Y.H.R. and D.A.L. contributed equally to this work.
A KCNQ channel opener for experimental neonatal seizures and status epilepticus†
Article first published online: 30 MAR 2009
Copyright © 2009 American Neurological Association
Annals of Neurology
Volume 65, Issue 3, pages 326–336, March 2009
How to Cite
Raol, Y. H., Lapides, D. A., Keating, J. G., Brooks-Kayal, A. R. and Cooper, E. C. (2009), A KCNQ channel opener for experimental neonatal seizures and status epilepticus. Ann Neurol., 65: 326–336. doi: 10.1002/ana.21593
Potential conflict of interest: Nothing to report.
- Issue published online: 30 MAR 2009
- Article first published online: 30 MAR 2009
- Manuscript Accepted: 31 OCT 2008
- Manuscript Revised: 18 SEP 2008
- Manuscript Received: 7 JUL 2008
- NIH (National Institute of Neurological Disorders and Stroke). Grant Numbers: R21 NS55765, R01 NS49119
- Miles Family Fund
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.
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.
Unlike phenobarbital or diazepam, flupirtine prevented animals from experiencing development of status epilepticus when administered before 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 status epilepticus. Flupirtine caused dose-related sedation and suppressed electroencephalographic activity but did not result in respiratory suppression or result in any mortality.
Flupirtine appears more effective than either of two commonly used antiepileptic 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. Ann Neurol 2009;65:326–336