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

Yasmine Iacone; Tatiana P. Morais; François David; Francis Delicata; Joanna Sandle; Timea Raffai; Harri Rheinallt Parri; Johan Juhl Weisser; Christoffer Bundgaard; Ib Vestergaard Klewe; Gábor Tamás; Morten Skøtt Thomsen; Vincenzo Crunelli; Magor L. Lőrincz

doi:10.1111/epi.16926

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

Yasmine Iacone, Tatiana P. Morais, François David, Francis Delicata, Joanna Sandle, Timea Raffai, Harri Rheinallt Parri, Johan Juhl Weisser, Christoffer Bundgaard, Ib Vestergaard Klewe, Gábor Tamás, Morten Skøtt Thomsen, Vincenzo Crunelli, Magor L. Lőrincz

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1729-1743
Number of pages	15
Journal	Epilepsia
Volume	62
Issue number	7
Early online date	20 May 2021
DOIs	https://doi.org/10.1111/epi.16926
Publication status	Published - 1 Jul 2021

Bibliographical note

© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Funding: Wellcome Trust, Grant/Award Number: 91882; Országos Tudományos Kutatási Alapprogramok, Grant/Award Number: FK123831 and NN125601; Hungarian Brain Research Program, Grant/Award Number: KTIA_NAP_13-2-2014-0014; Ministry of Human Capacities, Hungary, Grant/Award Number: 20391-3/2018/FEKUSTRAT; Marie Skłodowska-Curie Actions, Grant/Award Number: H2020-MSCA-ITN-2016-722053; Ester Floridia Neuroscience Research Foundation; Magor L. Lőrincz is a grantte of the János Bolyai Fellowship.

Keywords

Childhood absence epilepsy
cortex
lh current
thalamocortical neurons
thalamus

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10.1111/epi.16926Licence: CC BY 3.0

Systemic administration of ivabradine, a hyperpolarizationactivated cyclic
© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Final published version, 1.9 MBLicence: CC BY 3.0

Cite this

Iacone, Y., Morais, T. P., David, F., Delicata, F., Sandle, J., Raffai, T., Parri, H. R., Weisser, J. J., Bundgaard, C., Klewe, I. V., Tamás, G., Thomsen, M. S., Crunelli, V., & Lőrincz, M. L. (2021). Systemic administration of ivabradine, a hyperpolarization‐activated cyclic nucleotide‐gated channel inhibitor, blocks spontaneous absence seizures. Epilepsia, 62(7), 1729-1743. https://doi.org/10.1111/epi.16926

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abstract = "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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note = "{\textcopyright} 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Funding: Wellcome Trust, Grant/Award Number: 91882; Orsz{\'a}gos Tudom{\'a}nyos Kutat{\'a}si Alapprogramok, Grant/Award Number: FK123831 and NN125601; Hungarian Brain Research Program, Grant/Award Number: KTIA_NAP_13-2-2014-0014; Ministry of Human Capacities, Hungary, Grant/Award Number: 20391-3/2018/FEKUSTRAT; Marie Sk{\l}odowska-Curie Actions, Grant/Award Number: H2020-MSCA-ITN-2016-722053; Ester Floridia Neuroscience Research Foundation; Magor L. L{\H o}rincz is a grantte of the J{\'a}nos Bolyai Fellowship.",

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doi = "10.1111/epi.16926",

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Iacone, Y, Morais, TP, David, F, Delicata, F, Sandle, J, Raffai, T, Parri, HR, Weisser, JJ, Bundgaard, C, Klewe, IV, Tamás, G, Thomsen, MS, Crunelli, V & Lőrincz, ML 2021, 'Systemic administration of ivabradine, a hyperpolarization‐activated cyclic nucleotide‐gated channel inhibitor, blocks spontaneous absence seizures', Epilepsia, vol. 62, no. 7, pp. 1729-1743. https://doi.org/10.1111/epi.16926

TY - JOUR

T1 - Systemic administration of ivabradine, a hyperpolarization‐activated cyclic nucleotide‐gated channel inhibitor, blocks spontaneous absence seizures

AU - Iacone, Yasmine

AU - Morais, Tatiana P.

AU - David, François

AU - Delicata, Francis

AU - Sandle, Joanna

AU - Raffai, Timea

AU - Parri, Harri Rheinallt

AU - Weisser, Johan Juhl

AU - Bundgaard, Christoffer

AU - Klewe, Ib Vestergaard

AU - Tamás, Gábor

AU - Thomsen, Morten Skøtt

AU - Crunelli, Vincenzo

AU - Lőrincz, Magor L.

N1 - © 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Funding: Wellcome Trust, Grant/Award Number: 91882; Országos Tudományos Kutatási Alapprogramok, Grant/Award Number: FK123831 and NN125601; Hungarian Brain Research Program, Grant/Award Number: KTIA_NAP_13-2-2014-0014; Ministry of Human Capacities, Hungary, Grant/Award Number: 20391-3/2018/FEKUSTRAT; Marie Skłodowska-Curie Actions, Grant/Award Number: H2020-MSCA-ITN-2016-722053; Ester Floridia Neuroscience Research Foundation; Magor L. Lőrincz is a grantte of the János Bolyai Fellowship.

PY - 2021/7/1

Y1 - 2021/7/1

N2 - 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.

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 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.

KW - Childhood absence epilepsy

KW - cortex

KW - lh current

KW - thalamocortical neurons

KW - thalamus

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U2 - 10.1111/epi.16926

DO - 10.1111/epi.16926

M3 - Article

C2 - 34018186

SN - 0013-9580

VL - 62

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EP - 1743

JO - Epilepsia

JF - Epilepsia

IS - 7

ER -

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

Abstract

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Keywords

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