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A KCNQ channel opener for experimental neonatal seizures and status epilepticus

Authors

  • YogendraSinh H. Raol PhD,

    1. Division of Neurology, Children's Hospital of Philadelphia
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    • Y.H.R. and D.A.L. contributed equally to this work.

  • David A. Lapides BA,

    1. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA
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    • Y.H.R. and D.A.L. contributed equally to this work.

  • Jeffery G. Keating PhD,

    1. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA
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  • Amy R. Brooks-Kayal MD,

    1. Division of Neurology, Children's Hospital of Philadelphia
    2. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA
    3. Division of Neurology, Department of Pediatrics, University of Colorado at Denver School of Medicine and Children's Hospital, Denver, CO
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  • Edward C. Cooper MD, PhD

    Corresponding author
    1. Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA
    • Penn Epilepsy Center, Department of Neurology, 3 West Gates Building, 3400 Spruce Street, University of Pennsylvania, Philadelphia, PA 19104
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  • Potential conflict of interest: Nothing to report.

Abstract

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 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.

Interpretation

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

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