Mechanisms For A Decrease In Mortality Of Endotoxemic Mice By Berberine

Objective:Mortality of patients with septic shock is still 40%-60% in spite of a rapid progress in antibiotics and other therapeutic methods in clinical practice. One of the major reasons is that the main active component of endotoxin, lipopolysaccharide (LPS), mediates disturbance of immune and inflammatory response and causes extensive tissue damage. However, up to now, there has been no satisfactory method to decrease mortality of endotoxemia. As a traditional medicine, which is used to treat intestinal tract infection, berberine not only has actions to treat heart failure, arrhythmia and tumors, but also can regulate immune and inflammatory response in vivo. In this study, we observed effect of berberine on mortality and organ histological changes in endotoxemic mice and further investigated the mechanisms of its actions.Methods:This study included three parts: Firstly, we examined the effects of berberine on the mortality of mice challenged with LPS. Secondly, mice were sacrificed at 12 h and 24 h after LPS administration, and heart, lung, liver, kidney and small intestine were collected for the HE staining. Then we observed the effect of berberine on histological changes of the above organs in mice challenged with LPS. Lastly, we investigated the effect of berberine on plasma tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), interferon-γ (IFN-γ), nitric oxide (NO) and interleukin-10 (IL-10) contents in LPS-treated mice. Plasma TNF-α, IL-12, IFN-γ, and IL-10 contents were measured with enzyme-linked immunosorbent assay (ELISA), and NO content was determined with the technique of nitrate reductase.Results:1. Pretreatment with berberine remarkably reduced the mortality of mice challengedwith LPS in a time and dose-dependent manner with optimal dosage of 50 mg/kg. Pretreatment with berberine at a dosage of 50 mg/kg for 5 days decreased the mortality of LPS-challenged mice by 57%. Especially, treatment with berberine, even administered 1 h after LPS (28 mg/kg) exposure, also reduced mortality of endotoxemic mice by 31%.2. Berberine reduced histological injury of lung, liver, kidneys and small intestine inmice challenged with LPS.3. There was a distinct decrease in plasma TNF-a, IFN-y and NO contents and increase in plasma IL-10 production in berberine pretreatment group compared with LPS group. There was no significant difference in plasma IL-12 level between berberine pretreatment group and LPS group.Conclusion:Berberine remarkably decreases mortality and attenuates tissue injury of lung, liver, kidneys and small intestine in mice challenged with LPS, which may be related to its decreasing plasma TNF-a, IFN-y and NO levels and increasing plasma IL-10 level during endotoxemia. These findings provide a new strategy for the treatment of endotoxemia.