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.
Highlights
Recurrent spontaneous motor seizures are characteristic of temporal lobe epilepsy (TLE) [1]
Our results show a similar level of Gap43 in CRS–non-convulsive seizures (NCS) compared to CT rats while it was increased in the DZP and CRS–TLE groups
The Hspa8, which we found up-regulated in DZP rats but not in both groups treated with CRS (CRS–TLE and CRS–NCS) is a chaperone protein that has an important role in heat-induced stress
Summary
Recurrent spontaneous motor seizures are characteristic of temporal lobe epilepsy (TLE) [1]. The animal model of TLE induced by pilocarpine (Pilo) reproduces the main clinical and pathophysiological features of human TLE, including mossy fiber sprouting, hippocampal sclerosis and gliosis [4,5] In this model, SE is followed by a latent period of 7–44 days until the appearance of spontaneous recurrent motor seizures [4]. Carisbamate (CRS, RWJ-333369; S-2-O-carbamoyl-1 -o-chlorophenyl-ethanol) is a new drug that possesses the property to dramatically modify epileptogenesis in an experimental model of TLE [6,7,8] These findings were observed when CRS was applied starting 1 h after SE induced by lithium–pilocarpine (LiPilo). Some animals that underwent LiPilo SE developed non-convulsive seizures (NCS) instead of the convulsive seizures commonly observed in this model These NCS recall absence seizures characterized by behavioral arrest accompanied by bilateral synchronous spike-and-wave-discharges [9,10]. The mechanisms underlying these CRS-induced changes in the nature of LiPilo-induced epilepsy are still unknown
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