Abstracts

Rationale: Carbamazpine (CBZ) is a first-line anti-epileptic drug, but is known to aggravate many generalized seizure types in humans and animal models. In vivo studies in Genetic Absence Epileptic Rats from Strasbourg (GAERS) have indicated that enhancement of GABA_A receptor activity plays a critical role in the mechanism underlying this aggravation. Oxcarbazepine (OXC) is a close structural analogue of CBZ but has fewer side effects. This study examined whether OXC and its major active metabolite in humans, MHD, differed from CBZ in their propensity to aggravate seizures in vivo in GAERS and to potentiate GABA_A activity in vitro.Methods: 1) Seizure activity was quantified in vivo by a 90-minute EEG recording in 14 week-old ovariectomized GAERS after intraperitoneal injections of OXC, MHD and CBZ at doses shown to be effective against rat models of focal and convulsive seizures. 2) GABA_A receptor modulation was measured in vitro in Xenopus oocytes expressing recombinant GABA_A receptors (subunit combination α1β2γ2). Modulating doses of OXC and MHD (1-100 μM) were tested in the presence of GABA (EC₂₀; 6x10^-6M). Results: OXC at 15 and 30 mg/kg significantly increased %time in seizure compared to vehicle (48.5% and 77.6% increase, respectively, p<0.05, n=8), similar to the seizure aggravation seen with CBZ (20mg/kg) (88.9% increase from vehicle, p<0.001, n=8). However MHD, when tested at the same doses (15 and 30 mg/kg) did not aggravate seizures. 2) In vitro OXC potentiated GABAA receptors in a dose-dependent manner at therapeutic concentrations (1 - 100 μM). In comparison, MHD was a significantly less effective potentiator of GABAA receptors. Conclusions: These data show that OXC aggravates seizures in GAERS and potentiates GABA