title: Carbamazepine aggravates absence seizures in two dedicated mouse models.
abstract: BACKGROUND
  The aim of this study was to evaluate the effect of carbamazepine (CBZ) upon chemically induced absence seizures and in a genetic absence seizures model in the mouse.
  
  
  METHODS
  The γ-butyrolactone (GBL)-induced acute absence seizures and the stargazer spontaneous absence seizures mice models were used to characterize the aggravation of absence seizures induced by oral CBZ treatment. The effect of CBZ upon GABA inward-currents in Ltk cells expressing human recombinant α1β2γ2, α2β2γ2, α3β2γ2 and α5β2γ2 GABAA receptors was evaluated by means of patch clamp.
  
  
  RESULTS
  GBL administration induced motor impairment in NMRI mice. High dose CBZ (25mg/kg body weight) had no effect on motor performance but exacerbated the behavioral incoordination observed for GBL. Also, coadministration of a high dose CBZ and GBL impaired spontaneous locomotion. Moreover, CBZ was investigated after oral administration to evaluate the potential to aggravate GBL-induced acute spike-and-wave discharges (SWD) in the electroencephalogram. High dose CBZ significantly aggravated SWD induced by GBL. Likewise, in the stargazer mouse model of genetic spontaneous absence seizures, CBZ significantly aggravated SWD frequency and duration. Pre-treatment with the T-type Ca(2+) channel blocker ethosuximide (200mg/kg body weight) prevented the CBZ aggravation of SWD induced by GBL and in the stargazer mouse. CBZ increased in a concentration dependent manner sub-maximal α1β2γ2 and α3β2γ2 GABA currents.
  
  
  CONCLUSIONS
  CBZ aggravates absence seizures as assessed in two dedicated mouse models of absence seizures. Facilitation of sub-maximal α1β2γ2, and α3β2γ2 GABA currents by CBZ may play a role in CBZ-induced GABA-mediated aggravation of absence seizures.
authors.affiliation: Department of Research and Development, BIAL - Portela & Cª, S.A., S. Mamede do Coronado, Portugal.
authors.forename: Nuno Marques
authors.initials: NM
authors.lastname: Pires
authors.affiliation: Department of Research and Development, BIAL - Portela & Cª, S.A., S. Mamede do Coronado, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Bonifácio
authors.affiliation: Department of Research and Development, BIAL - Portela & Cª, S.A., S. Mamede do Coronado, Portugal; Department of Pharmacology & Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal. Electronic address: psoares.silva@bial.com.
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D015107:4-Butyrolactone; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000378:metabolism; D002220:Carbamazepine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology; D005013:Ethosuximide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011597:Psychomotor Performance / Q000187:drug effects; D011963:Receptors, GABA-A / Q000187:drug effects / Q000235:genetics
chemical_list: D000927:Anticonvulsants; D020747:Calcium Channels, T-Type; D011963:Receptors, GABA-A; D002220:Carbamazepine; D005013:Ethosuximide; D015107:4-Butyrolactone
keywords: Absence seizures; Carbamazepine; Ethosuximide; Stargazer mouse; γ-Butyrolactone