Analysis of the antiepileptic, ethosuximide impacts on neurogenesis of rat forebrain stem cells

Abstract

Specific GABAergic interneurons in the hilus are lost in animal models with temporal-lobe epilepsy (TLE). Some preclinical evidence has indicated that GABAergic cells may provide relief from seizures in these models. This study was aimed to examine the ability of ethosuximide, an anticonvulsant drug, to promote neurogenesis in 3-day-old rat forebrain cortex stem cells. Most of the cells were found to be nestin-positive undifferentiated neural stem cells prior to their exposure to ethosuximide. It was noted that the number and percentage of tubulin β-III immunopositive neurons were increased after 6 days treatment with ethosuximide. Upon bFGF withdrawal, exposure to ethosuximide differentiated the stem cells to MAP2 positive neural cells (7.18 ± 0.43, 21.766 ± 0.55 and 41.57 ± 0.5 for control, 0.1 and 1 μM, respectively). GABA immunofluorescence images illustrated that ethosuximide increased GABAergic neurons (7.19 ± 0.32, 23.23 ± 0.55, and 46.30 ± 0.44 for control, 0.1 and 1 μM, respectively). Additionally, BrdU immunofluorescence assay showed that ethosuximide-enhanced nucleus proliferation in the neuronal stem cells. Therefore, the results of this study suggest that ethosuximide may compensate damage caused by seizure attacks and possibly other neuronal loss disorders.

Preclinical Assessment of a New Hybrid Compound C11 Efficacy on Neurogenesis and Cognitive Functions after Pilocarpine Induced Status Epilepticus in Mice

“…In our study, LEV was administered chronically for 10 days at a dose of 10 mg/kg starting 72 h after SE induction. The LEV dose was selected based on our previous studies [13,27], but we also took into account the relatively low dose of C11 (20 mg/kg). It was reasonable to choose similar doses for both the aforementioned anticonvulsants.…”

“…Similar results were obtained by Sakai et al [12], indicating that prenatal VPA exposure in mice impairs neuronal migration in the adult dentate gyrus through the decreased expression of CXC motif chemokine receptor 4 (Cxcr4) in NPCs and, consequently, increases seizure susceptibility, whereas voluntary running overcomes these adverse effects. Sondosi and coworkers [13] showed that ethosuximide (ETS) has the ability to induce neuronal differentiation into GABAergic neurons that may explain one of the mechanisms of antiepileptic effects of ETS in rat forebrain stem cells.…”

A Long-Term Treatment with Arachidonyl-2′-Chloroethylamide Combined with Valproate Increases Neurogenesis in a Mouse Pilocarpine Model of Epilepsy

“…Although acute seizures lead to an increase of proliferation of newborn cells, hippocampal neurogenesis is reduced at chronic stages of epilepsy [27]. Moreover, treatment with antiepileptic drugs may also have various impact on neurogenesis [7,8,9,10]. …”

“…Epileptic seizures should be distinguished among the most common stimuli, as they change not only the extent, but also the pattern of neurogenesis. In addition to seizures, antiepileptic drugs also have a significant impact on neurogenesis [7,8,9,10,11]. One of the well-known first-line antiepileptic drugs is valproic acid (VPA).…”

“…It has already been shown in many animal models of epilepsy that the endocannabinoid system plays a critical role in modulating seizure activity [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19]. We have studied synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA) alone and in combination with different antiepileptic drugs (AEDs) in various animal models of epilepsy.…”