Jiau Shyi-Shiaw, Cheng Pao-Yun, Lee Yen-Mei, Huang Wen-Hsin, Ko Ya-Fang, Yen Mao-Hsiung
Division of Cardiology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
J Biomed Sci. 2006 Nov;13(6):833-43. doi: 10.1007/s11373-006-9115-5. Epub 2006 Nov 9.
Dextromethorphan (DM), an anti-tussive agent, has been claimed to have anti-inflammatory and immunomodulatory effects in vitro. In our preliminary screening test, LK-4, an analog of DM, can afford more protection against circulatory failure induced by LPS than that of DM. Thus, the aim of this study was to evaluate the effects of LK-4 on sepsis induced by intravenous (i.v.) administration of lipopolysaccharide (LPS; 10 mg/kg) in anesthetized Wistar rats and survival rate by intraperitoneal administration of LPS (70 mg/kg) in conscious ICR mice. Results demonstrated that posttreatment with LK-4 (3 and 5 mg/kg, i.v.) significantly attenuated the deleterious hemodynamic changes (e.g., hypotension and tachycardia) in rats treated with LPS. Meanwhile, LK-4 (3 mg/kg) significantly inhibited the elevation of plasma tumor necrosis factor-alpha, as well as values of GOT and GPT, and BUN and creatinine caused by LPS. The induction of inducible NO synthase and the overproduction of NO and superoxide anions by LPS were also reduced by LK-4. Moreover, infiltration of neutrophils into the lungs and liver of rats 8 h after treatment with LPS was also reduced by LK-4. Furthermore, LK-4 increased the survival rate of mice insulted by toxic dose of LPS. In conclusion, the beneficial effects of LK-4 on LPS-induced sepsis result from its anti-inflammatory and anti-oxidant effects. Thus, LK-4 can be potentially used as a therapeutic agent for sepsis in the future.
右美沙芬（DM）是一种镇咳药，据称在体外具有抗炎和免疫调节作用。在我们的初步筛选试验中，DM的类似物LK-4比DM能为脂多糖（LPS）诱导的循环衰竭提供更多保护。因此，本研究的目的是评估LK-4对麻醉的Wistar大鼠静脉注射（i.v.）脂多糖（LPS；10mg/kg）诱导的脓毒症的影响，以及对清醒ICR小鼠腹腔注射LPS（70mg/kg）后的存活率的影响。结果表明，LK-4（3和5mg/kg，静脉注射）后处理显著减轻了LPS处理大鼠的有害血流动力学变化（如低血压和心动过速）。同时，LK-4（3mg/kg）显著抑制了LPS引起的血浆肿瘤坏死因子-α升高以及谷草转氨酶、谷丙转氨酶、尿素氮和肌酐值的升高。LK-4还降低了LPS诱导的诱导型一氧化氮合酶的诱导以及NO和超氧阴离子的过量产生。此外，LK-4还降低了LPS处理8小时后大鼠肺和肝中中性粒细胞的浸润。此外，LK-4提高了受毒性剂量LPS攻击的小鼠的存活率。总之，LK-4对LPS诱导的脓毒症的有益作用源于其抗炎和抗氧化作用。因此，LK-4未来有可能用作脓毒症的治疗药物。
