Department of Physiology, Faculty of Medicine, University of Ondokuz Mayıs, Samsun, Türkiye.
Department of Pharmacology, Faculty of Medicine, University of Samsun, Samsun, Türkiye.
Pflugers Arch. 2024 Mar;476(3):337-350. doi: 10.1007/s00424-023-02900-1. Epub 2023 Dec 30.
In this study we used ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, to identify its effect on spike-wave discharges (SWDs); and aimed to determine the role of IVA on the effects of T-type calcium channel blocker NNC 55-0396, GABA receptor agonist muscimol and antagonist bicuculline in male WAG/Rij rats. After tripolar electrodes for electrocorticogram (ECoG) recordings were placed on the WAG/Rij rats' skulls, 5, 10, and 20 mg/kg IVA were intraperitoneally administered for 7 consecutive days and ECoG recordings were obtained on days 0, 3, 6, and 7 for three hours before and after injections. While acute injection of 5, 10, and 20 mg/kg IVA did not affect the total number and the mean duration of SWDs, subacute administration (7 days) of IVA decreased the SWDs parameters 24 hours after the 7 injection. Interestingly, when IVA was administered again 24 hours after the 6 IVA injection, it increased the SWDs parameters. Western-blot analyses showed that HCN1 and HCN2 expressions decreased and HCN4 increased in the 5-month-old WAG/Rij rats compared to the 1-month-old WAG/Rij and 5-month-old native Wistar rats, while subacute IVA administration increased the levels of HCN1 and HCN2 channels, except HCN4. Subacute administration of IVA reduced the antiepileptic activity of NNC, while the proepileptic activity of muscimol and the antiepileptic activity of bicuculline were abolished. It might be suggested that subacute IVA administration reduces absence seizures by changing the HCN channel expressions in WAG/Rij rats, and this affects the T-type calcium channels and GABA receptors.
在这项研究中，我们使用了伊伐布雷定（IVA），一种超极化激活环核苷酸门控（HCN）通道阻滞剂，以确定其对棘波放电（SWD）的影响；并旨在确定IVA 对 T 型钙通道阻滞剂 NNC 55-0396、GABA 受体激动剂 muscimol 和拮抗剂 bicuculline 在雄性 WAG/Rij 大鼠中的作用。在 WAG/Rij 大鼠颅骨上放置了用于脑电描记术（ECoG）记录的三极电极后，连续 7 天腹腔内给予 5、10 和 20 mg/kg 的 IVA，并在注射前和注射后 3 小时获得 ECoG 记录，共 7 天。虽然急性注射 5、10 和 20 mg/kg 的 IVA 并不影响 SWD 的总数量和平均持续时间，但亚急性（7 天）给药可在 7 次注射后 24 小时降低 SWD 参数。有趣的是，当在第 6 次 IVA 注射后 24 小时再次给予 IVA 时，它会增加 SWD 参数。Western-blot 分析显示，与 1 个月大的 WAG/Rij 和 5 个月大的本地 Wistar 大鼠相比，5 个月大的 WAG/Rij 大鼠中的 HCN1 和 HCN2 表达减少，HCN4 增加，而亚急性 IVA 给药增加了 HCN1 和 HCN2 通道的水平，除了 HCN4。亚急性 IVA 给药降低了 NNC 的抗癫痫活性，而 muscimol 的致癫痫活性和 bicuculline 的抗癫痫活性则被消除。这可能表明，亚急性 IVA 给药通过改变 WAG/Rij 大鼠中的 HCN 通道表达来减少失神发作，这会影响 T 型钙通道和 GABA 受体。
