Hippocampal Proteome of Rats Subjected to the Li-Pilocarpine Epilepsy Model and the Effect of Carisbamate Treatment

Abstract

In adult rats, the administration of lithium–pilocarpine (LiPilo) reproduces most clinical and neuropathological features of human temporal lobe epilepsy (TLE). Carisbamate (CRS) possesses the property of modifying epileptogenesis in this model. Indeed, about 50% of rats subjected to LiPilo status epilepticus (SE) develop non-convulsive seizures (NCS) instead of motor seizures when treated with CRS. However, the mechanisms underlying these effects remain unknown. The aim of this study was to perform a proteomic analysis in the hippocampus of rats receiving LiPilo and developing motor seizures or NCS following CRS treatment. Fifteen adult male Sprague–Dawley rats were used. SE was induced by LiPilo injection. CRS treatment was initiated at 1 h and 9 h after SE onset and maintained for 7 days, twice daily. Four groups were studied after video-EEG control of the occurrence of motor seizures: a control group receiving saline (CT n = 3) and three groups that underwent SE: rats treated with diazepam (DZP n = 4), rats treated with CRS displaying NCS (CRS-NCS n = 4) or motor seizures (CRS-TLE n = 4). Proteomic analysis was conducted by 2D-SDS-PAGE. Twenty-four proteins were found altered. In the CRS-NCS group, proteins related to glycolysis and ATP synthesis were down-regulated while proteins associated with pyruvate catabolism were up-regulated. Moreover, among the other proteins differentially expressed, we found proteins related to inflammatory processes, protein folding, tissue regeneration, response to oxidative stress, gene expression, biogenesis of synaptic vesicles, signal transduction, axonal transport, microtubule formation, cell survival, and neuronal plasticity. Our results suggest a global reduction of glycolysis and cellular energy production that might affect brain excitability. In addition, CRS seems to modulate proteins related to many other pathways that could significantly participate in the epileptogenesis-modifying effect observed.

Neurochemical Changes and c-Fos Mapping in the Brain after Carisbamate Treatment of Rats Subjected to Lithium–Pilocarpine-Induced Status Epilepticus

“…Based on previous studies, we can hypothesize that CRS reduces neuronal excitability by acting synergistically on several neurotransmitter systems and pathways. Supporting these data, we recently reported [ 16 ] that CRS-NCS rats display alterations in proteins related to cellular respiration and energy production processes, which may also impact on neuronal excitability. Among altered proteins we observed a reduction of alpha-synuclein in rats treated with CRS and an increase of the same protein in CRS-treated animals displaying NCS instead of convulsive seizures [ 16 ].…”

“…Supporting these data, we recently reported [ 16 ] that CRS-NCS rats display alterations in proteins related to cellular respiration and energy production processes, which may also impact on neuronal excitability. Among altered proteins we observed a reduction of alpha-synuclein in rats treated with CRS and an increase of the same protein in CRS-treated animals displaying NCS instead of convulsive seizures [ 16 ]. A recent hypothesis suggests that epigenetic alterations in some proteins such as alpha-synuclein may be associated with the formation of new ion channels that may disrupt membrane conductance and underlie the change in epilepsy type induced by CRS treatment [ 17 ].…”

Altered Proteins in the Hippocampus of Patients with Mesial Temporal Lobe Epilepsy

“…Previous studies also reported an up-regulation of DPYSL2 in autopsy and human biopsy tissue from epileptic patients [15]. This protein was also up-regulated in the MTLE model induced by pilocarpine compared to the control, and treatment with a disease modifier neuromodulator, carisbamate, normalized the expression of DPYSL2 [32]. Carisbamate treatment reversed the increase in the protein expression and caused a change in the expression of limbic seizures for absence seizures in treated animals [32].…”

The impact of postsynaptic density 95 blocking peptide (Tat‐NR2B9c) and an iNOS inhibitor (1400W) on proteomic profile of the hippocampus in C57BL/6J mouse model of kainate‐induced epileptogenesis

“…Previous studies have provided important insights into the underlying cellular and molecular processes of epileptogenesis, highlighting neuroinflammation, the innate immune response, microglial activation, synaptic reorganization, and oxidative stress as key mechanisms in this regard (Bitsika et al, ; Keck et al, , ; Li et al, ; Liu et al, ; Marques‐Carneiro et al, ; Walker et al, ). Many of these observations are unsurprising, given the burgeoning knowledge base surrounding the mechanisms and pathways believed to contribute to the development of epilepsy (Aronica et al, ; Becker, ; Godale & Danzer, ; Lukawski et al, ; Pitkänen et al, ).…”

“…Few studies have explored the proteomic signature of epileptogenesis to date (Bitsika et al, ; Keck et al, , ; Li et al, ; Liu et al, ; Marques‐Carneiro et al, ; Walker et al, ), all of which have been relatively small scale investigations involving small numbers of animals. In this respect, the current study is no different.…”