Premium
Anticonvulsant effects of the BK‐channel antagonist paxilline
Author(s) -
Sheehan Jesse J.,
Benedetti Brett L.,
Barth Alison L.
Publication year - 2009
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1167.2008.01888.x
Subject(s) - picrotoxin , anticonvulsant , bk channel , antagonist , chemistry , epilepsy , pharmacology , potassium channel blocker , potassium channel , seizure threshold , medicine , anesthesia , endocrinology , neuroscience , psychology , receptor , biochemistry
Summary 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 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.