Anticonvulsant effect of retigabine during postnatal development in rats

Abstract

Retigabine is a new-generation antiepileptic drug that exerts therapeutic action through the activation of KCNQ channel dependent M-type potassium currents. While retigabine has been extensively studied in adult animals using a wide variety of seizure models, its effects in developing animals have not been examined. There has only been one previous report of retigabine efficacy in juvenile rats (Mazarati et al., 2008), which examined efficacy against kindled seizures and did not examine ages younger than postnatal day (P) 14. To determine the efficacy of retigabine during brain development we pretreated rats with retigabine (0-30 mg/kg) at three ages corresponding to the neonatal period through late childhood/early adolescence (i.e., P7, P14, or P25). Seizures were induced 30 min later using a chemoconvulsant (pentylenetetrazol, PTZ) model, which has been widely used to determine anticonvulsant efficacy of many other antiepileptic drugs in neonatal animals. In a dose and age-dependent manner, retigabine reduced the severity of PTZ evoked seizures, increased the latency to seizure onset, and decreased the incidence of full maximal seizures. The minimum effective dose was found to be 5mg/kg for P7 animals, 2.5mg/kg for P14 animals, and 1mg/kg for P25 animals. These findings allow a direct comparison between retigabine and previously studied antiepileptic drugs against PTZ seizures during development, and provide the first report of the effective dose range of retigabine in neonatal animals.