Anticonvulsant effects of the BK-channel antagonist paxilline.

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.

• Authors: Jesse J Sheehan, Brett L Benedetti, Alison L Barth
• Journal: Epilepsia (Epilepsia) Vol. 50 Issue 4 Pg. 711-20 (Apr 2009) ISSN: 1528-1167 [Electronic] United States
• PMID: 19054419 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Indoles
• Potassium Channel Blockers
• Proto-Oncogene Proteins c-fos
• Picrotoxin
• paxilline
• Pentylenetetrazole

Topics

• Analysis of Variance
• Animals
• Animals, Newborn
• Cell Count (methods)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Electroencephalography (methods)
• Hippocampus (drug effects, metabolism)
• Indoles (therapeutic use)
• Mice
• Mice, Inbred C57BL
• Neocortex (drug effects, metabolism)
• Pentylenetetrazole
• Picrotoxin
• Potassium Channel Blockers (therapeutic use)
• Proto-Oncogene Proteins c-fos (metabolism)
• Psychomotor Performance (drug effects)
• Seizures (chemically induced, drug therapy, pathology, physiopathology)
• Time Factors