Abstract: The core mechanism of postoperative cognitive dysfunction (POCD) involves a cascade activation of perioperative neuroinflammatory responses. Surgical trauma releases damage-associated molecular patterns (DAMPs), which activate the peripheral TLR4/NF-κB pathway, leading to the release of pro-inflammatory cytokines (IL-1β, TNF-α). These cytokines disrupt blood-brain barrier integrity or transmit signals via the vagus nerve to the central nervous system, driving the polarization of microglia toward the pro-inflammatory M1 phenotype and activating astrocytes. Activated glial cells release reactive oxygen species (ROS) and inflammatory mediators, which directly impair neuronal mitochondrial function, suppress synaptic plasticity, and induce glutamate excitotoxicity. Perioperative synergistic factors (e.g., anesthetics, postoperative pain, circadian rhythm disruption) further amplify neuroinflammation by activating the NLRP3 inflammasome, suppressing clock gene (Bmal1/Per2) expression, and enhancing gut microbiota dysbiosis-mediated lipopolysaccharide (LPS)-TLR4 signaling, thereby forming a “peripheral-central” inflammatory vicious cycle. Imbalanced glial polarization (dysfunctional M1/M2 phenotype switching) and interactions between inflammatory factors and neurons (e.g., HMGB1-mediated overactivation of NMDA receptors) collectively contribute to synaptic dysfunction and cognitive decline. Elucidating the dynamic regulatory network of neuroinflammation is pivotal l for developing precise interventions for POCD.

Key words: postoperative cognitive dysfunction, neuroinflammation, microglia