Z944, a Novel Selective T-Type Calcium Channel Antagonist Delays the Progression of Seizures in the Amygdala Kindling Model
Z944, a Novel Selective T-Type Calcium Channel Antagonist Delays the Progression of Seizures in the Amygdala Kindling Model
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DOI：
10.1371/journal.pone.0130012
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发表时间：
2015-08-14
期刊：
影响因子：
3.7
通讯作者：
Powell, Kim L.
中科院分区：
文献类型：
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作者：
Casillas-Espinosa, Pablo Miguel;Hicks, Ashleigh;Powell, Kim L.
颞叶癫痫（TLE）是最常见的耐药癫痫。目前的治疗是对症的，抑制癫痫发作，但对癫痫发生没有疾病修饰作用。我们研究了强效t型钙通道拮抗剂Z944在TLE杏仁核点燃模型中作为抗癫痫剂和抗点燃进展的作用。比较Z944 （5mg/kg、10mg/kg、30mg/kg和100mg/kg）在完全点燃大鼠（5次V级癫痫发作）中的抗癫痫效果，并与对照药、乙氧亚胺（ETX, 100mg/kg）和卡马西平（30mg/kg）进行比较。每只动物以随机方式接受7种治疗。确定六种药物后刺激引起的癫痫发作类型和持续时间。为了研究延迟点燃进程的影响，在每次点燃刺激前30分钟，幼稚动物接受Z944 (30mg/kg), ETX （100mg/kg）或车辆，最多30次刺激，每次刺激后记录癫痫发作类型和持续时间。药物治疗结束后，采用qPCR方法检测海马和杏仁核Ca(V)3.1、Ca(V)3.2和Ca(V)3.3 mRNA表达水平。与对照剂相比，Z944对完全点燃大鼠的癫痫发作没有明显的抑制作用。接受Z944的动物需要更多的刺激才能唤醒III类
Temporal lobe epilepsy (TLE) is the most common form of drug resistant epilepsy. Current treatment is symptomatic, suppressing seizures, but has no disease modifying effect on epileptogenesis. We examined the effects of Z944, a potent T-type calcium channel antagonist, as an anti-seizure agent and against the progression of kindling in the amygdala kindling model of TLE. The anti-seizure efficacy of Z944 (5mg/kg, 10mg/kg, 30mg/kg and 100mg/kg) was assessed in fully kindled rats (5 class V seizures) as compared to vehicle, ethosuximide (ETX, 100mg/kg) and carbamazepine (30mg/kg). Each animal received the seven treatments in a randomised manner. Seizure class and duration elicited by six post-drug stimulations was determined. To investigate for effects in delaying the progression of kindling, naive animals received Z944 (30mg/kg), ETX (100mg/kg) or vehicle 30-minutes prior to each kindling stimulation up to a maximum of 30 stimulations, with seizure class and duration recorded after each stimulation. At the completion of drug treatment, Ca(V)3.1, Ca(V)3.2 and Ca(V)3.3 mRNA expression levels were assessed in the hippocampus and amygdala using qPCR. Z944 was not effective at suppressing seizures in fully kindled rats compared to vehicle. Animals receiving Z944 required significantly more stimulations to evoke a class III (p