Effects of eslicarbazepine acetate on acute and chronic latrunculin A-induced seizures and extracellular amino acid levels in the mouse hippocampus.

Germán Sierra-Paredes,Ana I Loureiro,Germán Sierra-Marcuño,Lyndon C Wright,Patrício Soares-Da-Silva

doi:10.1186/s12868-014-0134-2

Germán Sierra-Paredes, Ana I Loureiro + Show 3 more

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https://doi.org/10.1186/s12868-014-0134-2

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Abstract

BackgroundLatrunculin A microperfusion of the hippocampus induces acute epileptic seizures and long-term biochemical changes leading to spontaneous seizures. This study tested the effect of eslicarbazepine acetate (ESL), a novel antiepileptic drug, on latrunculin A-induced acute and chronic seizures, and changes in brain amino acid extracellular levels. Hippocampi of Swiss mice were continuously perfused with a latrunculin A solution (4 μM, 1 μl/min, 7 h/day) with continuous EEG and videotape recording for 3 consecutive days. Microdialysate samples were analyzed by HPLC and fluorescence detection of taurine, glycine, aspartate, glutamate and GABA. Thereafter, mice were continuously video monitored for two months to identify chronic spontaneous seizures or behavioral changes. Control EEG recordings (8 h) were performed in all animals at least once a week for a minimum of one month.ResultsOral administration of ESL (100 mg/kg), previous to latrunculin A microperfusion, completely prevented acute latrunculin A-induced seizures as well as chronic seizures and all EEG chronic signs of paroxysmal activity. Hippocampal extracellular levels of taurine, glycine and aspartate were significantly increased during latrunculin A microperfusion, while GABA and glutamate levels remained unchanged. ESL reversed the increases in extracellular taurine, glycine and aspartate concentrations to basal levels and significantly reduced glutamate levels. Plasma and brain bioanalysis showed that ESL was completely metabolized within 1 h after administration to mainly eslicarbazepine, its major active metabolite.ConclusionESL treatment prevented acute latrunculin A-induced seizures as well as chronic seizures and all EEG chronic signs of paroxysmal activity, supporting a possible anti-epileptogenic effect of ESL in mice.

Highlights

Latrunculin A microperfusion of the hippocampus induces acute epileptic seizures and long-term biochemical changes leading to spontaneous seizures
Following oral administration of eslicarbazepine acetate (ESL), the major metabolite in plasma obtained from a statelite group of mice was eslicarbazepine, followed by relatively low amounts of OXC (Figure 1B); no trace amounts of ESL and R-licarbazepine were detected
The ESL dose of 100 mg/kg administered 60 min before the test resulted in 90% protection against MES-induced seizures

Summary

Introduction

Latrunculin A microperfusion of the hippocampus induces acute epileptic seizures and long-term biochemical changes leading to spontaneous seizures. This study tested the effect of eslicarbazepine acetate (ESL), a novel antiepileptic drug, on latrunculin A-induced acute and chronic seizures, and changes in brain amino acid extracellular levels. Latrunculin A hippocampal microperfusion in freely moving rats induces acute epileptic seizures, followed by the occurrence of chronic sporadic spontaneous seizures, in association with changes in extracellular concentrations of excitatory and inhibitory amino acids [25,26]. ESL was found to prevent acute seizures induced by latrunculin A hippocampal microperfusion and reduce the increases in glutamate and aspartate induced by latrunculin A [25]. Rats, in contrast to mice and humans, extensively convert ESL to oxcarbazepine [27]

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