Abstracts

Rationale: Hypoxic-ischemic encephalopathy (HIE) is a common cause of seizures in full-term infants and survivors often experience neurological problems in later life. Current antiepileptic drugs, that were developed using adult animal models, are not fully effective in treating neonatal seizures. Evidence from clinical and basic science research studies suggests that KCNQ potassium channels play a very important role in controlling excitation in early-life. Our earlier study demonstrated that flupirtine, a KCNQ channel opener, was more efficacious than diazepam or phenobarbital for the treatment of chemoconvulsant-induced neonatal seizures. In the current study we demonstrate that flupirtine effectively treats hypoxia-ischemia (HI) induced electroclinical seizures in a neonatal rat model of HIE.Methods: HI was induced by ligating the carotid artery and exposing 7-day-old rats to hypoxia. A group of rat pups was treated with 50mg/kg flupirtine or vehicle prior to hypoxia and were scored for behavioral seizure intensity during hypoxia. To study the effects of flupirtine on electroclinical seizures, a separate group of rats was given flupirtine 5 minutes after the occurrence of the first electroclinical seizure during hypoxia and the effect of treatment on subsequent seizure development was assessed. Electroclinical seizures were defined as an EEG pattern that differs from background in either amplitude, frequency or both, evolves over time, contains spikes or sharps lasting for 10 seconds or more and is associated with a change in the rat s behavior. The EEG was monitored using bilateral wire electrodes implanted in the parietal cortices. Results: None of the rats treated with flupirtine (50 mg/kg of body weight) prior to hypoxia (n = 7) developed seizures, whereas all vehicle treated or untreated rats (n = 9) developed seizures upon exposure to hypoxia (P<0.005, two-sided Fisher exact test). Flupirtine (25 mg/kg of body weight) given 5 minutes after the first electroclinical seizure significantly reduced the number and total duration of subsequent seizures during hypoxia (P < 0.03, unpaired student s t-test; n = 7 in HI + untreated/vehicle treated group, n = 6 in HI + flupirtine group). The flupirtine given after the first electroclinical seizure also significantly reduced the number of animals that developed electroclinical seizures (16% in flupirtine treated group vs. 100% in untreated or vehicle treated group of rats) during the reperfusion period (the period immediately after HI-induction). Further, for the 16% of rats that developed electroclinical seizures, there were significantly fewer seizures compared to untreated or vehicle treated HI rats.Conclusions: Our results suggest that flupirtine effectively treats HI induced acute neonatal seizures. Further studies are underway to determine the therapeutic time window in which flupirtine is effective for treatment of these seizures.