多药转运蛋白对癫痫大鼠脑内奥卡西平浓度的影响  

PGP and MRP are involved in the regulation of penetration of oxcarbazepine through blood-brain barrier in rat after pilocarpine induced seizures

作　　者：马爱梅[1] 张守文[2] 胡风云[1] 刘玉玺[2] 

机构地区：[1]山西省人民医院神经内科,太原030012 [2]山西医科大学附属第三医院神经内科

出　　处：《中国神经精神疾病杂志》2009年第12期726-729,共4页Chinese Journal of Nervous and Mental Diseases

基　　金：山西省青年科技研究基金资助项目(编号:2006021044)

摘　　要：目的观察多药转运蛋白家族的成员P-糖蛋白(P-glycoprotein,PGP)和多药耐药蛋白(multi-drugre-sistance associated protein,MRP)对匹罗卡品慢性癫痫大鼠模型海马内神经元细胞外液中奥卡西平浓度的影响,证明奥卡西平是否为PGP和MRP的底物,探讨PGP和MRP参与难治疗性癫痫耐药的机制。方法建立匹罗卡品慢性癫痫动物模型,将32只大鼠分为对照组、模型组、维拉帕米干预组、丙磺舒干预组(每组8只),于腹腔注射奥卡西平(80mg/kg)后30、60、90、120、150min,通过微透析及高效液相色谱技术,检测大鼠海马神经元细胞外液中的药物浓度。结果维拉帕米干预后,癫痫大鼠海马细胞外液中奥卡西平的浓度于给药后90～120min(1.26±0.09、0.93±0.10)明显高于模型组(0.87±0.06、0.66±0.04),两组比较有统计学差异(P<0.05);丙磺舒干预后60～150min,大鼠海马内细胞外液中奥卡西平的浓度(1.07±0.11、1.32±0.13、1.02±0.10、0.87±0.08)显著高于模型组(0.81±0.08、0.87±0.06、0.66±0.04、0.58±0.06)(P<0.05)。结论奥卡西平是PGP和MRP的底物,PGP和MRP能够选择性的将奥卡西平泵出血脑屏障外,降低癫痫病灶内的药物浓度,上述机制可能参与了难治性癫痫患者对奥卡西平产生耐药。Objective To study the effect of inhibitors of the muhidrug transporters including P-glycoprotein （PGP） and multi-drug resistance-associated protein （MRP） on the regulation of concentration of oxcarbazepine in the extra- cellular fluid of the hippocampus after pilocarpine induced seizures in rats. To investigate whether oxcarbazepine are sub- strate for PGP and MRP and whether brain expressions of PGP and MRP are involved in multidrug resistance mechanisms of refractory epilepsy. Methods The epileptic rats model were established by repeated peritoneal injection treatment with pi- locarpine. Thirty-two Wistar rats were divided into four groups ： control group, pilocarpine epileptic model group, verapamil treated group and probenecid treated group. At 30, 60, 90, 120 and 150 rain following systemic injection of oxcarbazepine （80 mg/kg）, dialysate was collected and the concentration of oxcarbazepiue in the extracellular fluid of hippocampus was determined by microdialysis and high-performance liquid chromatography technique. Results After systemic injection of oxcarbazepine , the concentration of oxcarbazepine in extracellular fluid of the hippocampus during 90 - 150 min （ 1.26 ± 0. 09,0. 93 ± 0. 10）were much higher in verapamil treated group than in pilocarpine epileptic model group （0. 87 ± 0, 06, 0.66 ±0.04 ） （ P 〈 0.05 ） and the concentration of oxearbazepine in the hippocampus during 60 - 150 rain （ 1.07 ± 0. 11, 1.32 ±0. 13,1.02±0. 10,0. 87±0. 08）were higher in probenecid treated group than in pilocarpine epileptic model group （0. 81 ± 0. 08,0. 87 ± 0. 06,0. 66 ± 0. 04,0. 58 ± 0. 06 ） （ P 〈 0. 05 ）. Conclusions Oxcarbazepine are substrates for PGP and MRP and,penetration of oxcarbazepine through blood-brain barrier are restricted by PGP and MRP. Increased expres- sions of PGP and MRP in brain maybe involved in the mechanisms of multidrug resistance of refractory epilepsy.

关 键 词：P-糖蛋白 多药耐药蛋白 奥卡西平 难治性癫痫 

分 类 号：R742.1[医药卫生—神经病学与精神病学]