Abstract
Studies in genetic absence epileptic rats from Strasbourg (GAERS) indicate that enhancement of gamma aminobutyric acid (GABA(A)) receptor activity is a critical mechanism in the aggravation of seizures by carbamazepine (CBZ). We examined whether structural analogs of CBZ, oxcarbazepine (OXC), and its active metabolite, monohydroxy derivative (MHD), also potentiate GABA(A) receptor current and aggravate seizures. In vitro studies in Xenopus oocytes compared the three drugs' effect on GABA(A) receptor currents. In vivo studies compared seizure activity in GAERS after intraperitoneal drug administration. OXC potentiated GABA(A) receptor current and aggravated seizures in GAERS, similarly to the effect of CBZ. Conversely, MHD showed only a minor potentiation of GABA(A) receptor current and did not aggravate seizures. A hydroxyl group at the C-10 position on the CBZ tricyclic structure in MHD reduces GABA(A) receptor potentiation and seizure aggravation. Reports of the aggravation of absence seizures in patients taking OXC may result from circulating unmetabolized OXC rather than MHD.
References
Jan 1, 1992·Neuroscience·Z LiuC Marescaux
Aug 1, 1987·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·J Wagner, K Schmid
Aug 1, 1986·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·H SchützT Winkler
Jan 1, 1994·Epilepsia·M SchmutzH R Olpe
Jan 1, 1994·Epilepsia·P LloydW Dieterle
Apr 1, 1997·Epilepsy Research·D A HosfordZ Cao
Dec 13, 2000·Neuroscience·S PirkerG Sperk
May 4, 2004·Seizure : the Journal of the British Epilepsy Association·Karen J McLeanFrank J E Vajda
Sep 24, 2004·Epilepsy & Behavior : E&B·Dieter Schmidt, Christian E Elger
Mar 30, 2005·Clinical Neuropharmacology·Charlott WallengrenTerence J O'Brien
Apr 30, 2005·The Journal of Pharmacology and Experimental Therapeutics·Ralph ClinckersYvette Michotte
Aug 10, 2006·The Journal of Pharmacology and Experimental Therapeutics·Lige LiuTerence J O'Brien
Citations
Aug 26, 2009·Epilepsia·Ernest R Somerville
Feb 22, 2012·Science Translational Medicine·Elizabeth TringhamTerrance P Snutch
May 29, 2010·Pharmacological Reports : PR·Bogusława Pietrzak, Elzbieta Czarnecka
Jun 22, 2010·European Journal of Pharmacology·Chiara Di RestaAndrea Becchetti
Aug 17, 2010·Epilepsy & Behavior : E&B·Denise MilovanPatrício Soares-da-Silva
Dec 7, 2013·The European Journal of Neuroscience·Thomas W ZhengDidier Pinault
Dec 10, 2014·Epilepsia·Tae Hwan KimSteven Petrou
Jun 28, 2011·Pharmacology, Biochemistry, and Behavior·Latha Ramakrishnan, Cassie Desaer
Feb 7, 2015·Neuropharmacology·Sam A BookerImre Vida
Jul 15, 2017·PloS One·Pablo M Casillas-EspinosaSlavé Petrovski
Sep 12, 2009·Current Treatment Options in Neurology·Matthew S StanfordRobyn M Baldridge
Oct 16, 2018·Frontiers in Pharmacology·Jaya KumarSrijit Das
Jun 27, 2019·Pharmaceuticals·Daria A BelinskaiaNatalia N Shestakova
Dec 2, 2020·Brain Sciences·Andrea BecchettiAlida Amadeo