围术期使用头孢唑啉可改善小鼠术后认知功能障碍但引起肠道炎症。

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Perioperative use of cefazolin ameliorates postoperative cognitive dysfunction but induces gut inflammation in mice.

背景与目的

新出现的证据表明，长期使用多种抗生素可通过肠道功能失调导致认知功能障碍。头孢唑啉通常使用3至5天以预防围术期感染。本研究旨在探讨围手术期使用头孢唑啉对炎症反应和术后认知的影响。

方  法

在用脂多糖（LPS）处理的小鼠C8-B4小神经胶质细胞中测定头孢唑啉的抗炎作用。检测LPS处理后6和24小时的白细胞介素（IL）-6和IL-1β。对6至8周龄的CD-1小鼠进行剖腹手术。在手术前1小时腹膜内注射300mg / kg的头孢唑啉，然后在手术后每天注射一次，持续5天。他们的学习和记忆是通过Barnes迷宫和恐惧条件试验评估的，这些试验在手术后1周开始。在手术后24小时和6天收集脑和结肠以确定炎性细胞因子。在手术后6和19天收集结肠及其腔内容物以测定细菌菌群。在注射头孢唑啉后0.5,1和2小时测量血清和脑中的头孢唑啉浓度。

结  果

在LPS刺激的C8-B4细胞中，IL-6和IL-1β水平降低到250μg/ ml头孢唑啉。剖腹手术增加了小鼠在训练期后第1天和第8天识别Barnes迷宫中目标孔的时间，并减少了恐惧条件反射测试中与背景相关的僵硬行为。头孢唑啉减轻了这些手术效果，但也减少了没有进行手术的小鼠中与背景相关的僵硬行为。剖腹手术后24小时，海马和大脑皮质中的IL-6，大脑皮质中的IL-1β，血清和结肠中的IL-6和IL-1β均增加。头孢唑啉减弱了这些作用。使用头孢唑林处理没有进行手术的小鼠5天以诱导结肠生态功能失调并且结肠中的IL-6和IL-1β以及大脑皮层中的IL-1β均增加。结肠生态功能失调在单独用头孢唑啉治疗的小鼠中消失，但在手术后19天通过手术和头孢唑林持续存在。在注射头孢唑啉后，检测到血清中高的头孢唑啉浓度但未检测到脑中的浓度。

结  论

这些结果表明，头孢唑啉具有直接的抗炎作用，可以减轻手术引起的小鼠术后记忆和学习障碍。在没有进行手术的小鼠中单独使用头孢唑林可以通过短暂的肠道生态功能失调产生认知功能障碍。

原始文献摘要

BACKGROUND Emerging evidence indicates that long-time use of multiple antibiotics can induce cognitive dysfunction via gut dysbiosis. Cefazolin is often used for 3 to 5 days to prevent perioperative infection. This study is to detect the impact of perioperative use of cefazolin on inflammatory responses and postoperative cognition.

METHODS The anti-inflammatory effect of cefazolin was determined in mouse C8-B4 microglial cells treated with lipopolysaccharide (LPS). Interleukin (IL)-6 and IL-1β at 6 and 24 h after LPS treatment were detected. Six- to 8-week-old CD-1 mice were subjected to laparotomy. Cefazolin at 300 mg/kg was injected intraperitoneally 1 h before surgery and then once per day for 5 days after surgery. Their learning and memory were assessed by Barnes maze and fear conditioning tests which started 1 week after the surgery. The brain and colon were harvested 24 h and 6 days after surgery to determine inflammatory cytokines. The colon and its luminal contents were harvested 6 and 19 days after surgery for the determination of bacteria flora. Cefazolin concentrations in the serum and brain were measured 0.5, 1, and 2 h after cefazolin injection.

RESULTS IL-6 and IL-1β levels were decreased by 250 μg/ml cefazolin in the LPS-stimulated C8-B4 cells. Laparotomy increased the time for mice to identify the target hole in the Barnes maze on day 1 and day 8 after training sessions and reduced context-related freezing behavior in fear conditioning test. Cefazolin attenuated these surgical effects but reduced context-related freezing behavior in mice without surgery. IL-6 in the hippocampus and cerebral cortex, IL-1β in the cerebral cortex, and IL-6 and IL-1β in the serum and colon were increased 24 h after laparotomy. Cefazolin attenuated these effects. Cefazolin treatment for 5 days in mice without surgery induced colon dysbiosis and increased IL-6 and IL-1β in the colon and IL-1β in the cerebral cortex. Colon dysbiosis disappeared in mice treated with cefazolin alone but persisted in mice with surgery and cefazolin 19 days after surgery. High cefazolin concentrations in the serum but not in the brain were detected after cefazolin injection.

CONCLUSIONS These results suggest that cefazolin has a direct anti-inflammatory effect and can attenuate surgery-induced postoperative memory and learning impairment in mice. Cefazolin alone may induce cognitive dysfunction possibly by transient gut dysbiosis in mice without surgery.

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                   贵州医科大学高鸿教授课题组

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