Systemic administration of Ivabradine, an HCN channel inhibitor, blocks spontaneous absence seizures

Iacone, Y.; Morais, T. P.; David, F.; Delicata, F.; Sandle, J.; Raffai, T.; Parri, R.; Weisser, J. J.; Bundgaard, C.; Klewe, I. V.; Tamas, G.; Thomsen, M. S.; Crunelli, V.; Lorincz, M. L.

doi:10.1101/2021.02.17.431588

bioRxiv · 10.1101/2021.02.17.431588

Systemic administration of Ivabradine, an HCN channel inhibitor, blocks spontaneous absence seizures

Iacone, Y.·Morais, T. P.·David, F.·Delicata, F.·Sandle, J.·Raffai, T.·Parri, R.·Weisser, J. J.·Bundgaard, C.·Klewe, I. V.·Tamas, G.·Thomsen, M. S.·Crunelli, V.·Lorincz, M. L.

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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 pro-absence 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, that 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 in 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 EEG recordings in freely moving Genetic Absence Epilepsy from Strasbourg Rats (GAERS) to assess the action of oral administration of ivabradine, with and without elacridar, on ASs. Ivabradine was also microinjected in the CIN and VB of GAERS 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 in 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 anti-absence 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, Y., Morais, T. P., David, F., Delicata, F., Sandle, J., Raffai, T., Parri, R., Weisser, J. J., Bundgaard, C., Klewe, I. V., Tamas, G., Thomsen, M. S., Crunelli, V., Lorincz, M. L.. 2021-02-17. Systemic administration of Ivabradine, an HCN channel inhibitor, blocks spontaneous absence seizures. https://doi.org/10.1101/2021.02.17.431588

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