Abstracts

Rationale: Symptomatic seizures are common in neonates and are often resistant to treatment with approved antiepileptic drugs. Evidence suggests that selective neuronal KCNQ potassium channel openers may be very useful as therapeutic agents for neonatal seizures. Mutations that decrease the openings of these channels cause the genetic syndrome benign familial neonatal seizures. In animal studies, blockade of KCNQ channels during the neonatal period results in severe seizures, but has milder effects in older animals. Selective KCNQ channel openers have recently been identified that reduce the membrane depolarization required for openings and increases peak open probability. In this study, we evaluated the effectiveness of flupirtine, a KCNQ channel opener, in a rodent model of induced neonatal seizures. Methods: Status epilepticus was elicited in post-natal day 10 (P10) Sprague-Dawley rat pups by intraperitoneal (IP) administration of 2 mg/kg kainic acid (KA). Seizure severity was quantified using a five stage behavioral rating scale (5-most severe). Animals were pretreated with flupirtine (10-50 mg/kg IP), phenobarbital (10-50 mg/kg IP), or vehicle prior to KA. Other pups were injected with KA and allowed to progress to stage 4 or 5 seizures before flupirtine, phenobarbital or vehicle was given to attempt to reverse the seizure activity. In a subset of rat pups, cortical EEG was recorded, before and after drug administration. Results: Flupirtine pretreatment caused a dose-related suppression (10-50 mg/kg) of KA-induced seizure behavior. None of the 50 mg/kg flupirtine-treated animals (0/7) entered into stage 5 behavioral seizures. In contrast, 89% of KA treated animals (8/9) and all (9/9) of the KA plus phenobarbital pretreated (10-50 mg/kg) animals entered into stage 5 seizures. Animals allowed to enter stage 5 before being given flupirtine (50 mg/kg) showed a prompt diminishment of seizure behavior, and none remained in stage 5 seizures by 15 minutes after receiving flupirtine (0/5). In contrast, all animals allowed to enter stage 5 before phenobarbital treatment (50 mg/kg) remained in stage 5 seizures by 15 minutes after drug administration (5/5). None of the animals (0/4) that were treated with flupirtine after onset of stage 4 seizures progressed to stage 5 seizures. In contrast, all animals treated with phenobarbital after onset of stage 4 seizures progressed to stage 5 seizures (4/4). Preliminary EEG recordings demonstrate marked reduction in spike density and spike amplitude within 2-4 minutes of flupirtine treatment, with further reductions continuing over the succeeding 30 minutes period.Conclusions: These results support the hypothesis that KCNQ channel openers may potently suppress evoked seizures in a rodent model of neonatal seizures. In contrast, the current clinical first-line agent, phenobarbital, appears relatively ineffective in this model. Source of funding R21 NS055765.