新型大麻制剂O-1602和大麻二酚对DSS诱导的小鼠结肠炎的抗炎作用及其机制  

Roles of novel cannabinoid chemicals O-1602 and cannabidiol in DSS-induced mouse colitis

作　　者：冯雅静[1] 李永渝[1] 林旭红[1] 李琨[1] 余良英[1] 曹明华[1] 徐菁[1] 

机构地区：[1]同济大学医学院病理生理教研室,同济大学消化系统疾病研究所,上海200092

出　　处：《中国病理生理杂志》2012年第8期1441-1447,共7页Chinese Journal of Pathophysiology

基　　金：国家自然科学基金资助项目(No.30971168;No.81141050)

摘　　要：目的:研究新型大麻类制剂O-1602和大麻二酚(CBD)对硫酸葡聚糖钠(DSS)诱导的小鼠实验性结肠炎的抗炎作用,并通过测定p38丝裂原活化蛋白激酶(MAPK)的活化程度,探讨其可能的作用机制。方法:对C57BL/6小鼠给予含4%DSS的饮用水连续饮用7 d,建立实验性结肠炎模型。造模期间分别给小鼠腹腔注射O-1602(5 mg/kg)、CBD(1 mg/kg)或p38 MAPK抑制剂SB203580(5μmol/kg)。造模结束后用结肠炎评分系统对各组结肠炎局部情况进行评估;同时检测血浆中肿瘤坏死因子α(TNF-α)、白细胞介素6(IL-6)和细胞因子诱导的中性粒细胞趋化因子1(CINC-1)的水平(ELISA法),以及肺组织髓过氧化物酶(MPO)活性,以评价各处理组结肠炎的炎症反应情况;采用Western blotting法检测结肠组织p38及p-p38蛋白表达水平;免疫组化方法检测结肠G蛋白偶联受体55(GPR55)的表达。结果:O-1602和CBD能够改善小鼠实验性结肠炎的病理损害,降低血浆TNF-α、IL-6和CINC-1的水平以及肺组织MPO的活性(P<0.05);O-1602、CBD以及SB203580处理组结肠组织,p38磷酸化程度较结肠炎组显著降低(P<0.05);免疫组化提示小鼠结肠GPR55受体表达较少,主要分布在黏膜下层,结肠炎时GPR55表达变化不明显。结论:GPR55在小鼠结肠有较少表达,揭示O-1602和CBD能够减轻DSS诱导的小鼠结肠炎炎症反应,其作用机制可能与抑制p38 MAPK信号通路有关。To investigate the roles of 0 -1602 and cannabidiol （CBD） in dextran sulfate sodium （DSS） -induced mouse colitis. METHODS： The model of colitis was induced in C57BL/6 mice by drinking water con- taining 4% DSS for 7 days. The model mice were treated with O - 1602 （5 mg/kg）, CBD （ 1 mg/kg） or SB203580 [ an inhibitor of p38 mitogen - activated protein kinase （MAPK） at dose of 5 μmol,/kg]. A colitis scoring system was used to e- valuate the colon local lesion, and the systemic inflammatory responses were observed by detecting the plasma levels of tumor necrosis factor et （TNF -or）, interleukin 6 （IL -6） and cytokine -induced neutrophil chemoattractant 1 （CINC - 1 ）, and the activity of myeloperoxidase （MPO） in the lung tissues. The expression of G protein - coupled receptor 55 （GPR.55） was detected by the method of immunohistochemistry. The expression of p38 and phosphorylated p38 （p- p38） in colon tissues was determined by Western blotting. RESULTS ： O - 1602 and CBD improved the pathological changes in the mice with DSS - induced colitis and decreased the plasma levels of TNF - et, IL - 6 and CINC - 1, and the activity of MPO in the lung tissues （P 〈 0.05）. Lower expression of p -p38 was observed after treatment with 0 - 1602, CBD and SB203580 （P 〈 0.05）. The expression of GPR55 was mainly in the submucosa of mouse colon tissues. CONCLUSION： 0 -1602 and CBD show protective effect on the mice with experimental colitis, and the anti -inflammatory roles of 0 - 1602 and CBD are related to the inhibition of p38 MAPK. The expression level of GPR55 in the submucosa of mouse colontissue is low.

关 键 词：炎症性肠病 大麻素类 P38 MAPK信号通路 G蛋白偶联受体55 

分 类 号：R363.2[医药卫生—病理学]