Anticonvulsant activity of BmK AS, a sodium channel site 4-specific modulator.
The anticonvulsant activity of BmK AS, a sodium channel site 4-selective modulator purified from scorpion venom (Buthus martensi Karsch), was investigated in unanesthetized rats with acute pentylenetetrazole (PTZ)- and pilocarpine-induced seizures. Rats were microinjected in the CA1 region with either saline or BmK AS, followed by epileptogenic doses of PTZ or pilocarpine 30 minutes later. The anticonvulsant efficacy of BmK AS in PTZ- or pilocarpine-evoked seizure-like behavior and cortical epileptiform EEG activity was assessed. Intrahippocampal injections of BmK AS (0.05-1 μg in 1 μL) produced dose-dependent anticonvulsant activity in the PTZ model, suppressing seizure-associated behavior and reducing both the number and duration of high-amplitude, high-frequency discharges (HAFDs) on the EEG. In contrast, BmK AS did not affect the epileptiform EEG in the pilocarpine model over the same dose range, although it did increase the latency to status epilepticus onset and slightly, but significantly, reduced the seizure score. In summary, our results demonstrate that the sodium channel site 4-selective modulator BmK AS is an effective inhibitor of PTZ- but not pilocarpine-induced acute seizures. These results indicate that BmK AS may serve as a novel probe in exploring the role of different sodium channel subtypes in an epileptogenic setting and as a potential lead in developing antiepileptic drugs specifically for the therapy of sodium channel site 4-related epilepsy.
Laboratory of Neuropharmacology and Neurotoxicology, Shanghai University, Shanghai, People's Republic of China.
Rong
R
Zhao
Chun-Chun
CC
Weng
Qi
Q
Feng
Lulan
L
Chen
Xu-Ying
XY
Zhang
Hong-Yan
HY
Zhu
Yun
Y
Wang
Yong-Hua
YH
Ji
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000187:drug effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010433:Pentylenetetrazole / Q000633:toxicity; D010455:Peptides / Q000494:pharmacology*; D010862:Pilocarpine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D012604:Scorpion Venoms / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
D000927:Anticonvulsants; C119407:BmK AS polypeptide; D003292:Convulsants; D010455:Peptides; D012604:Scorpion Venoms; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D010862:Pilocarpine; D013779:Tetrodotoxin; D014635:Valproic Acid; D010433:Pentylenetetrazole