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Forkhead Box O1-p21 Mediates Macrophage Polarization in Postoperative Cognitive Dysfunction Induced by Sevoflurane
Jun-Bao Fu1, Zhi-Hua Wang1, Yong-Ying Ren1
1Department of Anesthesiology, Linyi Central Hospital, Linyi, Shandong, China.
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.
Insights
Sevoflurane anesthesia impairs cognitive function in mice by promoting M1 macrophage polarization, a process linked to reduced Forkhead box O1 (FoxO1) and p21 expression. This research provides insights into preventing anesthetic-induced cognitive dysfunction.
Area of Science:
- Neuroscience
- Immunology
- Anesthesiology
Background:
- Postoperative cognitive dysfunction (POCD) is a significant concern following anesthesia.
- Sevoflurane is a commonly used anesthetic agent, but its impact on cognitive function requires further elucidation.
- Macrophage polarization plays a critical role in neuroinflammation and cognitive processes.
Purpose of the Study:
- To investigate the role of Forkhead box O1 (FoxO1) and p21 in sevoflurane-induced macrophage polarization.
- To understand the mechanisms underlying sevoflurane's effect on cognitive function and neuroinflammation.
- To explore potential therapeutic targets for preventing POCD.
Main Methods:
- Mice were exposed to sevoflurane anesthesia or served as controls.
- Cognitive function was assessed using the trace fear conditioned reflex test.
- Systemic inflammation markers (CD163, TNF-α) were measured via ELISA.
- Macrophage phenotypes (M1/M2) were analyzed using immunofluorescence and RT-PCR.
- Expression levels of FoxO1 and p21 proteins were determined by Western blot.
Main Results:
- Sevoflurane anesthesia significantly decreased cognitive function in mice.
- Anesthesia increased serum concentrations of CD163 and TNF-α.
- Macrophage polarization shifted towards the M1 phenotype with increased M1 markers and decreased M2 markers.
- Expression of FoxO1 and p21 proteins was significantly reduced in the anesthesia group.
- Elevated M1 macrophage polarization correlated with decreased cognitive function.
Conclusions:
- Sevoflurane anesthesia induces cognitive dysfunction, partly through promoting M1 macrophage polarization.
- Reduced expression of FoxO1 and p21 may contribute to this M1 polarization.
- Understanding these mechanisms offers a basis for developing strategies to prevent and treat anesthetic-induced cognitive dysfunction.
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