Systemic administration of ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel inhibitor, blocks spontaneous absence seizures.
Systemic administration of ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel inhibitor, blocks spontaneous absence seizures.
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已知超极化激活的环核苷酸门控（HCN）通道参与失神发作（AS）的产生，并且有证据表明皮质和丘脑HCN通道功能障碍可能具有前失神作用。许多HCN通道阻滞剂是可用的，但它们在AS中的作用仅通过局部脑注射或体外模型系统进行了研究，因为它们的脑可用性有限。在此，我们研究了注射P-糖蛋白抑制剂依克立达后口服伊伐布雷定（一种获批用于治疗人类心力衰竭的HCN通道阻滞剂）对AS的影响，已知依克立达可增加该外排转运蛋白的药物底物向脑中的渗透。还在体内显微注射到体感皮层的皮层起始网络（CIN）和丘脑腹侧基底核（VB）以及脑切片中的皮层和丘脑皮层神经元后，检测了伊伐布雷定的作用。我们使用来自斯特拉斯堡的自由活动遗传缺失癫痫大鼠（GAERS）的脑电图记录，评估伊伐布雷定经口给药（联合和不联合依克立达）对AS的作用。还将伊伐布雷定显微注射到体内GAERS的CIN和VB中，并应用于Wistar CIN和GAERS VB切片，同时分别记录膜片钳皮层第5/6层和丘脑皮层神经元。伊伐布雷定口服给药显著且呈剂量依赖性地减少AS。伊伐布雷定注射至CIN可消除AS并引起小振幅4-7-Hz波（无尖峰），而在VB中效力较低。此外，伊伐布雷定应用于GAERS VB和Wistar CIN切片分别选择性降低皮质第5/6层锥体和丘脑皮质神经元的HCN通道依赖性。这些结果提供了第一次证明的抗缺席行动的全身给予HCN通道阻滞剂，这类药物作为一种新的治疗途径AS的潜力。
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. 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. 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. 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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DOI：
10.1056/nejmoa0902014
发表时间：
2010-03-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
Glauser TA;Cnaan A;Shinnar S;Hirtz DG;Dlugos D;Masur D;Clark PO;Capparelli EV;Adamson PC;Childhood Absence Epilepsy Study Group
通讯作者：
Childhood Absence Epilepsy Study Group
影响因子：
5.5
作者：
Kuisle, Mira;Wanaverbecq, Nicolas;Luthi, Anita
通讯作者：
Luthi, Anita
DOI：
10.1016/b978-0-12-804066-9.00033-x
发表时间：
2017-01-01
期刊：
MODELS OF SEIZURES AND EPILEPSY, 2ND EDITION
影响因子：
--
作者：
Jarre, Guillaume;Guillemain, Isabelle;Depaulis, Antoine
通讯作者：
Depaulis, Antoine
影响因子：
5.6
作者：
Blumenfeld, H
通讯作者：
Blumenfeld, H
影响因子：
5.3
作者：
David, Franois;Schmiedt, Joscha T.;Crunelli, Vincenzo
通讯作者：
Crunelli, Vincenzo