The Sodium Channel B4-Subunits are Dysregulated in Temporal Lobe Epilepsy Drug-Resistant Patients.

Mariam A Sheilabi,Louise Y Takeshita,Edward J Sims,Francesco Falciani,Alessandra P Princivalle

doi:10.3390/ijms21082955

Mariam A Sheilabi, Louise Y Takeshita + Show 3 more

Open Access

https://doi.org/10.3390/ijms21082955

Copy DOI

Abstract

Temporal lobe epilepsy (TLE) is the most common type of partial epilepsy referred for surgery due to antiepileptic drug (AED) resistance. A common molecular target for many of these drugs is the voltage-gated sodium channel (VGSC). The VGSC consists of four domains of pore-forming α-subunits and two auxiliary β-subunits, several of which have been well studied in epileptic conditions. However, despite the β4-subunits’ role having been reported in some neurological conditions, there is little research investigating its potential significance in epilepsy. Therefore, the purpose of this work was to assess the role of SCN4β in epilepsy by using a combination of molecular and bioinformatics approaches. We first demonstrated that there was a reduction in the relative expression of SCN4B in the drug-resistant TLE patients compared to non-epileptic control specimens, both at the mRNA and protein levels. By analyzing a co-expression network in the neighborhood of SCN4B we then discovered a linkage between the expression of this gene and K+ channels activated by Ca2+, or K+ two-pore domain channels. Our approach also inferred several potential effector functions linked to variation in the expression of SCN4B. These observations support the hypothesis that SCN4B is a key factor in AED-resistant TLE, which could help direct both the drug selection of TLE treatments and the development of future AEDs.

Highlights

Temporal lobe epilepsy (TLE) is one of the most common causes of epilepsy in adults and can arise sporadically or with a clear familial recurrence [1]
The initial approach to the treatment of TLE relies on the administration of antiepileptic drugs (AEDs); about 60% of TLE patients are responsive to pharmaco-therapies
We have identified genes co-expressed with SCN4B in hippocampus of TLE patients from a publicly available dataset

Summary

Introduction

Temporal lobe epilepsy (TLE) is one of the most common causes of epilepsy in adults and can arise sporadically or with a clear familial recurrence [1]. The initial approach to the treatment of TLE relies on the administration of antiepileptic drugs (AEDs); about 60% of TLE patients are responsive to pharmaco-therapies. The remaining 40% are not responsive to AEDs, despite the use of 2–3 different drug regimens, including combination therapy: surgical approaches are considered [2]. One study found that 14% of the patients following temporal lobe surgery achieved long-term AED discontinuation, 50% achieved monotherapy and 33% remained on polytherapy [3]. This treatment is very invasive and has several undesirable side-effects, given the temporal lobes’ role in processing sensory input [4,5]. Considering that surgery is not always successful, it is important to understand why AED resistance occurs in these individuals [6]

Objectives

Methods

Results

Discussion

Conclusion