Anticonvulsant effects of the BK-channel antagonist paxilline.
OBJECTIVE
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.


CONCLUSIONS
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.
Sheehan
Jesse J
JJ
Department of Biological Sciences and Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA.
Benedetti
Brett L
BL
Barth
Alison L
AL
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count / Q000379:methods; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000379:methods; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism; D010433:Pentylenetetrazole; D010852:Picrotoxin; D026902:Potassium Channel Blockers / Q000627:therapeutic use*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
D007211:Indoles; D010433:Pentylenetetrazole; D010852:Picrotoxin; D026902:Potassium Channel Blockers; D016760:Proto-Oncogene Proteins c-fos; C048220:paxilline