The Role of Damage-Associated Molecular Patterns in Perioperative Neurocognitive Disorders: A Narrative Review

Abstract

Perioperative neurocognitive disorders (PND), such as postoperative delirium (POD) and cognitive dysfunction (POCD), frequently affect older surgical patients and significantly impair postoperative quality of life. During surgical procedures, damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1), mitochondrial DNA, and S100 proteins are released from injured cells and implicated in the pathogenesis of PND. These molecules activate innate immune pathways through pattern recognition receptors (PRRs) such as toll-like receptors (TLRs) and receptors for advanced glycation end products (RAGE). The systemic inflammatory response potentially compromises blood–brain barrier integrity, allowing peripheral immune cells to infiltrate the central nervous system. The resulting neuroinflammation disrupts synaptic function and neuronal connectivity, leading to cognitive impairments. Sustained activation of immune pathways creates a feedback loop where proinflammatory cytokines (eg, IL-1β and TNF-α) amplify DAMP release and immune activation, perpetuating chronic inflammation and cognitive dysfunction. Therapeutic strategies targeting DAMP-mediated pathways, such as glycyrrhizin (an HMGB1 inhibitor), dexmedetomidine (an anti-inflammatory anesthetic), and TLR4 inhibitors (eg, TAK-242), have shown promise in reducing neuroinflammation and protecting cognitive function in preclinical models. However, clinical translation requires validated biomarkers and further trials to ensure their safety and efficacy. This review offers a focused perspective on DAMP-specific mechanisms and emerging therapeutic interventions that modulate these pathways. By contributing to the current understanding of DAMPs in the context of PND, this work supports future research efforts aimed at developing biomarkers and targeted interventions to help mitigate postoperative neurocognitive complications in surgical patients.