Prophylactic Glycyrrhizin Attenuates Sevoflurane-Surgery-Induced Recognition Memory Deficit and Neuroinflammation in Middle-aged Mice via HMGB1-TLR4 Pathway Modulation

BackgroundPerioperative neurocognitive disorders (PND) encompass delayed neurocognitive recovery (dNCR; ≤30 days) and postoperative neurocognitive disorder (NCD; >30 days). While the HMGB1-TLR4/NF-κB axis drives acute neuroinflammation, the temporal dynamics of this signaling beyond the acute phase and distinct contributions of HMGB1 versus TLR4 to dNCR-to-NCD transition remain elusive. This study investigated whether glycyrrhizin attenuates sevoflurane-surgery-induced recognition memory deficit via modulation of HMGB1-TLR4 signaling.MethodsEight-month-old male C57BL/6J mice underwent right common carotid artery dissection under prolonged sevoflurane anesthesia (3%, 2 h) with or without glycyrrhizin pretreatment (30 mg/kg, i.p., 1 h preoperatively; n = 15/group for Batch 1, n = 7/group for Batch 2). Cognitive function was assessed via open field, novel object recognition, Y-maze, and Morris water maze. Hippocampal neuroinflammation (cytokines, microglia/astrocyte activation), HMGB1-TLR4-NF-κB signaling, synaptic proteins (synaptophysin, PSD-95), and histological alterations (Nissl staining) were evaluated at postoperative day 7 and day 20.ResultsProlonged sevoflurane exposure combined with surgical trauma induced recognition memory impairment and reduced platform crossings in the Morris water maze, both attenuated by glycyrrhizin. While peripheral IL-6 normalized by day 7, hippocampal cytokines (IL-6, IL-1β, TNF-α) and glial activation persisted through day 20. At the molecular level, HMGB1 was elevated at day 7 but normalized by day 20, whereas TLR4/NF-κB remained elevated at both time points; glycyrrhizin suppressed this cascade. Synaptic proteins were reduced and CA3/dentate gyrus exhibited Nissl staining reductions at days 7 and 20, protected by glycyrrhizin, whereas CA1 Nissl staining showed no significant alterations at either time point.ConclusionsThese findings demonstrate a temporal dissociation between HMGB1 normalization and sustained TLR4/NF-κB activation following sevoflurane-surgery in middle-aged mice. Prophylactic glycyrrhizin attenuates recognition memory deficits and suppresses hippocampal neuroinflammation, though mechanistic inferences remain speculative and require rigorous validation.