Key result
Oral administration of ivabradine markedly and dose-dependently reduced absence seizures in rat models.
Why the study?
HCN channels are implicated in absence seizures, but HCN blockers had only been studied via localized brain injection or in vitro due to limited brain availability.
Does systemic administration of ivabradine reduce absence seizures in a rat model of genetic absence epilepsy?
Does systemic administration of ivabradine reduce absence seizures in a rat model of genetic absence epilepsy?
Systemic administration of the HCN channel blocker ivabradine reduces absence seizures in a rat model, suggesting a potential novel therapeutic avenue for absence epilepsy.
May support preclinical testing of systemic HCN blockade in absence seizure models; leaves open translation to patients.
OBJECTIVE: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are known to be involved in the generation of absence seizures (ASs), and there is evidence that cortical and thalamic HCN channel dysfunctions may have a proabsence role. Many HCN channel blockers are available, but their role in ASs has been investigated only by localized brain injection or in in vitro model systems due to their limited brain availability. Here, we investigated the effect on ASs of orally administered ivabradine (an HCN channel blocker approved for the treatment of heart failure in humans) following injection of the P-glycoprotein inhibitor elacridar, which is known to increase penetration into the brain of drug substrates for this efflux transporter. The action of ivabradine was also tested following in vivo microinjection into the cortical initiation network (CIN) of the somatosensory cortex and in the thalamic ventrobasal nucleus (VB) as well as on cortical and thalamocortical neurons in brain slices. METHODS: We used electroencephalographic recordings in freely moving Genetic Absence Epilepsy Rats From Strasbourg (GAERSs) to assess the action of oral administration of ivabradine, with and without elacridar, on ASs. Ivabradine was also microinjected into the CIN and VB of GAERSs in vivo and applied to Wistar CIN and GAERS VB slices while recording patch-clamped cortical Layer 5/6 and thalamocortical neurons, respectively. RESULTS: Oral administration of ivabradine markedly and dose-dependently reduced ASs. Ivabradine injection into CIN abolished ASs and elicited small-amplitude 4-7-Hz waves (without spikes), whereas in the VB it was less potent. Moreover, ivabradine applied to GAERS VB and Wistar CIN slices selectively decreased HCN channel-dependent properties of cortical Layer 5/6 pyramidal and thalamocortical neurons, respectively. SIGNIFICANCE: These results provide the first demonstration of the antiabsence action of a systemically administered HCN channel blocker, indicating the potential of this class of drugs as a novel therapeutic avenue for ASs.
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Iacone et al. (2021) studied Absence seizures. Ivabradine (with and without elacridar) was evaluated on Absence seizures. Oral administration of ivabradine markedly and dose-dependently reduced absence seizures in rat models.
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