Postoperative delirium (POD) is a serious complication in elderly patients undergoing surgery; however, its underlying mechanisms remain poorly understood. In this study, we investigated whether dexmedetomidine (DEX) ameliorates POD-like behavior by regulating microglial autophagy through the MAPK14 pathway. DEX targets were identified through transcriptomic analysis, and MAPK14 was validated as a key mediator by using molecular docking. In vitro experiments employed LPS-stimulated BV2 microglia to evaluate the effects of DEX on apoptosis (flow cytometry) and autophagy (transmission electron microscopy, BCL-2/Beclin-1/LC3-II/p62). In the aged C57BL/6 J mouse model of anesthesia/surgery-induced POD, animals received intraperitoneal injections of DEX or MAPK14 overexpression, followed by behavioral tests (open-field test and Y-maze test). Subsequently, hippocampal tissue was subjected to enzyme-linked immunosorbent assay and Western blot analyses to assess the levels of inflammatory factors and autophagy. DEX treatment effectively inhibited LPS-induced apoptosis in BV2 microglia while enhancing autophagy, as evidenced by increased LC3-II and Beclin-1 expression and decreased p62 and Bcl-2 levels. In the aged mouse POD model, DEX administration significantly reduced levels of neuroinflammatory factors and S100β while protecting against neuronal damage in the hippocampal CA1 and dentate gyrus regions. Behavioral assessments revealed substantial cognitive improvements in DEX-treated aged mice with delirium-like phenotype. All these therapeutic effects were abolished by MAPK14 overexpression. DEX attenuates POD by inhibiting MAPK14 to restore microglial autophagy and suppress neuroinflammation, thereby offering a novel therapeutic strategy for elderly patients. Furthermore, MAPK14 activation may serve as a biomarker for DEX responsiveness. • Dexmedetomidine alleviates postoperative delirium-like behavior in aged mice. • Its neuroprotective effects are mediated by inhibition of MAPK14 phosphorylation. • MAPK14 inhibition restores microglial autophagy and suppresses neuroinflammation. • This leads to reduced hippocampal damage and improved cognitive function. • MAPK14 is identified as a potential biomarker for predicting DEX responsiveness.
Yao et al. (Sun,) studied this question.