用Ro15-4513逆转氟西泮耐受性并观察GABA_A受体亚单位表达的影响  

Modification of GABAA Receptor Subunit Expression in Audiogenic Seizure Rat Cortex and Hippocampus Following Tolerance to Flurazepam and Reversal of Tolerance by Co- administration of Rol5-4513

作　　者：郭文[1] 王丽[1] 

机构地区：[1]北京大学第一医院儿科,北京100034

出　　处：《中国当代儿科杂志》2003年第5期412-416,共5页Chinese Journal of Contemporary Pediatrics

基　　金：国家自然科学基金资助项目(No.30170994)

摘　　要：目的苯二氮革类抗痫药长期应用,可使2/3病人产生抗惊厥作用耐受性。本研究探讨苯二氮(?)类抗惊厥药物的耐受性和用氟马西尼(Ro15-4513)逆转耐受性的受体分子机制。方法 一组大鼠腹腔注射氟西泮2周,产生有氟西泮耐受性而无依赖性的听源性惊厥大鼠模型。另一组大鼠于氟西泮用药第8天起,每天腹腔注射1次Ro15-4513,共7 d,观察对耐受性的影响;对照组腹腔注射同等体积的20％丙二醇。每组5只。用竞争性定量RT-PCR测定大鼠脑皮质运动区和海马区的GABAA受体α1、α3、α5、γ2L和γ2S亚单位mRNA的含量。结果 与对照组相比,氟西泮耐受组大鼠皮质运动区的α1亚单位下降24％,α3下降17％,α5上升33％,γ2L下降35％,γ2s下降45％,差异均有显著性(P<0.05或0.01);海马区的α1下降33％,γ2L下降35％,γ2s下降27％,与对照组比较差异均有显著性(P<0.05)。合用Ro15-4513组大鼠皮质运动区GABAA受体α1、α3、α5、γ2L和γ2s亚单位mRNA含量与对照组相比差异均无显著性(P>0.05);海马区α1、α5、γ2L和γ2s亚单位mRNA含量与对照组相比也同样差异无显著性(P>0.05)。结论听源性惊厥大鼠的氟西泮耐受机制与中枢GABAA受体α1、α3、α5、γ2L和γ2s亚单位mRNA皮质运动区含量的适应性改变有关。Ro15-4513通过影响皮质运动区和海马?Objective Some patients who have been administrated benzodizepine for a long period will develop medicine tolerance. This study aims to investigate the molecular mechanism underlying this tolerance to benzodiazepine and the reversal of this tolerance by Rol5-4513. Methods One group of audiogenic seizure rats was administrated flurazepam for two weeks (the flurazepam group), which resulted in tolerance without behavioral signs of withdrawal to flurazepam. Another group was co-administrated Rol5-4513 daily for 7 days from the eighth day of flurazepam treatment (the Rol5-4513 group) to observe the effect of Rol5-4513 on the tolerance to flurazepam. The control group was administrated the same volume of propylene glycol as in the flurazepam group or the Rol5-4513 group. GABAA receptor subunit α1, α3, α5, γ2L and 72S were assayed using quantitative competitive RT-PCR in rat FrPaM and hippocampus. Results In the flurazepam group the content of mRNA encoding for α1, α3, γ2L and 72s was all significantly decreased (by 24%, 17%, 35% and 45% respectively) in FrPaM, whereas that of α5 was significantly increased (by 33%) compared with the control group. In hippocampus, α1, γ2L,and γ2S mRNA contents were significantly decreased (by 33% , 35% and 27% respectively). In the Rol5-4513 group, no significant changes were found with α1, α3,α5, γ2L and 72s in FrPaM, and α1,α5, γ2L, and γ23 in hippocampus compared with the control group. Conclusions The accomodated change in GABAA receptor subunit α1 ,α3,α5, γ2L and γ2S in FrPaM and hippocampus may be associated with the mechanism for flurazepam tolerance in audiogenic seizure rats. Rol5-4513 can reverse the tolerance to flurazepam by affecting the modification of GABAA receptor subunit α1, α3, α5, γ2L, and γ2S subunit expression.

关 键 词：氟西泮 抗癫痫药 Ro15-4513 氟马西尼 苯二氮ZHUO类 

分 类 号：R965[医药卫生—药理学]