Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine, School of Medicine, Ji-nan University, Guangzhou, China.
Acta Pharmacol Sin. 2011 Nov;32(11):1364-72. doi: 10.1038/aps.2011.102. Epub 2011 Oct 3.
To investigate the mechanisms responsible for the protective action of berberine (Ber) against gut damage in endotoxemic mice.
Male BALB/c mice were administered intragastrically with distilled water (0.1 mL/10 g), Ber (50 mg/kg) alone, yohimbine (2 mg/kg) alone, or Ber (50 mg/kg) in combination with yohimbine (2 mg/kg) for 3 d. On the third day, lipopolysaccharide (LPS, 18 mg/kg) or normal saline was intraperitoneally injected one hour after the intragastric administration. Following the treatment, intestinal injury in the ileum was histopathologically accessed; enterocyte apoptosis was examined using TUNEL method; Toll-like receptor 4 (TLR4) mRNA expression was measured using RT-PCR assay; inhibitor protein-κBα (I-κBα) phosphorylation and myeloperoxidase content were examined using Western blloting. The macrophage inflammatory protein-2 (MIP-2) production was measured using ELISA assay.
Mice challenged with LPS caused extensive ileum injury, including a significantly increased injury score, decreased intestinal villus height, reduced gut mucosal weight and increased intestinal permeability. Furthermore, LPS significantly induced enterocyte apoptosis, increased TLR4 mRNA expression, I-κBα phosphorylation, MIP-2 production and myeloperoxidase content in the ileum. Pretreatment with Ber significantly alleviated all the alterations in the ileum in the endotoxemic mice. Pretreatment with the α2-adrenoceptor antagonist yohimbine did not block the protective action of Ber against LPS-induced intestinal injury. In addition, treatment with yohimbine alone did not prevent LPS-induced intestinal injury.
Pretreatment with Ber provides significant protection against LPS-induced intestinal injury in mice, via reducing enterocyte apoptosis, inhibiting the TLR4-nuclear factor κB-MIP-2 pathway and decreasing neutrophil infiltration that are independent of α2-adrenoceptors.
研究小檗碱（Ber）对内毒素血症小鼠肠道损伤的保护作用机制。
雄性 BALB/c 小鼠连续 3 天每天经口给予蒸馏水（0.1 mL/10 g）、Ber（50 mg/kg）、育亨宾（2 mg/kg）或 Ber（50 mg/kg）与育亨宾（2 mg/kg）联合处理。第三天，经口给药 1 小时后，腹腔内注射脂多糖（LPS，18 mg/kg）或生理盐水。治疗后，通过组织病理学评估回肠的肠道损伤；采用 TUNEL 法检测肠上皮细胞凋亡；采用 RT-PCR 检测 Toll 样受体 4（TLR4）mRNA 表达；采用 Western blot 检测抑制蛋白-κBα（I-κBα）磷酸化和髓过氧化物酶含量。采用 ELISA 法检测巨噬细胞炎症蛋白-2（MIP-2）的产生。
LPS 攻击小鼠引起广泛的回肠损伤，包括损伤评分显著增加、肠绒毛高度降低、肠黏膜重量减少和肠道通透性增加。此外，LPS 显著诱导肠上皮细胞凋亡，增加 TLR4 mRNA 表达、I-κBα 磷酸化、MIP-2 产生和髓过氧化物酶含量。Ber 预处理显著减轻了内毒素血症小鼠回肠的所有变化。预先给予 α2-肾上腺素能受体拮抗剂育亨宾并不能阻断 Ber 对 LPS 诱导的肠道损伤的保护作用。此外，单独给予育亨宾处理并不能预防 LPS 诱导的肠道损伤。
Ber 预处理对 LPS 诱导的小鼠肠道损伤具有显著的保护作用，其机制可能是通过减少肠上皮细胞凋亡、抑制 TLR4-核因子 κB-MIP-2 途径和减少中性粒细胞浸润，而与 α2-肾上腺素能受体无关。
