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

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.

ROCK/PKA Inhibition Rescues Hippocampal Hyperexcitability and GABAergic Neuron Alterations in a Oligophrenin-1 Knock-Out Mouse Model of X-Linked Intellectual Disability

“…ROCK/PKA inhibitors such as Y-27632 and Fasudil have already been successfully used in Ophn1-dependent form of intellectual disability (Meziane et al, 2016;Compagnucci et al, 2016;Redolfi et al, 2016;Allegra et al, 2017). Moreover, these compounds have also shown anticonvulsant effects in specific seizure models (Inan et al, 2008;Kourdougli et al, 2015;Çarçak et al, 2018), suggesting that they could be employed as an adjuvant or alternative therapy for refractory epilepsy. Here, based on in vitro results (Powell et al, 2012), we first investigated whether a single pharmacological treatment could abolish the enhanced excitability in Ophn1 KO mice in vivo, and we found that such treatment was not effective (Fig.…”

Bumetanide Prevents Brain Trauma-Induced Depressive-Like Behavior

“…This inflammation could have several effects, among which, cell-death is one of the most prominent effects. It has been shown in other models that inflammation is associated with a massive loss of hippocampal formation write in epilepsy (Aldenkamp and Bodde, 2005; Swartz et al, 2006; Jefferys, 2010; Peng et al, 2013) or TBI models (Swartz et al, 2006; Morrison et al, 2011; Belousov et al, 2012; Acosta et al, 2013) and more particularly in the DG region (Lowenstein et al, 1992; Kourdougli et al, 2015; Sun et al, 2015). In that context, neuronal cell death and more specifically Parvalbumin positive cell death is one particular phenomenon both in epilepsy (Huusko et al, 2015) and in TBI models (Santhakumar et al, 2001; Cantu et al, 2014; Huusko and Pitkänen, 2014).…”

TGF‐β signaling directly regulates transcription and functional expression of the electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), via Smad4 in mouse astrocytes

“…The phenotypes resulting from the knockout of the mammalian TGF‐β isoforms are very distinct (reviewed in Dünker & Krieglstein, 2000). We have recently shown that TGF‐β2 regulates functional expression of the neuronal K + /Cl ‐ cotransporter 2 (KCC2) (Roussa et al, 2016), a molecular component increasingly appreciated in the context of epilepsy (Kelley et al, 2016; Kourdougli, Varpula, Chazal, & Rivera, 2015). We have hypothesized that TGF‐β2 is the isoform required for 4AP‐dependent NBCe1 regulation.…”