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 Ro15-4513

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

Abstract:

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.