大麻素受体1抑制剂促进线粒体生物发生改善脓毒症小鼠肠麻痹的机制研究

Mechanism of Cannabinoid Receptor 1 Inhibitor Promoting Mitochondrial Biogenesis to Improve Intestinal Paralysis in Septic Mice

目的观察大麻素受体1(cannabinoid receptor 1,CB1)抑制剂AM251是否可以促进肠神经元线粒体生物发生,改善脓毒症小鼠肠动力。方法60只C57小鼠随机分sham组、LPS组和AM251组,每组各20只。LPS组在腹腔注射LPS 30mg/kg建立小鼠脓毒症模型。AM251组在建立脓毒症模型后30min腹腔注射AM2513mg/kg。48h后按分组分别测定小鼠肠动力变化、线粒体生物发生相关蛋白的变化及结肠神经元线粒体数量和体积的变化。结果与sham组比较,CB1受体抑制剂AM251可明显改善小鼠肠动力,降低肠运输时间(325.0s vs 187.5s,P=0.006),增加小肠推进率(47%vs 70%,P<0.001),缩短结肠排珠时间(375s vs 82s,P<0.001);同时增加结肠线粒体生物发生相关蛋白Nrf-1(0.414 vs 0.807,P=0.003)、TFAM(0.739 vs 0.332,P=0.003)、COX-Ⅳ(0.371 vs 0.817,P=0.001)的表达;增加结肠肠神经元线粒体的数量(P=0.015)和体积(P=0.004)。结论CB1受体抑制剂可以促进肠神经元线粒体生物发生,改善脓毒症小鼠肠动力。

Objective To observe whether the(cannabinoid receptor 1,CB1)receptor inhibitor AM251 can promote the mitochondrial biogenesis of enteric neurons and improve the intestinal motility of septic mice.Methods 60 C57 mice were randomly divided into Sham group,LPS group and AM251 group,with 20 mice in each group.In the LPS group,30 mg/kg LPS was injected into the abdominal cavity to establish a mouse sepsis model.The AM251 group was intraperitoneally injected with AM2513mg/kg 30 minutes after the sepsis model was established.After 48 hours,the changes in intestinal motility of mice,the changes in mitochondrial biogenesis-related proteins,and the changes in the number and volume of colonic neuron mitochondria were measured respectively.Results Compared with the Sham group,the CB1 receptor inhibitor AM251 can significantly improve the intestinal motility of mice,reduce the intestinal transit time(325.0s vs 187.5s,P=0.006),and increase the small intestinal advancement rate(47%vs 70%,P<0.001),shorten the time of colon bead discharge(375s vs 82s,P<0.001).At the same time,it can increase colonic mitochondrial biogenesis-related protein Nrf-1(0.414 vs 0.807,P=0.003),TFAM(0.739 vs 0.332,P=0.003),COX-Ⅳ(0.371 vs 0.817,P=0.001)expression,and increase the number(P=0.015)and volume(P=0.004).Conclusion CB1 receptor inhibitor can promote enteric neuron mitochondrial biogenesis and improve intestinal motility in septic mice.