四氢嘧啶类衍生物ZL-5015抗内毒素作用的实验研究  

Experimental study on anti-endotoxin activity of a tetrahydropyrimidine derivative,ZL-5015

作　　者：邱小惠[1] 林嘉[1] 余传林[1] 陈娜娜[1] 雷林生[1] 

机构地区：[1]南方医科大学药学院,广东广州510515

出　　处：《中国病理生理杂志》2015年第6期1137-1141,共5页Chinese Journal of Pathophysiology

基　　金：高等学校博士学科点专项科研基金(No.20114433110013)

摘　　要：目的:探讨1,3-二环戊基-1,2,3,6-四氢嘧啶-4,5-二甲酸二乙酯(ZL-5015)对内毒素攻击小鼠的保护作用及机制。方法:腹腔注射脂多糖(70 mg/kg)制备小鼠内毒素中毒死亡模型和内毒素血症模型。脂多糖(10mg/L)刺激小鼠腹腔巨噬细胞产生炎症相关细胞因子作为体外炎症模型。ELISA法检测细胞白细胞介素1β(IL-1β)、白细胞介素10(IL-10)和肿瘤坏死因子α(TNF-α)的含量。Real-time PCR检测细胞因子mRNA的表达水平。结果:ZL-5015(100和200 mg/kg)预防性灌胃给药能小幅提高内毒素中毒小鼠的存活率和存活时间,在中毒早期能降低内毒素血症小鼠血清中IL-1β和TNF-α的水平,提高IL-10的水平。体外实验表明,ZL-5015(10、20和40μmol/L)能抑制内毒素刺激的腹腔巨噬细胞IL-1β和TNF-α蛋白及mRNA的表达,促进IL-10蛋白及mRNA的表达。结论:四氢嘧啶类化合物ZL-5015能提高内毒素中毒小鼠的存活率和存活时间,但作用较弱,其作用机制可能与抑制促炎细胞因子IL-1β和TNF-α、促进抑炎细胞因子IL-10的表达有关。[ ABSTRACT] AIM：To investigate the protective effect of 1, 3-dicyclopentyl-1, 2, 3, 6-tetrahydropyrimidine-4, 5-dicarboxylic acid diethyl ester （ZL-5015） on lethal endotoxin-challenged mice and to explore the underlying mechanism. METHODS：Mouse model of lethal endotoxin challenge and endotoxemia were established by intraperitoneal administration of lipopolysaccharide （LPS） at a dose of 70 mg/kg to the C57BL/6J mice.Mouse peritoneal macrophages stimulated with LPS （10 mg/L） were used as an in vitro inflammatory model.The levels of interleukin-1β（ IL-1β） , interleukin-10 （ IL-10） and tumor necrosis factor-α（TNF-α） were measured by enzyme-linked immunosorbent assay （ELISA）.Real-time PCR was used to evaluate the mRNA expression of the cytokines.RESULTS：Prophylactic treatment of the mice with ZL-5015 （100 and 200 mg/kg, ig） slightly increased the survival rate, extended the survival time, decreased the serum levels of IL-1βand TNF-α, and increased the serum level of IL-10 in the early stage of endotoxemia as compared with model group.The results of in vitro study demonstrated that treatment of the endotoxin-stimulated mouse peritoneal macrophages with ZL-5015 （10, 20 and 40μmol/L） inhibited the expression of IL-1βand TNF-αat both mRNA and protein levels but promoted the expression of IL-10 at both mRNA and protein levels.CONCLUSION： The tetrahydropyrimidine derivative ZL-5015 shows a moderate anti-endotoxin effect by increasing the survival rate and extending the survival time of the mice challenged by endotoxin, which may result from inhibition of the expression of pro-inflammatory cytokines such as IL-1βand TNF-α, and promotion of the expression of anti-inflammatory cytokine IL-10.

关 键 词：四氢嘧啶类化合物 内毒素 白细胞介素1Β 白细胞介素10 肿瘤坏死因子α 

分 类 号：R962[医药卫生—药理学] R363[医药卫生—药学]