RT Journal Article
SR Electronic
T1 Systemic administration of Ivabradine, an HCN channel inhibitor, blocks spontaneous absence seizures
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.02.17.431588
DO 10.1101/2021.02.17.431588
A1 Yasmine Iacone
A1 Tatiana P. Morais
A1 François David
A1 Francis Delicata
A1 Joanna Sandle
A1 Timea Raffai
A1 H. Rheinallt Parri
A1 Johan Juhl Weisser
A1 Christoffer Bundgaard
A1 Ib Vestergaard Klewe
A1 Gábor Tamás
A1 Morten Skøtt Thomsen
A1 Vincenzo Crunelli
A1 Magor L. Lőrincz
YR 2021
UL http://biorxiv.org/content/early/2021/02/17/2021.02.17.431588.abstract
AB 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 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.Methods We 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.Results Oral 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.Significance These 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.Competing Interest StatementY.I., J.J.W, C.B., M.S.T. and I.V.K. are Lundbeck A/S employees. The other authors declare no conflict of interest.