Anticonvulsant effects of the BK-channel antagonist paxilline
Anticonvulsant effects of the BK-channel antagonist paxilline
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DOI：
10.1111/j.1528-1167.2008.01888.x
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发表时间：
2009-04-01
期刊：
影响因子：
5.6
通讯作者：
Barth, Alison L.
中科院分区：
文献类型：
--
作者：
Sheehan, Jesse J.;Benedetti, Brett L.;Barth, Alison L.
在啮齿动物模型和人类中，增强通过Ca 2+和电压门控K+通道BK（Slo，maxiK，KCNMA 1）的电流的突变与癫痫发作疾病相关。以前我们已经发现癫痫发作本身诱导BK通道的功能获得，这与新皮层神经元的兴奋性升高有关。在这项研究中，我们试图检查BK通道拮抗剂的施用是否具有体内抗惊厥活性。注射γ-氨基丁酸（GABA）（A）拮抗剂印防己毒素或戊四唑。在诱导初始癫痫发作后24小时，在BK通道拮抗剂paxilline或生理盐水的存在下，对动物再次注射化学惊厥剂。评估强直-阵挛性发作的存在和持续时间。腹腔注射帕西林足以消除印防己毒素处理动物的强直-阵挛性发作。Paxilline可减少戊四唑注射动物的癫痫发作持续时间和强度，BK通道拮抗剂Paxilline在印防己毒素和戊四唑癫痫发作模型中均具有显著的抗惊厥活性，这种作用可能与先前在体外新皮层神经元中观察到的BK通道的惊厥依赖性功能获得有关。
Mutations that enhance currents through the Ca2+- 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.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.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.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.