Forkhead Box O1-p21 Mediates Macrophage Polarization in Postoperative Cognitive Dysfunction Induced by Sevoflurane

Abstract

Purpose: The current study was conducted in order to investigate the role of Forkhead box O1 and p21-mediated macrophage polarization in postoperative cognitive dysfunction induced by sevoflurane. Methods: There involved a total of 30 healthy mice that were randomly divided into two groups: control group (without any treatment) and anaesthesia group (treated with sevoflurane inhalation). The effects of sevoflurane on cognitive function (memory) in mice were studied by trace fear conditioned reflex, and the effects of systemic inflammation and behavior after operation were measured by enzyme-linked immunosorbent assay (ELISA), the concentrations of CD163 and tumor necrosis factor-α (TNF-α) were measured. The expression of macrophage phenotype was observed by immunofluorescence staining, the expression levels of M1 and M2 markers mRNA were detected by real-time fluorescence quantitative PCR (RT-PCR), and the expression levels of FoxO1 and p21 were analyzed by immunoblotting (Western blot). Results: Compared with the control group, the freezing time in the anesthesia group was lower than that in the control group (P<0.01), indicating that sevoflurane anesthesia led to the decrease of cognitive ability. The blood concentrations of CD163 and TNF-α increased significantly at 24 h after the operation with sevoflurane anesthesia (P<0.05). Fluorescence microscopic observation showed that M2 was the main type of macrophages in normal tissues, while M1 and M2 phenotypes were highly expressed in sevoflurane anesthetized tissues at the same time, especially in M1 phenotypes (P<0.01). The polarization of macrophages in the anesthetic group showed the high level of M1 mRNA, and the expression levels of TNF-α, monocyte chemotactic protein 1(MCP-1) and Interleukin-6 (IL-6)mRNA in the anesthetic group were significantly higher than those in the control group (P<0.05). The expression levels of M2 mRNA such as transforming growth factor-β (TGF-β) and IL-10 were significantly lower than those in the control group (P<0.05). Compared with the control group, the expression of FoxO1 and p21 protein in the anesthesia group was significantly lower than that in the control group with a significant statistical difference (P<0.01). Conclusion: This study offers a theoretical basis and insight for further understanding of the prevention and treatment of cognitive dysfunction induced by anesthetic drugs.

Hippocampal gene expression patterns in Sevoflurane anesthesia associated neurocognitive disorders: A bioinformatic analysis

“…Sevoflurane was found to impair the AMPK/FoxO3a signaling pathway activation leading to apoptosis of mouse hippocampal neurons ( 39 ) and in mouse cerebral cortex ( 40 ). FoxO signaling is implicated in increased M1 type polarization of macrophages in Sevoflurane related postoperative cognitive dysfunction ( 41 ). Sevoflurane and NCD related pathways were found highly correlated and largely supported by existing literature.…”

Effects of propofol on macrophage activation and function in diseases

“…Sevoflurane pretreatment promotes the formation of an anti-inflammatory phenotype in microglia/macrophages by up-regulating the phosphorylation of GSK-3β and Nrf2 nuclear transposition, and it has a neuroprotective effect on middle cerebral artery occlusion (MCAO) ( Cai et al, 2021a ). However, sevoflurane inhibits FoxO1, regulates p21 and increases the expression of TNF-α, monocyte chemotactic protein-1 (MCP-1) and IL-6, which may increase the polarization of M1 macrophages, induce a central nervous system (CNS) inflammatory response, and lead to cognitive impairment ( Fu et al, 2020 ). This pathway suggests that inhaled anesthetics have different effects on prognosis via regulation of the process of M1-type polarization of macrophages due to different pathological conditions.…”

“…Dexmedetomidine and propofol inhibit the expression of lipopolysaccharide (LPS)-stimulated high mobility group box 1 (HMGB1) in macrophages ( Chang et al, 2013 ; Jia et al, 2017 ). The volatile anesthetic sevoflurane modulates macrophage recruitment, polarization, differentiation, apoptosis and pyroptosis by regulating the caspase-1, reactive oxygen species (ROS), forkhead box O1 (FoxO1), p21, and glycogen synthase kinase-3 (GSK-3β)/nuclear factor-E2-related factor 2 (Nrf2) pathways, which are involved in local immunity and tumor growth ( Jin et al, 2013 ; Fu et al, 2020 ; Sztwiertnia et al, 2020 ; Cai et al, 2021a ). Opioids, such as morphine, also inhibit the phagocytosis of macrophages and are associated with the reduction of macrophage colony-stimulating factor-induced proliferation and differentiation ( Sacerdote et al, 2003 ).…”

Inhibition of SET domain–containing (lysine methyltransferase) 7 alleviates cognitive impairment through suppressing the activation of NOD-like receptor protein 3 inflammasome in isoflurane-induced aged mice

“…Elderly patients who undergo surgery under general anesthesia are likely to develop postoperative cognitive dysfunction (POCD), which is a common postoperative complication. [1][2][3] Studies suggest that POCD is caused by temporary impairment of brain function, and it will increase the incidence of Alzheimer's disease or other complications and hinder a normal recovery of the body, significantly affecting the quality of life of elderly patients after surgery. 4,5 Although the specific pathogenesis of POCD is not clear, several hypotheses could explain the mechanism of POCD.…”