Abstract
Rational polytherapy in the treatment of refractory epilepsy has been the main therapeutic modality for several years. In treatment with two or more antiepileptic drugs (AEDs), it is of particular importance that AEDs be selected based on their high anticonvulsant properties, minimal side effects, and impact on the formation of new neurons. The aim of the study was to conduct an in vivo evaluation of the relationship between treatments with synthetic cannabinoid arachidonyl-2′-chloroethylamide (ACEA) alone or in combination with valproic acid (VPA) and hippocampal neurogenesis in a mouse pilocarpine model of epilepsy. All studies were performed on adolescent male CB57/BL mice with using the following drugs: VPA (10 mg/kg), ACEA (10 mg/kg), phenylmethylsulfonyl fluoride (PMSF—a substance protecting ACEA against degradation by fatty acid hydrolase, 30 mg/kg), pilocarpine (PILO, a single dose of 290 mg/kg) and methylscopolamine (30 min before PILO to stop peripheral cholinergic effects of pilocarpine, 1 mg/kg). We evaluated the process of neurogenesis after a 10-day treatment with ACEA and VPA, alone and in combination. We observed a decrease of neurogenesis in the PILO control group as compared to the healthy control mice. Furthermore, ACEA + PMSF alone and in combination with VPA significantly increased neurogenesis compared to the PILO control group. In contrast, VPA 10-day treatment had no impact on the level of neurons in comparison to the PILO control group. The combination of ACEA, PMSF and VPA considerably stimulated the process of creating new cells, particularly neurons, while chronic administration of VPA itself had no influence on neurogenesis in the mouse pilocarpine model of epilepsy. The obtained results enabled an in vivo evaluation of neurogenesis after treatment with antiepileptic drugs in an experimental model of epilepsy.
Highlights
Temporal lobe epilepsy (TLE) is the most common type of partial or localization-related epilepsy
The obtained results indicated a decrease of neurogenesis in the pilocarpine (PILO) control group in comparison to the results of control healthy mice obtained from our previous research [11]
In the control healthy group the total number of bromodeoxyuridine (BrDU) positive cells in the dentate gyrus of mice averaged 2964 ± 232, while the results from the PILO studies indicated that in the PILO control group the total number of BrdU positive cells in the dentate gyrus of mice averaged 1776 ± 150 (t8 = 4.332; n = 5; p = 0.0025; Figure 1)
Summary
Temporal lobe epilepsy (TLE) is the most common type of partial or localization-related epilepsy. Epilepsy treatment was mainly aimed at stopping seizures. Because human TLE is the most common type of epilepsy, animal models of these conditions are thought to be best in helping us understand the problem of epileptogenesis and the neuronal alterations taking place in a given region of the brain after convulsions [6]. Antiepileptic drugs have a significant impact on neurogenesis [7,8,9,10,11]. An overview of in vitro/in vivo studies regarding VPA and its impact on convulsions, neuroprotection and neurogenesis often returns contradictory results [12,13,14]. Recent studies on Xenopus laevis tadpoles indicated that VPA induces abnormal visual avoidance and schooling behaviors [16]
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