Inhibition of the Sodium Calcium Exchanger Suppresses Alcohol Withdrawal-Induced Seizure Susceptibility.

Jamila Newton,Prosper N’Gouemo,Luli Rebecca Akinfiresoye

doi:10.3390/brainsci11020279

Jamila Newton, Prosper N’Gouemo + Show 1 more

Open Access

https://doi.org/10.3390/brainsci11020279

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Journal: Brain sciences	Publication Date: Feb 23, 2021
Citations: 5	License type: CC BY 4.0

Affiliation: Howard University

Abstract

Calcium influx plays important roles in the pathophysiology of seizures, including acoustically evoked alcohol withdrawal-induced seizures (AWSs). One Ca2+ influx route of interest is the Na+/Ca2+ exchanger (NCX) that, when operating in its reverse mode (NCXrev) activity, can facilitate Ca2+ entry into neurons, possibly increasing neuronal excitability that leads to enhanced seizure susceptibility. Here, we probed the involvement of NCXrev activity on AWS susceptibility by quantifying the effects of SN-6 and KB-R7943, potent blockers of isoform type 1 (NCX1rev) and 3 (NCX3rev), respectively. Male, adult Sprague–Dawley rats were used. Acoustically evoked AWSs consisted of wild running seizures (WRSs) that evolved into generalized tonic–clonic seizures (GTCSs). Quantification shows that acute SN-6 treatment at a relatively low dose suppressed the occurrence of the GTCSs (but not WRSs) component of AWSs and markedly reduced the seizure severity. However, administration of KB-R7943 at a relatively high dose only reduced the incidence of GTCSs. These findings demonstrate that inhibition of NCX1rev activity is a putative mechanism for the suppression of alcohol withdrawal-induced GTCSs.

Highlights

Seizures are the most common neurological deficits of the alcohol use disorder [1,2,3]; when associated with abrupt alcohol cessation, these seizures are referred to as “alcohol withdrawal-induced seizures” (AWSs)
We evaluated the extent to which SN-6 or KB-R7943 treatment at a dose of 1 mg/kg affected the severity of AWS
We found that SN-6 did not considerably reduce AWS severity, while KB-R7943 had no effect when compared to the control-treated group (Figure 2D)

Summary

Introduction

Seizures are the most common neurological deficits of the alcohol use disorder [1,2,3]; when associated with abrupt alcohol cessation, these seizures are referred to as “alcohol withdrawal-induced seizures” (AWSs). The altered expression of L- and P-type CaV channels does not play a critical role in the initiation of acoustically evoked AWSs [14,17,19], suggesting that other Ca2+ entry routes may play a key role in the generation of AWSs. One Ca2+ entry route of interest is the Na+/Ca2+ (NCX), a bidirectional Ca2+ transporter that controls the level of intracellular Ca2+ [21,22]. NCX1 is distributed ubiquitously, NCX2 is mainly expressed in the brain and spinal cord, and NCX3 is found in the brain and skeletal muscle [23,24,25,26,27,28] These three NCX isoforms display several functional

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