Abstract
ObjectiveHyperpolarization‐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.MethodsWe 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.ResultsOral 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.SignificanceThese 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.
Highlights
Absence seizures (ASs) are characterized by loss of consciousness and lack of voluntary movements accompanied by generalized spike-and-wave discharges (SWDs) in the electroencephalogram (EEG)
ASs are present in several epilepsies and are the only clinical symptom of childhood absence epilepsy (CAE),[1,2] which accounts for 10%–17% of all children with epilepsy[3] and carries a burdensome personal, familial, and societal impact.[4,5]
Because the cellular effects of IVA in neurons of key brain areas for AS generation have not been studied either in normal nonepileptic animals or in Genetic Absence Epilepsy Rats From Strasbourg (GAERSs), we investigated the ability of this drug to block hyperpolarization-activated cyclic nucleotide- gated (HCN) channel-mediated membrane properties of GAERS ventrobasal nucleus (VB) thalamocortical neurons (Figure 5F)
Summary
Absence seizures (ASs) are characterized by loss of consciousness and lack of voluntary movements accompanied by generalized spike-and-wave discharges (SWDs) in the electroencephalogram (EEG). The role for hyperpolarization-activated cyclic nucleotide- gated (HCN) channels in ASs has been extensively investigated, with many studies reporting a gain or loss of function, mainly involving HCN1 and HCN2 subtypes. Analysis of recombinant HCN2 variants in humans with febrile seizures and genetic epilepsy with febrile seizures plus shows an increased hyperpolarization-a ctivated current (Ih), the current generated by HCN channels.[12] several HCN1 variants have been identified in children with early infantile epileptic encephalopathy that lead to either a gain or a loss of function,[13] whereas in sporadic idiopathic generalized epilepsy patients, point mutations of HCN2 give rise
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