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Suppressive effect of Rho-kinase inhibitors Y-27632 and fasudil on spike-and-wave discharges in genetic absence epilepsy rats from Strasbourg (GAERS)

Naunyn-Schmiedeberg's Archives of Pharmacology volume 391, pages 1275–1283 (2018)Cite this article

Abstract

Rho/Rho-kinase (ROCK) signaling contributes to neuroinflammation, epileptogenesis, and seizures in convulsive-type epilepsies. However, this pathway has not been investigated in absence epilepsy. We investigated RhoA activity in genetic absence epilepsy rats from Strasburg (GAERS) and the effects of ROCK inhibitors Y-27632 and fasudil on spike-and-wave discharges (SWDs) of GAERS. ROCK level and activity were measured by Western blot analysis in the brain areas involved in absence seizures (i.e., cortex and thalamus) and hippocampus. Male GAERS were stereotaxically implanted with bilateral cortical electrodes for electroencephalogram (EEG) recordings and/or guide cannula into the right ventricle. ROCK inhibitors were administered by intraperitoneal injection (1–10 mg/kg for Y-27632 or fasudil) or intracerebroventricular injection (7–20 nmol/5 μl for Y-27632 or 10–100 nmol/5 μl for fasudil). EEG was recorded under freely moving conditions. Compared with Wistar rats, GAERS exhibited increased RhoA activity in the somatosensory cortex but not in the thalamus or hippocampus. The single systemic administration of Y-27632 and fasudil partially suppressed the duration and frequency of absence seizure, respectively. However, local brain administration caused a widespread suppressive effect on the total seizure duration, number of seizures, and the average individual seizure length. In summary, Rho/ROCK signaling may be involved in the pathophysiology of absence epilepsy. Furthermore, ROCK inhibitors can control the expression of absence seizure in GAERS, thus indicating that Y-27632 and fasudil have the potential to be used as novel anti-absence drugs.

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Acknowledgments

This project was supported by the Scientific and Technological Council of Turkey (TÜBİTAK-113S221). The authors are indebted to Berrin Çetin, Burcu Öztaş, and Ömer Gökhan Akarsu for their help in the Western blot experiments.

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Affiliations

  1. Department of Pharmacology Faculty of Pharmacy, Istanbul University, Istanbul, Turkey

    Nihan Çarçak

  2. Department of Medical Pharmacology, Faculty of Medicine, Marmara University, Istanbul, Turkey

    Melis Yavuz, Tuğba Eryiğit Karamahmutoğlu & Filiz Yılmaz Onat

  3. Department of Pharmacology Faculty of Medicine, Sütçüimam University, Kahramanmaras, Turkey

    Akif Hakan Kurt

  4. Department of Pharmacology, Faculty of Medicine, Mersin University, Mersin, Turkey

    Meral Urhan Küçük & Kansu Büyükafsar

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  1. Nihan Çarçak
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  2. Melis Yavuz
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  3. Tuğba Eryiğit Karamahmutoğlu
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  5. Meral Urhan Küçük
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  6. Filiz Yılmaz Onat
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Contributions

NÇ, FYO, and KB conceived and designed the experiments. NÇ, MY, TE, AHK conducted the experiments. KB, AHK, and MUK assisted with the Western blot experiments. NÇ, KB, AHK analyzed the data. NÇ, FYO, and KB wrote the manuscript. All authors read and approved the manuscript.

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Correspondence to Filiz Yılmaz Onat.

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Çarçak, N., Yavuz, M., Eryiğit Karamahmutoğlu, T. et al. Suppressive effect of Rho-kinase inhibitors Y-27632 and fasudil on spike-and-wave discharges in genetic absence epilepsy rats from Strasbourg (GAERS). Naunyn-Schmiedeberg's Arch Pharmacol 391, 1275–1283 (2018). https://doi.org/10.1007/s00210-018-1546-9

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Keywords

  • Absence epilepsy
  • Fasudil
  • GAERS
  • Rho
  • Rho-kinase
  • Y-27632