Abstracts

Rationale: Retigabine (manufactured by GlaxoSmithKline), is the first neuronal potassium channel opener indicated for the adjunctive treatment of focal (partial) seizures in adult patients. Pharmacological studies demonstrated that it acts a positive allosteric modulator of KCNQ2-5 (K(v) 7.2-7.5) ion channels. In vitro models showed that retigabine may also act as a positive modulator on GABAA receptors but that it does not act directly on glutamate receptors. To date, there is a paucity of data on the efficacy of retigabine in experimental models of partial limbic seizures. Methods: Systemic doses of retigabine (1, 2, 5, 10, 100, 300 mg/kg) on kainate (KA)-induced status epilepticus (SE) were examined in adult rats 30 min prior to injection of KA (16 mg/kg, i.p.). Additionally, a separate group of animals was injected with 1, 2 or 5 mg/kg of retigabine 2 hrs following KA-SE. Results: Doses 10 mg/kg produced deep, rapid sedation and was discontinued. One injection of 2 or 5 mg/kg was insufficient to prevent the induction of KA SE; however there was significant reduction or absence of stage 5-6 seizure behavior symptoms such as drooling and forelimb clonus in 50% of the animals. Two prior treatments (24 hrs and 30 min prior to KA injection) increased seizure behavior latency and attenuated spiking in the electroencephalogram (EEG). At 2 hrs after KA injection, during status epilepticus, 2 mg/kg of retigabine quickly calmed seizure behavior and reduced EEG spiking frequency and amplitude, whereas, 5 mg/kg increased the number of single spikes and synchronization of burst activity. Although histological analysis revealed that animals scored with stage 5-6 seizures exhibited typical hippocampal injury regardless of treatment, GluR1 subunit protein was selectively suppressed in the granule cell layer (GCL) and within the mossy fiber synapse in animals treated with retigabine. Animals with pre- or post-treatment of retigabine that were resistant to KA-SE did not exhibit significant injury only indicating that retigabine was neuroprotective if seizures were prevented. Conclusions: It appears that lower doses of retigabine had greater efficacy producing a potent anticonvulsant effect possibly due to an indirect effect on AMPA receptors that may reduce excitatory transmission. In contrast, higher doses produced ataxia and proconvulsant effects in this model of epilepsy indicating that the dosage used in humans must be scrutinized to produce the adequate clinical response.