Systemic administration of ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel inhibitor, blocks spontaneous absence seizures
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Systemic administration of ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel inhibitor, blocks spontaneous absence seizures. / Iacone, Yasmine; Morais, Tatiana P.; David, Francois; Delicata, Francis; Sandle, Joanna; Raffai, Timea; Parri, Harri Rheinallt; Weisser, Johan Juhl; Bundgaard, Christoffer; Klewe, Ib Vestergaard; Tamas, Gabor; Thomsen, Morten Skott; Crunelli, Vincenzo; Lorincz, Magor L.
In: Epilepsia, Vol. 62, No. 7, 2021, p. 1729-1743.Research output: Contribution to journal › Journal article › Research › peer-review
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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, Francois
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 - Tamas, Gabor
AU - Thomsen, Morten Skott
AU - Crunelli, Vincenzo
AU - Lorincz, Magor L.
PY - 2021
Y1 - 2021
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 - I-h current
KW - thalamocortical neurons
KW - thalamus
KW - OPERATIONAL CLASSIFICATION
KW - NETWORK MECHANISMS
KW - VALPROIC ACID
KW - CHILDHOOD
KW - EPILEPSY
KW - PACEMAKER
KW - RAT
KW - MODEL
KW - ANTICONVULSANT
KW - ETHOSUXIMIDE
U2 - 10.1111/epi.16926
DO - 10.1111/epi.16926
M3 - Journal article
C2 - 34018186
VL - 62
SP - 1729
EP - 1743
JO - Epilepsia
JF - Epilepsia
SN - 0013-9580
IS - 7
ER -
ID: 275433670