Development and pharmacologic characterization of the rat 6 Hz model of partial seizures.
Development and pharmacologic characterization of the rat 6 Hz model of partial seizures.
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DOI：
10.1111/epi.13764
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发表时间：
2017-06
期刊：
影响因子：
5.6
通讯作者：
Wilcox KS
中科院分区：
文献类型：
--
作者：
Metcalf CS;West PJ;Thomson KE;Edwards SF;Smith MD;White HS;Wilcox KS
小鼠6 Hz精神性癫痫发作模型是一种成熟的抗癫痫药物（ASD）临床前常用模型。尽管其广泛用于识别和区分小鼠中的新型ASD，但尚未开发出大鼠中的相应测定。我们建立了一种6 Hz的大鼠癫痫发作诱导方法，其癫痫发作行为与小鼠相似，包括点头、颌阵挛和前肢阵挛。使用Probit分析确定了在97%的大鼠（CC97）中激发这些癫痫发作行为的惊厥电流。在该模型中使用1.5×和2× CC97的刺激强度评估了许多原型ASD，这与小鼠6 Hz癫痫发作模型中使用的方法相当（例如，32和44 mA刺激强度）。评价的ASD包括卡马西平、氯巴占、氯硝西泮、艾司利卡西平、乙琥胺、依唑加滨、加巴喷丁、拉考沙胺、拉莫三嗪、左乙拉西坦、苯巴比妥、苯妥英、卢非酰胺、噻加滨、托吡酯和丙戊酸钠。获得每种化合物的中位有效剂量（ED 50）和中位毒性（运动损伤）剂量（TD 50）值。在1.5×CC97刺激强度和PI值> 1时有效的化合物包括氯巴占、乙琥胺、依唑加滨、左乙拉西坦、苯巴比妥和丙戊酸钠。在2×CC97刺激强度和PI值> 1时有效的化合物包括依佐加滨、苯巴比妥和丙戊酸钠。以与使用小鼠6 Hz模型相似的方式，大鼠6 Hz试验的开发将有助于抗癫痫药物的区分，以及耐药性癫痫慢性大鼠模型的研究设计和剂量选择。在较高刺激强度下具有可证实疗效的有限数量的已建立ASD表明，与小鼠6 Hz 44 mA模型一样，大鼠6 Hz癫痫发作模型可能是药物抗性癫痫发作的有用筛选工具。
The mouse 6 Hz model of psychomotor seizures is a well-established and commonly used pre-clinical model for antiseizure drug (ASD) discovery. Despite its widespread use both in the identification and differentiation of novel ASDs in mice, a corresponding assay in rats has not been developed. We established a method for 6 Hz seizure induction in rats, with similar seizure behaviors as those observed in mice including head nod, jaw clonus, and forelimb clonus. A convulsive current that elicits these seizure behaviors in 97% of rats (CC97) was determined using a Probit analysis. Numerous prototype ASDs were evaluated in this model using stimulus intensities of 1.5× and 2× the CC97, which is comparable to the approach used in the mouse 6 Hz seizure model (e.g., 32 and 44 mA stimulus intensities). The ASDs evaluated include carbamazepine, clobazam, clonazepam, eslicarbazepine, ethosuximide, ezogabine, gabapentin, lacosamide, lamotrigine, levetiracetam, phenobarbital, phenytoin, rufinamide, tiagabine, topiramate, and sodium valproate. Median effective dose (ED50) and median toxic (motor impairment) dose (TD50) values were obtained for each compound. Compounds that were effective at the 1.5×CC97 stimulus intensity at PI values > 1 included clobazam, ethosuximide, ezogabine, levetiracetam, phenobarbital, and sodium valproate. Compounds that were effective at the 2×CC97 stimulus intensity at PI values > 1 included ezogabine, phenobarbital, and sodium valproate. In a similar manner to use of the mouse 6 Hz model, development of a rat 6 Hz test will aid in the differentiation of antiseizure drugs, as well as in study design and dose selection for chronic rat models of pharmacoresistant epilepsy. The limited number of established ASDs with demonstrable efficacy at the higher stimulus intensity suggests that, like the mouse 6 Hz 44 mA model, the rat 6 Hz seizure model may be a useful screening tool for pharmacoresistant seizures.