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

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.

Targeted Inhibition of Upregulated Sodium-Calcium Exchanger in Rat Inferior Colliculus Suppresses Alcohol Withdrawal Seizures

“…We have previously reported that systemic administration of NCX rev activity inhibitors suppressed AWSs in adult male rats; these ndings suggest NCX remodeling, at least in the IC, the site of AWS initiation [32]. Here, we explored a potentially novel mechanism underlying AWSs-the upregulation of NCX1 in the IC.…”

“…Of interest is the Na + / Ca 2+ exchanger (NCX), a membrane transporter, when operating in its reverse mode (NCXrev), is also an essential pathway for Ca 2+ entry into neurons and may play a role in the pathophysiology of seizures, including of AWSs [27][28][29][30][31]. Accordingly, blocking the reverse mode activity of NCX (NCX rev ) suppressed acoustically evoked AWSs [32]. Three NCX isoforms, including type 1 (NCX), type 2 (NCX2), and type 3 (NCX3), are expressed in the brain, and each isoform has a distinct molecular expression pattern and pharmacological sensitivity [33][34][35][36][37][38].…”

Astrocyte-neuron circuits in epilepsy

“…The directionality of the passage of ions through the NCX is dependant on ion concentrations and the membrane potential of the astrocyte ( Khananshvili, 2014 ). Generally, NCX function is thought to facilitate seizures given the observation that pharmacological inhibition of NCX function ( Saito et al, 2009 ) and downregulation of NCX expression both have anticonvulsant effects ( Akinfiresoye et al, 2023 ; Newton et al, 2021 ; Saito et al, 2009 ). Experiments utilizing pharmacological inhibition specific to the reverse function of the NCX (in which Ca 2+ enters the cell) indicate that it is this aspect of NCX function which confers its proconvulsant properties ( Akinfiresoye et al, 2023 ; Martinez and N’Gouemo, 2010 ).…”

α-Conotoxin TxIB Improved Behavioral Abnormality and Changed Gene Expression in Zebrafish (Danio rerio) Induced by Alcohol Withdrawal

“…Calcium influx plays important role in alcohol-withdrawal-induced seizures. Newton J et al (Newton et al, 2021) reported using pharmacologic blocker (SN-6) to prevent calcium from flowing into neurons, which suppressed the occurrence of withdrawalinduced seizures in adult Sprague-Dawley rats, SN-6 also markedly reduced the seizure severity. Calcium ions are essential to many nervous system functions.…”