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Anticonvulsant effects of the BK-channel antagonist paxilline

  1. Jesse J. Sheehan,
  2. Brett L. Benedetti,
  3. Alison L. Barth

Article first published online: 19 NOV 2008

DOI: 10.1111/j.1528-1167.2008.01888.x

Issue

Epilepsia

Epilepsia

Volume 50, Issue 4, pages 711–720, April 2009

Additional Information

How to Cite

Sheehan, J. J., Benedetti, B. L. and Barth, A. L. (2009), Anticonvulsant effects of the BK-channel antagonist paxilline. Epilepsia, 50: 711–720. doi: 10.1111/j.1528-1167.2008.01888.x

Author Information

  1. Department of Biological Sciences and Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania, U.S.A.

*Address correspondence to Alison L. Barth, Department of Biological Sciences and Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, PA 15213, U.S.A. E-mail: barth@cmu.edu

Publication History

  1. Issue published online: 3 APR 2009
  2. Article first published online: 19 NOV 2008
  3. Accepted August 25, 2008; Early View publication November 19, 2008.

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Keywords:

  • Anticonvulsant;
  • Abnormal excitability;
  • Sensitization;
  • Channelopathy;
  • BK;
  • MaxiK

Summary

Purpose:  Mutations that enhance currents through the Ca2+- and voltage-gated K+ channel BK (Slo, maxiK, KCNMA1) have been associated with seizure disorders in both rodent models and humans. Previously we have found that seizures themselves induce a gain-of-function in BK channels that is associated with elevated excitability in neocortical neurons. In this study, we sought to examine whether administration of BK-channel antagonists possess anticonvulsant activity in vivo.

Methods:  Seizures were induced in animals by intraperitoneal (i.p.) injection of the γ-aminobutyric acid (GABA)A antagonists picrotoxin or pentylenetetrazole. Twenty-four hours following induction of the initial seizure episode, animals were reinjected with chemoconvulsant in the presence of the BK-channel antagonist paxilline or saline. The presence and duration of tonic–clonic seizures were evaluated.

Results:  Intraperitoneal injection of paxilline was sufficient to eliminate tonic–clonic seizures in picrotoxin-treated animals. Paxilline reduced seizure duration and intensity in pentylenetetrazole-injected animals.

Discussion:  The BK-channel antagonist paxilline possesses significant anticonvulsant activity in both picrotoxin and pentylenetetrazole seizure models, an effect that may be related to the seizure-dependent gain-of-function in BK channel previously observed in neocortical neurons in vitro.

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