Abstracts

Recently we have characterized the pharmacology of antiepileptic drugs (AEDs) in the lamotrigine (LTG)-resistant pentylenetetrazlole kindled (Epilepsia 2003; 44,42) and LTG-resistant amygdala kindled rat (Epilepsia 2004; 45(7):12). In this model of pharmacoresistant epilepsy, CBZ, PHT, and TPM were all inactive at non-toxic doses. In contrast, VPA and retigabine (Epilepsia 2005;46(8):217) were both effective. The broad-spectrum AED felbamate (FBM) displays a favorable preclinical profile in various models of epilepsy including the phenytoin-resistant amygdala kindled rat (Neuropharmacology 2000;39(10):1893-903). The present study aimed to evaluate the efficacy of FBM in the LTG-resistant amygdala kindled rat model of refractory epilepsy., Two groups of male Sprague-Dawley rats were kindled via basolateral amygdala stimulation according to the method described by Srivastava et al., (Epilepsia 2004; 45(7):12). One hour before each kindling stimulation, rats in the control group received 0.5% methylcellulose and rats in the experimental group received LTG (5 mg/kg, i.p.). Seizure severity and afterdischarge duration was recorded after each kindling stimulation. Treatment was continued until all rats displayed 4 consecutive Stage 5 seizures (Clin Neurophysiol 1972; 32:281-294). Two days later, both groups were challenged with 15 mg/kg, i.p LTG to confirm LTG-sensitivity (control) and LTG-resistance (experimental). The efficacy of FBM (100, 150 and 200, mg/kg administered 90 min prior to kindling stimulation) was then evaluated. The ED50 and 95% confidence intervals were calulated using Probit analysis., Felbamate dose-dependently reduced the seizure severity and decreased the ADD in the fully kindled LTG-resistant rat. At the highest dose tested (200 mg/kg), FBM decreased the seizure score from 5 [underline]+[/underline] 0 to 2.25 [underline]+[/underline] 0.6 and the ADD from 57 [underline]+[/underline] 5 sec. to 22 [underline]+[/underline] 30 sec. The calculated ED50 and (95% confidence intervals) for FBM against Stage 4 and 5 seizures was 169 and (131 - 206) mg/kg, respectively., In an animal model of pharmacoresistant epilepsy, the broad-spectrum AED FBM was found to effectively block the fully kindled secondarily generalized kindled seizure. In this particular model, FBM is as effective as VPA and the investigational AED retigabine (albeit less potent than retigabine). These findings demonstrated that the LTG-resistant kindled rat can be utilized to differentiate the AED profile of novel AEDs and confirm that FBM possesses a unique profile relative to CBZ, PHT, LTG, and TPM. Ongoing studies continue to evaluate the mechanism underlying the development of pharmaco-resistance in this model., (Supported by NINDS grant 1 R21-NS049624-01.)