Objective-Neonatal seizures occur frequently, are often refractory to anticonvulsants, and are associated with considerable morbidity and mortality. Genetic and electrophysiological evidence indicates that KCNQ voltage-gated potassium channels are critical regulators of neonatal brain excitability. This study tests the hypothesis that selective openers of KCNQ channels may be effective for treatment of neonatal seizures.Methods-We induced seizures in postnatal day 10 rats with either kainic acid or flurothyl. We measured seizure activity using quantified behavioral rating and electrocorticography. We compared the efficacy of flupirtine, a selective KCNQ channel opener, with phenobarbital and diazepam, two drugs in current use for neonatal seizures.Results-Unlike phenobarbital or diazepam, flupirtine prevented animals from developing status epilepticus (SE) when administered prior to kainate. In the flurothyl model, phenobarbital and diazepam increased latency to seizure onset, but flupirtine completely prevented seizures throughout the experiment. Flupirtine was also effective in arresting electrographic and behavioral seizures when administered after animals had developed continuous kainate-induced SE. Flupirtine caused doserelated sedation and suppressed EEG activity, but did not result in respiratory suppression or result in any mortality.Interpretation-Flupirtine appears more effective than either of two commonly used anti-epileptic drugs, phenobarbital and diazepam, in preventing and suppressing seizures in both the kainic acid and flurothyl models of symptomatic neonatal seizures. KCNQ channel openers merit further study as potential treatments for seizures in infants and children.Epileptic seizures occur commonly in the first days after birth. 1 Such neonatal seizures are usually symptomatic, arising as a result of developmental abnormalities, in utero injuries, perinatal hypoxia-ischemia, infection, and other causes. Patients experiencing neonatal seizures are at substantial risk of mortality and long-term morbidity, including static encephalopathy, cerebral palsy, and chronic epilepsy. 2, 3 The first-line drugs given to neonates, phenobarbital and phenytoin, are effective in less than 50% of cases 4 . Moreover, phenobarbital, benzodiazepines and phenytoin have been shown to cause widespread neuronal apoptosis when given to young rodents, raising concerns about administration of these drugs in human infants. Genetic, physiological, and pharmacological evidence calls attention to KCNQ potassium channels (also termed Kv7 and M-channels) as potential molecular targets for treatment of neonatal seizures. 9 Loss-of-function mutations in the KCNQ2 and KCNQ3 genes cause benign familial neonatal seizures (BFNS), an uncommon but highly penetrant, dominantly-inherited syndrome characterized by seizures that recur frequently over the first weeks of life. 10-12 Experimental inhibition of KCNQ channels in rodents, by pharmacological and genetic methods, dramatically promotes neuronal and network hyperexcitabi...
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