Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Brain Res. 2020 Jul 1;1738:146822. doi: 10.1016/j.brainres.2020.146822. Epub 2020 Apr 6.
Sepsis-associated encephalopathy (SAE) is frequently encountered in critically ill patients. Hyperglycemia is a common phenomenon among patients with sepsis, and glycemic control improves patient outcomes. Therefore, here, we aimed to explore whether glycemic control using insulin inhibits the pro-inflammatory cytokine response and glial activation in the cerebrum and is concomitantly associated with the relief of SAE. Using cecal ligation and puncture (CLP), sepsis was induced in male Sprague-Dawley rats. The CLP rats were administered intravenous glucose or subjected to subcutaneous insulin implant within the first hour after CLP. The survival rate, blood glucose (BG) values, and behavioral expression were assessed daily for 5 days after CLP. At day 5 after CLP, electroencephalography (EEG) recordings and blood-brain barrier (BBB) permeability testing were performed. Immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assays were used to evaluate glial activation and the pro-inflammatory cytokine response qualitatively and quantitatively, respectively. The glucose-treated CLP rats (BG > 390 mg/dL) exhibited a decline in survival rate; insensitivity to mechanical and thermal stimuli; slowed EEG activity; and an increase in BBB permeability, pro-inflammatory cytokine (TNF-α, IL-1β, and IL-6) levels, and glial activation (astrocytes and microglia) in the cerebral tissues compared with CLP rats (BG ~ 270 mg/dL). Double-immunofluorescence showed that activated astrocytes and microglia co-expressed phosphorylated nuclear factor kappa B and mitogen-activated protein kinases, respectively. Furthermore, glycemic control using insulin therapy maintained the BG at 120-160 mg/dL and inhibited the production of pro-inflammatory cytokines and glial activation in the cerebrum of septic rats. In addition, the survival rate, sensory threshold, EEG activity, and BBB permeability recovered to near-normal levels in septic rats after insulin therapy. Taken together, the results of this study elucidated the pathophysiological alterations in brains subjected to sepsis, especially regarding glycemic control. These findings improve our understanding of SAE and support the importance of glycemic control in sepsis.
脓毒症相关性脑病（SAE）在危重病患者中很常见。脓毒症患者常伴有高血糖，血糖控制可改善患者预后。因此，本研究旨在探讨胰岛素降血糖治疗是否能抑制大脑中的促炎细胞因子反应和神经胶质细胞激活，并同时缓解 SAE。我们使用盲肠结扎穿孔（CLP）的方法在雄性 Sprague-Dawley 大鼠中诱导脓毒症。CLP 后 1 小时内，CLP 大鼠接受静脉葡萄糖或皮下胰岛素植入治疗。CLP 后 5 天每天评估大鼠的存活率、血糖（BG）值和行为表现。CLP 后第 5 天，进行脑电图（EEG）记录和血脑屏障（BBB）通透性测试。免疫组织化学、免疫印迹和酶联免疫吸附试验分别用于定性和定量评估神经胶质细胞激活和促炎细胞因子反应。与 CLP 大鼠（BG~270mg/dL）相比，血糖治疗的 CLP 大鼠（BG>390mg/dL）表现出存活率下降；对机械和热刺激无反应；EEG 活动减慢；BBB 通透性、促炎细胞因子（TNF-α、IL-1β和 IL-6）水平以及大脑组织中的神经胶质细胞激活（星形胶质细胞和小胶质细胞）增加。双免疫荧光显示，活化的星形胶质细胞和小胶质细胞分别共表达磷酸化核因子κB 和丝裂原活化蛋白激酶。此外，胰岛素治疗可将 BG 维持在 120-160mg/dL，并抑制脓毒症大鼠大脑中促炎细胞因子和神经胶质细胞的激活。此外，胰岛素治疗后，脓毒症大鼠的存活率、感觉阈值、EEG 活动和 BBB 通透性恢复到接近正常水平。综上所述，该研究结果阐明了大脑在脓毒症中的病理生理改变，特别是血糖控制方面。这些发现提高了我们对 SAE 的认识，并支持血糖控制在脓毒症中的重要性。
