用Ro 15-4513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 Ro 15-4513

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：《儿科药学杂志》2003年第2期1-5,共5页Journal of Pediatric Pharmacy

基　　金：国家自然科学基金(30170994)

摘　　要：目的:探讨苯二氮(艹卓)类抗惊厥耐受性和用Ro 15-4513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。另一组大鼠于用药第8d,每天加用腹腔注射一次Ro 15-4513,观察对耐受性的影响。用竞争性定量RT-PCR测定大鼠脑皮质运动区和海马区的GABA_A受体α1、α3、a5、γ2L和γ2S亚单位mRNA的含量。结果: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％;海马区的α1下降33％,γ2L下降35％,γ2S下降27％,与对照组比较均有显著性差异。合用Ro 15-4513组大鼠皮质运动区GABA_A受体α1、α3、α5、γ2L和α2S亚单位mRNA含量与对照组相比均无显著性差异;海马区α1、α5、γ2L和γ2S亚单位mRNA含量与对照组相比也同样都无显著性改变。结论:听源性惊厥大鼠的氟西泮耐受机制与中枢GABA_A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区部分α及γ2亚单位的表达而产生逆转听源性惊厥大鼠对氟西泮耐受性的效应。Objective: To investigate (he molecular mechanism underlying the tolerance to benzodiazepine and reversal of ihe tolerance by Ro 15-4513. Methods: One group of audiogenic seizure rats were administrated with flurazepam for two weeks, which resulted in tolerance to flurazepam, in the absence of behavioral signs of withdrawal. Another rat group was co-administrated with one dose of Ro 15-4513 daily from the 8th day of the chronic flurazepam treatment to observe the effect of Rol5-4513 on the tolerance to flurazepam. GABAA receptor subunit α1、α3、α5、γ2L and γ2S were assayed using quantitative competitive RT-PCR in rat FrPaM and hippocampus. Results: In flurazepam group the content of mRNA encoding for α1、α3、α5、γ2Land γ2S were all significantly decreased (24%, 17% , 35%and45% respectively) in FrPaM, whereas that of α5 was significantly increased (33% ) compared with the control. In hippocampus, α1, γ2L, and γ2S mRNA content was significantly decreased (33%, 35% and 27% respectively). In Ro 15-4513 group, no significant change was found with α1、α3、α5、γ2Land γ2S in FrPaM, and α1、α3、α5、γ2L and γ2S in hippocampus, which was different from flurazepam group. Conclusions: The accommodated 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 rat. Ro 15-4513 could reverse the tolerance to flurazepam and affected the modification of GABAA receptor subunit α1、α3、α5、γ2Land γ2S subunil expression.

关 键 词：Ro15-4513 氟西泮 GABAA受体 亚单位 表达 苯二氮卓类 药物耐受性 抗惊厥药 

分 类 号：R971.6[医药卫生—药品]