Glycemic control with insulin attenuates sepsis-associated encephalopathy by inhibiting glial activation via the suppression of the nuclear factor kappa B and mitogen-activated protein kinase signaling pathways in septic rats

Abstract

© 2020 Elsevier B.V. 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.