title: Effects of eslicarbazepine acetate on acute and chronic latrunculin A-induced seizures and extracellular amino acid levels in the mouse hippocampus.
abstract: BACKGROUND
  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. 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.
  
  
  RESULTS
  Oral 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.
  
  
  CONCLUSIONS
  ESL 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain. german.sierra.paredes@usc.es.
authors.forename: Germán
authors.initials: G
authors.lastname: Sierra-Paredes
authors.affiliation: Department Research & Development, BIAL - Portela & Cª - S.A., 4745-457, S. Mamede do Coronado, Portugal. ana.loureiro@bial.com.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Loureiro
authors.affiliation: Department Research & Development, BIAL - Portela & Cª - S.A., 4745-457, S. Mamede do Coronado, Portugal. lyndon.wright@bial.com.
authors.forename: Lyndon C
authors.initials: LC
authors.lastname: Wright
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Santiago de Compostela, Santiago de Compostela, Spain. german.sierra.marcuno@usc.es.
authors.forename: Germán
authors.initials: G
authors.lastname: Sierra-Marcuño
authors.affiliation: Department Research & Development, BIAL - Portela & Cª - S.A., 4745-457, S. Mamede do Coronado, Portugal. psoares.silva@bial.com.|Department Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal. psoares.silva@bial.com.|MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal. psoares.silva@bial.com.|Department of Research and Development, BIAL, À Av. da Siderurgia Nacional, 4745-457, S. Mamede do Coronado, Portugal. psoares.silva@bial.com.
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000208:Acute Disease; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001224:Aspartic Acid / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002908:Chronic Disease; D003984:Dibenzazepines / Q000378:metabolism / Q000494:pharmacology*; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D012640:Seizures / Q000188:drug therapy* / Q000378:metabolism; D013654:Taurine / Q000378:metabolism; D053778:Thiazolidines; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000596:Amino Acids; D000927:Anticonvulsants; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003984:Dibenzazepines; D053778:Thiazolidines; D013654:Taurine; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C416835:eslicarbazepine acetate; C571001:eslicarbazepine; C037067:latrunculin A; D005998:Glycine