Abstracts

Rationale: Hypoxic encephalopathy is the most common cause of neonatal seizures and survivors often experience neurological problems such as epilepsy in later life. First-line drugs such as phenobarbital are poorly effective in treating neonatal seizures and are associated with a number of side effects. Potassium channels play a uniquely important role in controlling excitability in the developing brain due to immaturity of GABAergic inhibition. Our earlier study demonstrated that flupirtine, a potassium channel opener, was more efficacious than diazepam or phenobarbital for the treatment of chemoconvulsant-induced neonatal seizures. In the current study efficacy of flupirtine to inhibit hypoxia-induced neonatal seizures and its effects on early-developmental milestones were evaluated. Methods: Ten-day old (P10) Sprague-Dawley rats were treated with either vehicle or with 25, 35, 45 or 50 mg/kg flupirtine 15 minutes before they were exposed to hypoxia. Treated rats were scored for behavioral seizure intensity during hypoxia. The behavioral seizures consisted mainly of head shakes and tonic-clonic limb movements. Hypoxia-induced epileptiform discharges in P10 rats have been shown to last up to 7 days and therefore following hypoxia, rats were treated once a day, everyday for one week with the same dose that was initially given to block the induction of seizures. Rat pups were observed everyday and their body weight, body length, eye opening and righting reflex latency were noted from P10 to P21. Results: Pretreatment with 50mg/kg flupirtine (n=6) effectively blocked hypoxia-induced behavioral seizures. Also, 50mg/kg flupirtine given 15 minutes after rats were exposed to hypoxia (n=4) blocked the occurrence of acute electrographic seizures. However, treatment with 50mg/kg flupirtine once a day, everyday for multiple days was not well tolerated in terms of age appropriate weight gain. Pretreatment with 35 (n=3) or 45 (n=2) mg/kg flupirtine blocked all type of hypoxia-induced seizure activity, whereas, pretreatment with 25 mg/kg flupirtine (n=6) blocked tonic-clonic seizures in all of the treated rats but was effective in blocking head shakes in only 50% of the treated rats. All rats pretreated with vehicle (n=9) developed head shakes and multiple tonic-clonic seizures. Preliminary studies suggest that treatment with 45mg/kg flupirtine (n=2) adversely affects body length and weight gain but do not affect latency to righting reflex and eye opening. Treatment of rats with either 25 (n=2) or 35 (n=2) mg/kg flupirtine does not affect body weight, body length or latency to righting reflex and eye opening. Conclusions: These results suggest that 35mg/kg flupirtine is an optimal treatment dose for hypoxia-induced neonatal seizures in rats since it effectively blocks seizures without affecting short-term development. Studies are underway to confirm preliminary results and to determine the effects of optimal flupirtine dose on hypoxia-induced acute electrographic seizures as well as on development of spontaneous seizures and cognition later in life. Supported by Epilepsy Foundation of America grant to YHR.