Influence of Ivabradine on the Anticonvulsant Action of Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice

Abstract

Although the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in neuronal excitability and synaptic transmission is still unclear, it is postulated that the HCN channels may be involved in seizure activity. The aim of this study was to assess the effects of ivabradine (an HCN channel inhibitor) on the protective action of four classical antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) against maximal electroshock-induced seizures in mice. Tonic seizures (maximal electroconvulsions) were evoked in adult male albino Swiss mice by an electric current (sine-wave, 25 mA, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles of the combinations of ivabradine with classical antiepileptic drugs were measured in mice along with total brain antiepileptic drug concentrations. Results indicate that ivabradine (10 mg/kg, i.p.) significantly enhanced the anticonvulsant activity of valproate and considerably reduced that of phenytoin in the mouse maximal electroshock-induced seizure model. Ivabradine (10 mg/kg) had no impact on the anticonvulsant potency of carbamazepine and phenobarbital in the maximal electroshock-induced seizure test in mice. Ivabradine (10 mg/kg) significantly diminished total brain concentration of phenytoin and had no effect on total brain valproate concentration in mice. In conclusion, the enhanced anticonvulsant action of valproate by ivabradine in the mouse maximal electroshock-induced seizure model was pharmacodynamic in nature. A special attention is required when combining ivabradine with phenytoin due to a pharmacokinetic interaction and reduction of the anticonvulsant action of phenytoin in mice. The combinations of ivabradine with carbamazepine and phenobarbital were neutral from a preclinical viewpoint.

Testing broad-spectrum and isoform-preferring HCN channel blockers for anticonvulsant properties in mice

“…Consistent with previous studies (Cavalcante et al, 2019;Mansour and Ibrahim, 2015;Sawicka et al, 2017a;Sawicka et al, 2017b), ivabradine (10 mg/kg, i.p.) reduced seizure susceptibility, increasing the latency to s.c.PTZ-induced maximal tonic hindlimb extension seizures (Fig.…”

“…We know that systemic broad-spectrum HCN channel block is well tolerated, with ivabradine causing minimal side effects such as bradycardia and a retinal phenomenon known as phosphenes in humans (Bocchi and Salemi, 2019). Consistent with this, ivabradine does not alter motor performance, long term memory, or skeletal muscle strength in mice (Sawicka et al, 2017a). Furthermore, brain HCN4 knockout in mice is well tolerated (Kharouf et al, 2020).…”

“…For example, Cavalcante and colleagues show that ivabradine was not effective in the pilocarpine model of temporal lobe epilepsy (Cavalcante et al, 2019). Furthermore, ivabradine affects the potency of other anticonvulsants when administered J o u r n a l P r e -p r o o f (Sawicka et al, 2017a;Sawicka et al, 2017b). It is also important to note that FDA approved ivabradine crosses the blood brain barrier poorly (Savelieva and Camm, 2008), discouraging testing broad-spectrum HCN block in humans.…”

“…In addition, ivabradine has shown anticonvulsive effects in the subcutaneous PTZ (s.c.PTZ) seizure assay J o u r n a l P r e -p r o o f in mice (Cavalcante et al, 2019). The antiseizure effects of ivabradine have also been studied in conjunction with other classical antiepileptic drugs such as lacosamide, pregabalin, lamotrigine, and topiramate within the mouse maximal electroshock (MES) and tonic-clonic seizure models, although determining efficacy is complicated by drug-drug interactions (Sawicka et al, 2017a;Sawicka et al, 2017b).…”

Influence of dronedarone (a class III antiarrhythmic drug) on the anticonvulsant potency of four classical antiepileptic drugs in the tonic–clonic seizure model in mice

“…Accumulating evidence indicates that antiarrhythmic drugs also play an essential role in epilepsy patients. Previously, it has been documented that amiodarone, ivabradine, sotalol and propafenone (various anti-arrhythmic drugs) elevated the threshold for electroconvulsions and influenced the anticonvulsant properties of the selected classical antiepileptic drugs in the maximal electroshock-induced seizure test—an experimental model of tonic–clonic seizures (Banach et al 2016 , 2017 , 2018 ; Luszczki et al 2013 ; Sawicka et al 2017 ).…”