难治性癫痫患者内皮细胞中多药耐药基因的过表达。

Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy.

作者信息

Dombrowski S M, Desai S Y, Marroni M, Cucullo L, Goodrich K, Bingaman W, Mayberg M R, Bengez L, Janigro D

机构信息

Department of Neurological Surgery, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

出版信息

Epilepsia. 2001 Dec;42(12):1501-6. doi: 10.1046/j.1528-1157.2001.12301.x.

DOI:10.1046/j.1528-1157.2001.12301.x

PMID:11879359

Abstract

PURPOSE

It has been suggested that altered drug permeability across the blood-brain barrier (BBB) may be involved in pharmacoresistance to antiepileptic drugs (AEDs). To test this hypothesis further, we measured multiple drug resistance (MDR) gene expression in endothelial cells (ECs) isolated from temporal lobe blood vessels of patients with refractory epilepsy. ECs from umbilical cord or temporal lobe vessels obtained from aneurysm surgeries were used as comparison tissue.

METHODS

cDNA arrays were used to determine MDR expression. MDR protein (MRP1) immunocytochemistry and Western blot analysis were used to confirm cDNA array data.

RESULTS

We found overexpression of selected MDR and significantly higher P-glycoprotein levels in "epileptic" versus "control" ECs. Specifically, MDR1, cMRP/MRP2, and MRP5 were upregulated in epileptic tissue, whereas Pgp3/MDR3 levels were comparable to those measured in comparison tissue. The gene encoding cisplatin resistance--associated protein (hCRA-alpha) also was overexpressed in epileptic tissue. Immunocytochemical analysis revealed that MDR1 immunoreactivity was localized primarily in ECs; MRP1 protein levels also were significantly higher in epileptic tissue.

CONCLUSIONS

Complex MDR expression changes may play a role in AEDs pharmacoresistance by altering the permeability of AEDs across the BBB.

摘要

目的

有人提出，药物透过血脑屏障（BBB）的通透性改变可能与对抗癫痫药物（AEDs）的耐药性有关。为了进一步验证这一假说，我们测量了从难治性癫痫患者颞叶血管分离的内皮细胞（ECs）中多药耐药（MDR）基因的表达。来自脐带或动脉瘤手术中获取的颞叶血管的ECs用作对照组织。

方法

使用cDNA阵列来确定MDR的表达。采用MDR蛋白（MRP1）免疫细胞化学和蛋白质印迹分析来证实cDNA阵列数据。

结果

我们发现在“癫痫”ECs中，所选MDR的表达上调，且P-糖蛋白水平显著高于“对照”ECs。具体而言，MDR1、cMRP/MRP2和MRP5在癫痫组织中上调，而Pgp3/MDR3水平与对照组织中的测量值相当。编码顺铂耐药相关蛋白（hCRA-α）的基因在癫痫组织中也过表达。免疫细胞化学分析显示，MDR1免疫反应性主要定位于ECs；MRP1蛋白水平在癫痫组织中也显著更高。