瑞巴匹特预防葡聚糖硫酸酯钠诱发的小鼠结肠炎疗效观察及作用机制初探

Preventive effect of rebamipide enema on dextran sulfate sodium induced murine colitis and its mechanism

目的近年氧自由基在溃疡性结肠炎(UC)发病过程中作用受到关注,一种新型的黏膜保护剂瑞巴匹特被认为具有清除氧自由基的作用,有望成为治疗溃疡性结肠炎的新药物。本文观察瑞巴匹特灌肠和灌胃治疗葡聚糖硫酸酯钠(DSS)诱发的小鼠结肠炎效果并探讨可能的作用机制。方法 3%DSS予8周龄雄性BALB/c小鼠自由饮用7 d制成小鼠结肠炎模型。予DSS前5 d开始瑞巴匹特(45 mg/kg/d)灌肠或灌胃治疗直到造模结束,处死小鼠取结肠组织,测量小鼠体重、结肠长度,进行大体和病理评分,分光光度法测定髓过氧化物酶、丙二醛含量,免疫组化法测定核因子κB(NFκB)表达水平,RT-PCR法测定过氧化物酶体增殖体激活受体γ(PPARγ)mRNA表达。结果与安慰剂对照组比较,瑞巴匹特灌肠和灌胃治疗组小鼠大体和病理评分显著改善,髓过氧化物酶活性、丙二醛含量、NFκB活性明显降低,PPARγmRNA的表达显著升高。结论瑞巴匹特可有效预防DSS诱发的小鼠结肠炎,其抑制炎症作用至少部分与清除氧自由基,从而维持局部PPARγ表达和抑制NFκB活性有关。

Objective Although the pathophysiology of ulcerative colitis（UC） is not clear,previous reports suggested overproduction of free oxygen radicals is involved in the pathogenesis of this disease.Rebamipide as a radical scavenging agent may be useful as a new promising therapeutic medicine for UC.We designed the study to evaluate the preventive effect of rebamipide on dextran sulfate sodium（DSS） induced murine colitis and probe into its protective mechanism.Methods Experimental colitis was induced in BALB/c mice with 3% DSS in drinking water for 7 days.Rebamipide（45mg/kg/d） was administered by enema or gavage since 5 days before the beginning of DSS induction.At the end of experimental period,the mice were sacrificed.Body weight,colon length,macroscopic score,and histological score were evaluated.MPO,MDA were assayed by spectrophotometry.NF-κB activity was assayed by immunohistochemistry,and the PPARγ mRNA transcripts levels were detected by reverse transcription polymerase chain reaction（RT-PCR）.Results Evaluating from body weight,colon length,macroscopic score and histological score,rebamipide significantly improved the inflammation of the colon compared with DDS-induced colitis group.Rebamipide also significantly decreased the MPO activity,MDA content and NF-κB activity,and increased PPARγ expression in rectal-sigmoid tissue.Conclusion Rebamipide is effective against DSS-induced murine colitis.The mechanism of preventive effect of rebamipide is attributable to oxygen radical scavenging as well as interfering with inhibition of NF-κB activity and enhancement of PPAR γ expression.