Department of Pharmacology, Faculty of Pharmacy, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey.
Department of Medical Pharmacology, Faculty of Medicine, Marmara University, Istanbul, Turkey.
Pharmacology. 2022;107(3-4):227-234. doi: 10.1159/000520059. Epub 2022 Jan 10.
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel currents of Ih and absence epilepsy seizures are associated, but studies reveal differential results.
In our study, we aimed to investigate the role of the HCN channels on the expression of spike-and-wave discharges (SWDs) using the Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model.
HCN isoform levels from isolated brains of both naïve nonepileptic Wistar and GAERS groups were evaluated by enzyme-linked immunosorbent assay. ZD7288, an Ih inhibitor as well as an HCN channel antagonist, was administered intracerebroventricularly to the adult GAERS groups, and to evaluate their SWD activities, electroencephalography was recorded. The effect of ZD7288 on the cumulative total duration and number of SWDs and the mean duration of each SWD complex was evaluated.
The HCN2 levels in the cortex and hippocampus of the GAERS group were lower compared to the naïve nonepileptic Wistar group (p < 0.05). ZD7288 increased the number of SWDs at the 20th and 120th min with the highest administered dose of 7 μg (p < 0.05).
The Ih inhibitor ZD7288 increased the number of SWDs in a genetic absence epilepsy rat model, although this increase may not be significant due to the inconsistent time-dependent effects. In GAERS, the cortical and hippocampal HCN2 channel levels were significantly lower compared to the control group. Further studies are needed with higher doses of ZD7288 to determine if the effects will increase drastically.
超极化激活环核苷酸门控（HCN）通道电流 Ih 与癫痫发作缺失有关，但研究结果存在差异。
在本研究中，我们旨在使用斯特拉斯堡遗传性癫痫发作大鼠（GAERS）模型，研究 HCN 通道在棘波和尖波放电（SWD）表达中的作用。
通过酶联免疫吸附试验评估分离的无脑 HCN 同工型水平，包括天真无癫痫的 Wistar 组和 GAERS 组。将 Ih 抑制剂和 HCN 通道拮抗剂 ZD7288 脑室给药至成年 GAERS 组，记录脑电图以评估其 SWD 活动。评估 ZD7288 对累积总持续时间和 SWD 次数以及每个 SWD 复合物的平均持续时间的影响。
GAERS 组皮质和海马的 HCN2 水平低于天真无癫痫的 Wistar 组（p < 0.05）。ZD7288 在第 20 分钟和第 120 分钟增加 SWD 次数，最高给药剂量为 7 μg（p < 0.05）。
Ih 抑制剂 ZD7288 增加了遗传性癫痫发作大鼠模型中 SWD 的数量，尽管由于时间依赖性效应不一致，这种增加可能并不显著。与对照组相比，GAERS 的皮质和海马 HCN2 通道水平明显降低。需要用更高剂量的 ZD7288 进行进一步研究，以确定其效果是否会急剧增加。
