Suppressive effect of Rho-kinase inhibitors Y-27632 and fasudil on spike-and-wave discharges in genetic absence epilepsy rats from Strasbourg (GAERS)
- 186 Downloads
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.
KeywordsAbsence epilepsy Fasudil GAERS Rho Rho-kinase Y-27632
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.
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.
- Akin D, Ravizza T, Maroso M, Carcak N, Eryigit T, Vanzulli I, Aker RG, Vezzani A, Onat FY (2011) IL-1β is induced in reactive astrocytes in the somatosensory cortex of rats with genetic absence epilepsy at the onset of spike-and-wave discharges, and contributes to their occurrence. Neurobiol Dis 44:259–269CrossRefGoogle Scholar
- Çayan S, Saylam B, Tiftik N, Ünal ND, Apa DD, Efesoy O, Çimen B, Bozlu M, Akbay E, Büyükafşar K (2014) Rho-kinase levels in testicular ischemia-reperfusion injury and effects of its inhibitor, Y-27632, on oxidative stress, spermatogenesis, and apoptosis. Urology 83:675.e13–675.e18CrossRefGoogle Scholar
- Kennard JTT, Barmanray R, Sampurno S, Ozturk E, Reid CA, Paradiso L, D’Abaco GM, Kaye AH, Foote SJ, O’Brien TJ, Powell KL (2011) Stargazin and AMPA receptor membrane expression is increased in the somatosensory cortex of genetic absence epilepsy rats from Strasbourg. Neurobiol Dis 42:48–54CrossRefGoogle Scholar
- Kitaoka Y, Kitaoka Y, Kumai T, Lam TT, Kuribayashi K, Isenoumi K, Munemasa Y, Motoki M, Kobayashi S, Ueno S (2004) Involvement of RhoA and possible neuroprotective effect of fasudil, a rho kinase inhibitor, in NMDA-induced neurotoxicity in the rat retina. Brain Res 1018:111–118CrossRefGoogle Scholar
- Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd edn. Academic, San DiegoGoogle Scholar
- Russo E, Andreozzi F, Iuliano R, Dattilo V, Procopio T, Fiume G, Mimmi S, Perrotti N, Citraro R, Sesti G, Constanti A, De Sarro G (2014) Early molecular and behavioral response to lipopolysaccharide in the WAG/Rij rat model of absence epilepsy and depressive-like behavior, involves interplay between AMPK, AKT/mTOR pathways and neuroinflammatory cytokine release. Brain Behav Immun 42:157–168CrossRefGoogle Scholar
- Segain JP, De la Blétière DR, Sauzeau V, Bourreille A, Hilaret G, Cario-Toumaniantz C, Pacaud P, Galmiche JP, Loirand G (2003) Rho kinase blockade prevents inflammation via nuclear factor κB inhibition: evidence in Crohn’s disease and experimental colitis. Gastroenterology 124:1180–1187CrossRefGoogle Scholar
- Sitnikova E, Kulikova S, Birioukova L, Raevsky VV (2011) Cellular neuropathology of absence epilepsy in the neocortex: a population of glial cells rather than neurons is impaired in genetic rat model. Acta Neurobiol Exp (Wars) 71(2):263–8Google Scholar