Abstracts

Rationale: The risk of seizures is highest in the neonatal period and hypoxic encephalopathy is the most common cause for the occurrence of seizures in neonates. The first-line drugs, such as phenobarbital and phenytoin, are effective in treating neonatal seizures in less than 50% of patients and have been associated with a number of long-term side effects. Therefore, there is an urgent need to develop more efficacious and less toxic drugs for the treatment of neonatal seizures. Our recently published study showed that unlike diazepam and phenobarbital, flupirtine a potassium channel opener, completely blocked the induction of seizures in two different chemoconvulsant models of neonatal seizures in rodents. Moreover, flupirtine more effectively stopped electrographic and behavioral seizures when administered after animals had developed kainate-induced continuous seizures as compared to phenobarbital and diazepam. In this study, we evaluated the effectiveness of flupirtine for the treatment of hypoxia-induced seizures in a rodent model of induced neonatal seizures. Methods: Sprague-Dawley rat pups were exposed to global hypoxia for 15 minutes to induce seizures at post-natal day 10 (P10) according to published protocol. The behavioral seizures consisted of myoclonic jerks, automatisms and tonic-clonic head and limb movements. A subset of animals was pretreated with flupirtine (50 mg/kg IP) or vehicle 15 minutes before they were exposed to hypoxic conditions. A separate set of rat pups was implanted with electrodes in cortex to record EEG. After recovery from surgery, the rat pups were exposed to hypoxic condition and were injected with flupirtine or vehicle 15 minutes after hypoxia. Results: Pretreatment with 50mg/kg flupirtine inhibits development of hypoxia-induced behavioral seizures. None of the flupirtine-treated animals (n=6) developed seizures during exposure to hypoxia. All rats pretreated with vehicle (n=7) developed tonic-clonic head and trunk activity. Preliminary EEG recordings demonstrate marked reduction in number of electrographic seizures and total EEG power in rats that were treated with flupirtine 15 minutes after exposure to global hypoxia. Conclusions: These results suggest effectiveness of flupirtine in prevention of hypoxia-induced seizures in this neonatal rat model. Further studies are required to understand the effect of flupirtine treatment on development of epilepsy following early-life seizures.