Detrimental effect of post Status Epilepticus treatment with ROCK inhibitor Y-27632 in a pilocarpine model of temporal lobe epilepsy.

Nazim Kourdougli,Genevieve Chazal,Claudio Rivera,Saara Varpula

doi:10.3389/fncel.2015.00413

Abstract

Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults where 20–30% of the patients are refractory to currently available anti-epileptic drugs. The RhoA/Rho-kinase signaling pathway activation has been involved in inflammatory responses, neurite outgrowth and neuronal death under pathological conditions such as epileptic insults. Acute preventive administration of ROCK inhibitor has been reported to have beneficial outcomes in Status Epilepticus (SE) epilepsy. In the present study, we evaluate the effect of chronic post SE treatment with the ROCK inhibitor Y-27632 in a rat pilocarpine model of TLE. We used chronic i.p. injections of Y-27632 for 5 days in 6 week old control rats or rats subjected to pilocarpine treatment as a model of TLE. Surprisingly, our findings demonstrate that a systemic administration of Y-27632 in pilocarpine-treated rats increases neuronal death in the CA3 region and ectopic recurrent mossy fiber sprouting (rMFS) in the dentate gyrus of the hippocampal formation. Interestingly, we found that chronic treatment with Y-27632 exacerbates the down-regulation and pathological distribution of the K+-Cl− cotransporter KCC2, thus providing a putative mechanism for post SE induced neuronal death. The involvement of astrogliosis in this mechanism appears to be intricate as ROCK inhibition reduces reactive astrogliosis in pilocarpine rats. Conversely, in control rats, chronic Y-27632 treatment increases astrogliosis. Together, our findings suggest that Y-27632 has a detrimental effect when chronically used post SE in a rat pilocarpine model of TLE.

Highlights

Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults where 20–30% of the patients are refractory to currently available anti-epileptic drugs (Leonardi and Ustun, 2002; Engel et al, 2012)
The ROCK signaling pathway is involved in numerous fundamental cellular functions such as cell adhesion, apoptosis, inflammatory responses and neurite outgrowth
We have evaluated the effect of chronic ROCK inhibitor Y-27632 treatment during the early phase of epileptogenesis in the rat pilocarpine model

Summary

Introduction

Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults where 20–30% of the patients are refractory to currently available anti-epileptic drugs (Leonardi and Ustun, 2002; Engel et al, 2012). The signaling pathways and underlying cellular and molecular mechanisms involved in this reactive plasticity are of particular importance since they create a powerful hyperexcitable cerebral focus that drives recurrent disabling seizures (McNamara, 1994; Morimoto et al, 2004; Sloviter, 2008; Jefferys, 2010; Paz and Huguenard, 2015). The RhoA/Rho-kinase (Rho-ROCK) signaling pathway is highly activated under pathological conditions such as spinal cord injury, ischemia and post-traumatic epilepsy (Fournier et al, 2003; Dubreuil et al, 2006; Ding et al, 2010). Acute treatment with fasudil or Y-27632 promotes neuronal survival and restrains inflammatory responses in models of ischemia and epilepsy when used prior to insult both in vitro and in vivo (Yamashita et al, 2007; Inan and Büyükafs,ar, 2008; Ding et al, 2010; Gisselsson et al, 2010)

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