左乙拉西坦和托吡酯对癫大鼠脑P-糖蛋白表达的影响

Influence of Levetiracetam and Topiramate on P-glycoprotein expression at brain in epileptic rats

目的研究左乙拉西坦(LEV)和托吡酯(TPM)对癫大鼠脑P-糖蛋白(P-gp)表达的影响。方法将海人酸1.5μg(3μl)注射至SD大鼠海马制作癫模型(癫组),对照组大鼠海马注射3μl生理盐水(NS)。将癫组(18只)和对照组(15只)大鼠分别随机分为LEV、TPM和NS亚组(每亚组6只、5只),各亚组大鼠予相应药物(LEV50mg/kg、TPM40mg/kg、等体积NS)灌胃,每天1次,共30d。采用免疫组化EnVi-sion染色法检测大鼠颞叶、海马P-gp表达水平,采用LeicaQwin图像分析系统中平均整合灰度(MIB)值对P-gp表达水平进行半定量分析。结果癫各亚组大鼠颞叶和海马P-gp表达水平(MIB值)均显著高于其相应对照亚组(P<0.05～0.001);对照亚组中,LEV和TPM组与NS亚组间P-gp表达水平比较,差异无统计学意义;在癫组中,TPM亚组P-gp表达水平显著高于NS亚组(1550.3±371.9vs1049.7±282.8,P=0.004);而LEV亚组与NS亚组差异无统计学意义(1285.1±340.3vs1049.7±282.8,P=0.172)。结论癫发作可诱导大鼠脑P-gp高表达;TPM可诱导癫大鼠脑P-gp表达,而LEV不诱导P-gp表达,这可能是LEV治疗部分难治性癫患者有效的原因之一。TPM和LEV不增加正常大鼠脑P-gp表达。

Objective To investigate the influence of Levetiracetam （LEV） and Topiramate （TPM） on Pglycoprotein （P-gp） expression at brain in the epileptic rats. Methods The epileptic rat models were made with 1.5 μg（3 μl） Kainic acid stereotaxic injected into male SD rats＇ hippocampi（ epilepsy group） and the control group rats Were injected with-3 μl normal saline （NS）. The rats in epilepsy group（ 18 rats） and control group（ 15 rats） were randomized into TPM, LEV and NS subgroups （ 6 or 5 rats for each subgroup） to receive once-daily orally feeding of TPM（50 mg/kg）, LEV（40 mg/kg） and NS（same amount NS） for 30 d. Immunohistochemistry （EnVision） was used to measure the level of P-gp exprssion in the rats brain. The level of P-gp expression was semi-quantitatively analyzed by mean integrated blue （MIB） value in Leica Qwin imaging analysis ＆ measuring system. Results The expression levels（ MIB value） of P-gp in hippocampus and temporal lobe in epilepsy subgroups were significantly higher than those in the corresponding control subgroups （P 〈 0.05 -0. 001 ）. In control group, no significant differences of expression levels of P-gp were observed in LEV, TPM and NS subgroups. In epilepsy group, the expression levels of P-gp in TPM group was increased significantly compared with that in NS subgroup （ 1550.3 ± 371.9 vs 1049. 7 ± 282. 8, P = 0. 004） and there was no significant difference between LEV subgroup and NS subgroup （ 1285.1 ±340.3 vs 1049.7 ± 282.8, P = 0. 172）. Conclusions Seizures induce overexpression of P-gp at brain in the rats. TPM may enhance the expression of P-gp in epileptic rats brain but LEV do not. It may contributes to LEV antiepileptic efficacy in the part patients with pharmacoresistant epilepsy. The expression of P-gp at brain in normal rats is not significantly increased by TPM or LEV.