6 Hz角膜点燃耐药癫痫小鼠模型改良及3种中药方剂的作用

Modification of 6 Hz corneal kindled mouse model for drug-resistant epilepsy and its treatment by three traditional Chinese medicine prescriptions

耐药是癫痫治疗领域一大难题,而中药方剂可能有效治疗耐药癫痫。本研究建立改良的6 Hz角膜点燃耐药癫痫小鼠模型,验证其对4种抗癫痫药物的耐药情况,并利用该耐药癫痫模型对3种中药方剂进行药效学研究。研究发现:①80%C57BL/6J小鼠经过21天电流强度为44 mA的6 Hz角膜点燃刺激后被完全点燃,而相同刺激条件下的ICR小鼠和电流强度为24 mA的C57BL/6J小鼠均无法被完全点燃;②苯妥英钠(50 mg·kg^(-1))、丙戊酸钠(100 mg·kg^(-1))和拉莫三嗪(15 mg·kg^(-1))对6 Hz角膜点燃的C57BL/6J小鼠耐药癫痫发作没有明显作用,而左乙拉西坦(100 mg·kg^(-1))明显降低其发作等级(P<0.05)和大发作几率(P<0.05);③柴胡加龙骨牡蛎汤(9.36或28.08 g·kg^(-1))和天麻钩藤饮(14.82或44.46 g·kg^(-1))对6 Hz角膜点燃的C57BL/6J小鼠耐药癫痫发作没有明显作用,而风引汤(19.11 g·kg^(-1))显著降低动物发作等级(P<0.01)和大发作几率(P<0.05)。本研究结果表明,C57BL/6J小鼠6 Hz角膜点燃模型是潜在耐药癫痫模型,而风引汤对其有一定治疗作用,可能是临床治疗耐药癫痫的潜在中药方剂。

Drug-resistance is a challenge in the treatment of epilepsy, and traditional Chinese medicine（TCM） prescription may have a potential in therapy of the epilepsy. Here we established a modified 6 Hz corneal kindled mouse model of epilepsy, and verified its drug-resistance to four commonly used western medicines. We evaluated the efficacy of three classical TCM prescriptions in this drug-resistant epilepsy model. The results showed that：① most C57BL/6J mice with stimulation current intensity at 44 mA（8 out of 10） were fully kindled, while none ICR mice with stimulation current intensity at 44 mA or C57BL/6J mice with stimulation current intensity at 24 mA were fully kindled. Fully kindled mice exhibited epileptic electroencephalograms after 44 mA and 6 Hz corneal kindling stimulation and increased activation of astrocytes in the hippocampus（by staining the glial fibrillary acidic protein）;② 50 mg·kg^-1 phenytoin sodium, 100 mg·kg^-1 valproic acid sodium and 15 mg·kg^-1 lamotrigine had no significant effects on the drug-resistant seizures in 6 Hz corneal kindled C57BL/6J mice, while 100 mg·kg^-1 levetiracetam significantly reduced the seizure stage（P〈0.05） and incidence of generalized seizure（P〈0.05） in it;③ TCM prescriptions, Chai-Hu Plus Long-Gu Mu-Li decoction（9.36 or 28.08 g·kg^-1） and Tian-Ma Gou-Teng decoction（14.82 or 44.46 g·kg^-1）, had no significant effects on the drug-resistant seizures in 6 Hz corneal kindled C57BL/6J mice, while TCM prescription Feng-Yin decoction（19.11 g·kg^-1） significantly reduced both the seizure stage（P〈0.01） and incidence of generalized seizure（P〈0.05） in it. Thus, the modified 6 Hz corneal kindled C57BL/6J mouse model is an excellent drug-resistant epilepsy model, Feng-Yin decoction have antiepileptic effects on it, suggesting Feng-Yin decoction may be an effective TCM prescription for clinical treatment of drug-resistant epilepsy.