富马酸二甲酯对抗β淀粉样蛋白诱导的大鼠星形胶质细胞的氧化应激反应

摘要

目的 研究富马酸二甲酯(dimethylfumarate,DMF)通过调节核转录因子-E2相关因子2(Nrf2)对β淀粉样蛋白(A8)诱导的氧化应激的防御作用和作用机制.方法 将大鼠星形胶质细胞分为Aβ组、DMF组、Nrf2组和Nrf2+DMF组.采用RT-PCR检测各组细胞Nrf2、醌氧化还原酶1(Nqo1)、血红素氧化酶1(HO-1)和Kelch样环氧氯丙烷相关蛋白1(Keap1) mRNA表达水平,采用Western blot检测组蛋白去乙酰酶(HDAC)表达水平.结果 Nrf2组较Aβ组、Nrf2+ DMF组较DMF组Nrf2、Nqo1和HO-1 mRNA表达显著降低(P＜0.05).DMF组较Aβ组Nrf2、Nqo1和HO-1 mRNA表达显著升高,Keap1 mRNA表达显著降低(P＜0.05).Nrf2+ DMF组较Nrf2组Keap1 mRNA表达显著降低(P＜0.05).DMF组较Aβ组HDAC表达显著降低(6.41±0.43 vs9.01±1.54,P＜0.05),Nrf2+ DMF组较Nrf2组HDAC表达显著降低(6.72±0.30 vs8.76±0.74,P＜0.05).结论 DMF可能通过抑制HDAC表达,提高Nrf2水平,从而减弱Aβ诱导的大鼠星形胶质细胞的氧化应激反应.%Objective To study the effect of dimethyl fumarate (DMF) on Aβ-induced oxidative stress by regulating NF-E2-related factor 2 (Nrf2) expression and its mechanism.Methods Rat astrocytes were divided into Aβ group,DMF group,Nrf2 group and Nrf2 +DMF group.Expressions of Nrf2,Nqo1,Ho-1,Keap1 mRNA and HDAC were detected by RT-PCR and Western blot respectively.Results The expression levels of Nrf2,Nqo1 and HO-1 mRNA were significantly lower in Nrf2 group and Nrf2+DMF group than in Aβ group and DMF group (P＜0.05) and were significantly higher in DMF group than in Aβ group (P＜0.05) while the expression level of Keap1 mRNA was significantly lower in DMF group and Nrf2+DMF group than in Aβ group and Nrf2 group (P＜0.05).The expression level of HDAC was significantly lower in DMF group and Nrf2+DMF group than in Aβ group and Nrf2 group (6.41±0.43 vs 9.01±1.54,P＜0.05;6.72±0.30 vs 8.76± 0.74,P＜0.05).Conclusion DMF increases the Nrf2 expression by inhibiting the HDAC expression,thus reducing Aβ-induced oxidative stress in rat astrocytes.