly by sodium, calcium and potassium [2,3]
According to the guidelines of the Comprehensive in vitro Proarrhythmia Assay (CiPA), a set of six ion channels has been selected for which currents are important for both the repolarization and depolarization of the cardiac action potential (AP) [4]

Summary

Introduction

Epidemiological studies have consistently shown that people with epilepsy have a higher prevalence of structural cardiac disease than those without it [1]. The functioning of neurons, muscles and cardiac myocytes is based on action potentials (APs) generated by transmutational ion currents mediated mainly by sodium, calcium and potassium [2,3]. According to the guidelines of the Comprehensive in vitro Proarrhythmia Assay (CiPA), a set of six ion channels has been selected for which currents are important for both the repolarization and depolarization of the cardiac action potential (AP) [4]. There is some evidence, based on the effect of clinical drugs on cardiac APs, indicating the classification of cardiac ion channels into two classes [5,6,7]. The first class contains the most important cardiac ion channels, such as KV 11.1, NaV 1.5 and CaV 1.2.

Methods

Results

Conclusion