Systemic administration of ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel inhibitor, blocks spontaneous absence seizures.

Autor: Iacone Y; Neuroscience Research, H. Lundbeck A/S, Valby, Copenhagen, Denmark.; Biomedical Sciences, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark., Morais TP; Neuroscience Division, School of Biosciences, Cardiff University, Cardiff, UK., David F; Integrative Neuroscience and Cognition Center, University of Paris, Paris, France., Delicata F; School of Life and Health Sciences, Aston University, Birmingham, UK., Sandle J; Department of Anatomy, Physiology, and Neuroscience, MTA-SZTE Research Group for Cortical Microcircuits, University of Szeged, Szeged, Hungary., Raffai T; Department of Physiology, Anatomy, and Neuroscience, Faculty of Sciences, University of Szeged, Szeged, Hungary.; Department of Physiology, Faculty of Medicine, University of Szeged, Szeged, Hungary., Parri HR; School of Life and Health Sciences, Aston University, Birmingham, UK., Weisser JJ; Neuroscience Research, H. Lundbeck A/S, Valby, Copenhagen, Denmark., Bundgaard C; Neuroscience Research, H. Lundbeck A/S, Valby, Copenhagen, Denmark., Klewe IV; Neuroscience Research, H. Lundbeck A/S, Valby, Copenhagen, Denmark., Tamás G; Department of Anatomy, Physiology, and Neuroscience, MTA-SZTE Research Group for Cortical Microcircuits, University of Szeged, Szeged, Hungary., Thomsen MS; Neuroscience Research, H. Lundbeck A/S, Valby, Copenhagen, Denmark., Crunelli V; Neuroscience Division, School of Biosciences, Cardiff University, Cardiff, UK.; Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta., Lőrincz ML; Neuroscience Division, School of Biosciences, Cardiff University, Cardiff, UK.; Department of Physiology, Anatomy, and Neuroscience, Faculty of Sciences, University of Szeged, Szeged, Hungary.; Department of Physiology, Faculty of Medicine, University of Szeged, Szeged, Hungary.
Jazyk: angličtina
Zdroj: Epilepsia [Epilepsia] 2021 Jul; Vol. 62 (7), pp. 1729-1743. Date of Electronic Publication: 2021 May 20.
DOI: 10.1111/epi.16926
Abstrakt: 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.
(© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)
Databáze: MEDLINE
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