不同剂量(+)-2-(1-羟基-4-环己酮)乙基咖啡酸酯对大鼠关节炎模型和全血炎症模型的药效学研究  

Effects of( +)-2-( 1-hydroxyl-4-oxocyclohexyl) ethyl caffeate at different doses on rat arthritis model and whole blood inflammation model

作　　者：杨文 刘远儒 李洪林[1] 王蕊[1] YANG Wen;LIU Yuan-ru;LI Hong-lin;WANG Rui(Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China)

机构地区：[1]上海市新药设计重点实验室,华东理工大学药学院,上海200237

出　　处：《中国病理生理杂志》2018年第12期2247-2254,共8页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.21173076);国家重点研发计划(No.2016YFA0502304);NSFC-广东联合基金超级计算科学应用研究专项(No.U1501501).

摘　　要：目的:对(+)-2-(1-羟基-4-环己酮)乙基咖啡酸酯(HOEC)在大鼠关节炎模型上进行药效学评价,并利用大鼠全血花生四烯酸(AA)代谢模型,探究引起HOEC对关节炎的非剂量依赖性治疗作用的可能机理。方法:(1)采用大鼠胶原诱导性关节炎(CIA)模型,研究3个不同剂量的HOEC对CIA的治疗情况,并用免疫组化方法检测关节组织中胞质磷脂酶A_2(cPLA_2)、5-脂氧合酶(5-LOX)和环氧合酶2 (COX-2)的表达水平;(2) ELISA检测HOEC和其体内代谢物咖啡酸对大鼠全血AA代谢模型中代谢产物的作用。结果:(1) HOEC对大鼠CIA有治疗作用,但高剂量(10 mg/kg)组的治疗效果不如低(1 mg/kg)和中剂量(3 kg/kg)组;(2) HOEC对大鼠关节组织中cPLA2、5-LOX和COX-2的表达水平均有抑制作用;(3) HOEC对大鼠全血AA代谢模型中LOX和COX通路的代谢产物均有抑制作用,而咖啡酸对这些代谢产物的抑制作用弱于HOEC。结论:HOEC对大鼠CIA模型的抗炎作用可能与抑制关节组织中cPLA_2、5-LOX和COX-2的表达有关; HOEC对治疗大鼠CIA的非剂量依赖现象可能与其代谢产物咖啡酸对AA代谢产物生成的抑制作用弱于HOEC有关。AIM:To evaluate the pharmacodynamics of(+)-2-(1-hydroxyl-4-oxocyclohexyl)ethyl caffeate(HOEC),and to explore the possible causes of non-dose-dependent effects of HOEC on collagen-induced arthritis(CIA)rats using the arachidonic acid(AA)metabolic model in rat whole blood.METHODS:The rat CIA model was used to study the treatment with HOEC at3doses.The expression of cytoplasmic phospholipase A2(cPLA2),5-lipoxygenase(5-LOX)and cyclo-oxygenase-2(COX-2)was assayed by immunohistochemical method.The effects of HOEC and its in vivo metabolite caffeic acid(CA)on AA metabolite in rat whole blood were measured by ELISA.RESULTS:HOEC had a therapeutic effect on rat CIA,but the curative effect at low dose and middle dose(1and3mg/kg)was better than that at high dose(10mg/kg).The expression levels of cPLA2,5-LOX and COX-2in joint tissues were decreased.HOEC inhibited the metabolites of LOX and COX pathways in the rat whole blood AA metabolic model,while the inhibitory effect of CA on these metabolites was weaker than that of HOEC.CONCLUSION:The anti-inflammatory effect of HOEC on rat CIA may be associated with the inhibition of cPLA2,5-LOX and COX-2expression in the joint tissues.The non-dose-dependent therapeutic effect of HOEC on rat CIA may due to the weaker inhibitory activity of CA on AA metabolic model in rat whole blood than that of HOEC.

关 键 词：(+)-2-(1-羟基-4-环乙酮)乙基咖啡酸酯 胶原诱导性关节炎 花生四烯酸 

分 类 号：R684.3[医药卫生—骨科学] R363[医药卫生—外科学]