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The role of HCN channels on the effects of T-type calcium channels and GABAA receptors in the absence epilepsy model of WAG/Rij rats

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Abstract

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, GABAA 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 0th, 3rd, 6th, and 7th 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 7th injection. Interestingly, when IVA was administered again 24 hours after the 6th 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 GABAA receptors.

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All data generated or analyzed during this study are included in this published article.

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Funding

This work was supported by Scientific Research Projects of Ondokuz Mayıs University (PYO.TIP.1904.20.009).

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Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, University of Ondokuz Mayıs, Samsun, Türkiye

    Emre Soner Tiryaki, Gökhan Arslan, Mustafa Ayyıldız & Erdal Ağar

  2. Department of Pharmacology, Faculty of Medicine, University of Samsun, Samsun, Türkiye

    Caner Günaydın

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  1. Emre Soner Tiryaki
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Contributions

GA, EA, MA and EST planned the experiments; GA and EST conducted the electrophysiological experiments; EST and CG made biochemical experiments; GA, EST, and CG analyzed the data; GA, CG and EST made the graphics and statistical analysis; GA, EA, MA and EST wrote the manuscript.

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Correspondence to Gökhan Arslan.

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The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The experimental protocol was approved by the Local Ethics Committee of Ondokuz Mayis University (approval code no. 2019/48)

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Tiryaki, E.S., Arslan, G., Günaydın, C. et al. The role of HCN channels on the effects of T-type calcium channels and GABAA receptors in the absence epilepsy model of WAG/Rij rats. Pflugers Arch - Eur J Physiol 476, 337–350 (2024). https://doi.org/10.1007/s00424-023-02900-1

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