Abstracts

We have previously reported that the lamotrigine (LTG)-resistant amygdala kindled rat displays resistance to carbamazepine, phenytoin and topiramate, but not valproate (Srivastava et al., Epilepsia 2003).
This animal model may provide a unique system to evaluate novel antiepileptic drugs (AEDs). Since 1993 nine new AEDs have been introduced for the treatment of epilepsy. Although effective for the treatment of partial epilepsy none of these drugs have led to a significant reduction in the prevalence of refractory epilepsy.
Recently the broad spectrum AED, retigabine (RGB) has been found to be effective in suppressing refractory epileptiform discharges in vitro in combined hippocampal-entorhinal brain slices (Smith-Yockman et al., Epilepsia 2004, Armand et al., Epilepsia, 2000). RGB is unique among the AEDs because of its ability to enhance the M current through a shift in the activation kinetics of KCNQ2/3 channels. The present study was undertaken to assess the ability of retigabine (RGB) to block both behavioral and electrographic seizures in LTG-resistant amygdala kindled rats. Two groups of male Sprague Dawley rats were kindled via amygdala stimulation (Postma et al., Epilepsia, 2000). One hour before each kindling stimulation, rats in the control group received 0.5% methylcellulose and rats in the experimental group received LTG (5mg/kg, i.p.). Treatments were stopped once the control group were fully kindled. One day later, both groups were challenged with a higher dose of LTG (15 mg/kg, i.p.) to verify LTG- resistance in the experimental group (i.e., LTG- pretreated rats). The efficacy of RGB (10, 20 and 40 mg/kg administered 10 min prior to kindling stimulation) was then evaluated in both experimental groups. A stable (stage 4-5) kindled state was established in both vehicle- and LTG-treated animals over a period of 17-18 days. Upon subsequent challenge with a higher dose of LTG, the fully kindled seizure of the vehicle-treated rats, but not the LTG-treated rats, was blocked by LTG. RGB (10, 20, and 40 mg/kg) displayed a dose-dependent anticonvulsant effect in both LTG-sensitive and LTG- resistant animals. Specifically, RGB blocked the expression of the behavioral seizure and decreased the after-discharge duration in both groups. The present findings suggest that RGB is highly effective in LTG-resistant animal model of drug resistant epilepsy. These results support further clinical development in patients that are refractory to both first and second generation antiepileptic drugs. These findings also suggest that the LTG-resistant, amygdala-kindled rat may represent a novel model of pharmaco-resistant epilepsy. Ongoing studies continue to evaluate the mechanism underlying the development of pharmaco-resistance in this model. (Supported by NINDS grant 1 R21-NS049624-01.)