Anticonvulsant effects of the BK-channel antagonist paxilline

  • Epilepsia. 2009 Apr;50(4):711-20. doi: 10.1111/j.1528-1167.2008.01888.x.
Jesse J Sheehan  1 ,  Brett L Benedetti ,  Alison L Barth
Affiliations
  • 1. Department of Biological Sciences and Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA.
PMID: 19054419 DOI: 10.1111/j.1528-1167.2008.01888.x
Abstract

Purpose: Mutations that enhance currents through the CA(2+)- 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 gamma-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.

Products