Abstracts

Rationale: Phenobarbital, a GABA agonist, is the most commonly used drug for treating neonatal seizures; however, its efficacy in controlling neonatal seizures is still debated. The GABAergic system of the immature brain is underdeveloped compared to that of the mature brain, making it a sub-optimal target for the treatment of neonatal seizures. Moreover, phenobarbital is less effective when administered after an acute episode of brain injury and is associated with various side effects such as cognitive decline during adulthood. 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 studies demonstrate that flupirtine, a KCNQ channel opener, is more efficacious than diazepam and phenobarbital for the treatment of chemoconvulsant-induced neonatal seizures. In the current study, we compare the efficacy of flupirtine with phenobarbital in the treatment of hypoxia-ischemia (HI)-induced neonatal seizures when given during the reperfusion period, after the rats have experienced multiple seizures. Methods: HI was induced by ligating the carotid artery of 7 day-old rats and then exposing them to hypoxia for 2 hours. Five minutes after the rats were exposed to room air (reperfusion period), they were treated with either 25mg/kg flupirtine or phenobarbital. Synchronized video-EEG monitoring technique was used to determine the occurrence of electroclinical seizures, electrographic seizures, and EEG abnormalities. Results: Flupirtine treatment (n=5) given 5 minutes after the end of hypoxia reduced the number and total duration of electroclinical seizures during the immediate reperfusion period (p<0.05, Kruskal-Wallis test). In contrast, phenobarbital (n=4) treated rats developed similar numbers and duration of electroclinical seizures as untreated/vehicle treated HI rats (n=14). Conclusions: Flupirtine was effective in reducing the number and total duration of acute electroclinical seizures, even when given after 2 hours of hypoxia and multiple seizures. In contrast, phenobarbital showed no impact on these same measures.