Knocking out Sema4B prevents anesthesia/surgery-induced cognitive decline in aged mice by suppressing hippocampal neuroinflammation

Background: Perioperative neurocognitive disorders (PND) are common neurological consequences after surgery and anesthesia, particularly in the elderly. The purpose of this study was to examine how PND in old mice induced by isoflurane anesthesia was affected by the silencing of the Semaphorin 4B (Sema4B) gene. Methods: A model for PND was created using Sema4B knockout (Sema4B−/−) and wild-type (WT) aged mice subjected to isoflurane anesthesia and internal fixation following tibial fracture. Cognitive performance was assessed using the Morris water maze test. The expression of Sema4B and Ionized calcium-binding adapter molecule 1 (Iba1), as well as the activity of the Phosphatidylinositol 3-kinase (PI3K)/Protein Kinase B (AKT) signaling pathway in the hippocampus, were evaluated by Western blotting and immunofluorescence. Pro-inflammatory cytokine levels in the hippocampus were assessed using the enzyme-linked immunosorbent assay (ELISA). Results: Our findings showed that Sema4B expression in the hippocampus was significantly upregulated in aged PND model mice, and its knockout significantly improved spatial learning and memory, as indicated by reduced escape latency and increased time spent in the target quadrant and platform crossings. Additionally, Sema4B deletion inhibited microglial activation and reduced the hippocampal levels of pro-inflammatory cytokine. Notably, knockout of Sema4B also led to reactivation of the PI3K/AKT signaling pathway. Conclusions: These findings show that knocking down Sema4B may alleviate hippocampal neuroinflammation and improve postoperative cognitive impairment.

PND; Anesthesia; Sema4B; Cognitive impairment; Inflammation; Microglial activation

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