安运佳 王强 钱忆家 薛红 李若照 娄金波 刘运权

摘要：目的 探討平肝止痫复方联合卡马西平对难治性癫痫模型大鼠海马及颞叶皮质区多药耐药相关蛋白1（MRP1）、P糖蛋白（P-gp）表达的影响。方法 选择Wistar大鼠，采用颅内注射海人酸建立难治性癫痫大鼠模型，随机分为假手术组、模型组、卡马西平组（0.03 g/kg），平肝止痫复方组（4.80 g/kg），高、中、低剂量平肝止痫复方+卡马西平组（9.60+0.03 g/kg，4.80+0.03 g/kg，2.40+0.03 g/kg）。假手术组、模型组采用等体积蒸馏水灌胃，各组连续给药4周，RT-PCR检测海马及颞叶皮质区MRP1、P-gp mRNA 的表达;Western Blot检测（WB检测）海马及颞叶皮质区MRP1、P-gp蛋白的表达。结果 与假手术组比较，模型组海马区及颞叶皮质区的MRP1、P-gp mRNA含量及蛋白的表达均明显升高（P<0.01）;与模型组比较，平肝止痫复方联合卡马西平用药均能显著降低海马区及颞叶皮质区MRP1、P-gp mRNA含量及蛋白的表达（P<0.01，P<0.05）;与卡马西平组比较，平肝止痫复方联合卡马西平用药较好，其作用效果与给药剂量高低呈正相关。结论 平肝止痫复方联合卡马西平能够显著降低难治性癫痫大鼠MRP1、P-gp表达水平，逆转和降低海马区MRP1、P-gp蛋白的表达可能是平肝止痫复方联合卡马西平抗耐药性癫痫作用机制之一。

关键词：平肝止痫复方;卡马西平;难治性癫痫大鼠;耐药性蛋白

中图分类号：R285.5 文献标志码：A 文章编号：1007-2349（2021）04-0067-06

Effect of Pinggan Zhixian Compound Combined with Carbamazepine on the Expression of MRP1 and P-gp in Hippocampus and Temporal Lobe Cortex of Refractory Epilepsy Rats

AN Yun-jia1， WANG Qiang1， QIAN Yi-jia1， XUE Hong2， LI Ruo-zhao2， LOU Jin-bo2， LIU Yunquan1， 2

（1. Guizhou University of Traditional Chinese Medicine， Guiyang 550003， China， 2. The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine， Guiyang 550002， China）

【Abstract】Objective： To Study the effect of Pinggan Zhixian Compound combined with carbamazepine on the expression of multi-drug resistance related protein 1 （MRP1） and P-glycoprotein （P-gp） in the hippocampus and temporal lobe cortex of refractory epilepsy model rats. Methods： Wistar rats were selected and intracranial injection of kainic acid was used to establish a refractory epilepsy rat model. The rats were randomly divided into sham operation group， model group， carbamazepine group （0.03 g/kg）， and Pinggan Zhixian Compound group （4.80 g/kg）， high， medium， and low-dose Pinggan Zhi-epilepsy compound+carbamazepine group （9.60+0.03 g/kg， 4.80+0.03 g/kg， 2.40+0.03 g/kg）. The sham operation group and the model group were given intragastric administration with equal volume of distilled water. Each group was given continuous administration for 4 weeks. RT-PCR was used to detect the expression of MRP1 and P-gp mRNA in the hippocampus and temporal lobe cortex and Western Blot used to detect the hippocampus and temporal Expression of MRP1 and P-gp protein in temporal cortex. Results： Compared with those of the sham operation group， the MRP1， P-gp mRNA content and protein expression in the hippocampus and temporal lobe cortex of the model group were significantly increased （P<0.01）. Compared with those of the model group， the Pinggan Zhixian Compound combined with carbamazepine group could significantly reduce the MRP1， P-gp mRNA content and protein expression in the hippocampus and temporal lobe cortex areas （P<0.01， P<0.05）. Compared with the carbamazepine group， the Pinggan Zhixian Compound combined with carbamazepine group had a better drug effect， and its effect was positively correlated with the level of administration dose. Conclusion： Pinggan Zhixian Compound combined with carbamazepine can significantly reduce the expression levels of MRP1 and P-gp in refractory epilepsy rats. Reversing and reducing the expression of MRP1 and P-gp protein in hippocampus may be one of the mechanisms of anti-drug-resistant epilepsy of the combination of Pinggan Zhixian Compound and carbamazepine.

【Key words】Pinggan Zhixian Compound;carbamazepine;refractory epilepsy rats;drug resistance protein

癫痫是以脑神经元异常放电引起反复痫性发作为特征的一种慢性脑部疾病，全球癫痫患者高达6500万人，少部分患者进展成难治性癫痫[1-2]。临床上大约有三分之一的患者对抗癫痫药物（antiepileptic drug，AED）不敏感而使得癫痫发作不能得到有效控制，反复的癫痫发作导致神经元的坏死与凋亡、突触重塑，从而成为难治性癫痫（intractable epilepsy，IE）[3-5]。目前，阐明难治性癫痫的发病机制，预防和降低癫痫发作一直是癫痫研究的热点。

卡马西平作为癫痫的经典治疗药物，广泛的运用于临床及基础研究，课题组前期研究表明，平肝止痫复方对难治性大鼠具有显著的治疗效果[6-7]。在此基础上本次研究将探讨平肝止痫复方联合卡马西平及单用卡马西平对难治性癫痫大鼠的治疗效果，观察中药复方是否显著增强疗效。……