Methylene Blue for Prevention of Perioperative Neurocognitive Disorders: Mechanisms and Recent Clinical Evidence

Yu Wu,1 Jinbao Wang,1 Xiaojian Wan2 1Department of Anesthesiology, Bethune International Peace Hospital, Shijiazhuang, People’s Republic of China; 2Department of Intensive Care Unit, Changhai Hospital, Navy Medical University, Shanghai, People’s Republic of ChinaCorrespondence: Yu Wu, Email dr.wuyu@outlook.comBackground: Perioperative neurocognitive disorders (PND), encompassing postoperative delirium (POD) and delayed neurocognitive recovery (dNCR), affect 15– 40% of elderly surgical patients and are associated with accelerated long-term cognitive decline and increased mortality. Currently, no pharmacological agent is universally accepted for PND prevention. Methylene blue (MB), a phenothiazine derivative with unique mitochondrial redox properties, has emerged as a promising multimodal neuroprotectant.Objective: This review synthesizes evidence supporting MB’s neuroprotective mechanisms and evaluates emerging clinical data regarding its efficacy as a preventive strategy for PND in elderly surgical patients.Methods: We conducted a comprehensive narrative review of preclinical and clinical studies investigating MB’s role in perioperative neuroprotection, with particular emphasis on mechanistic pathways and randomized controlled trial evidence.Results: MB exerts neuroprotection through multiple convergent mechanisms: functioning as an alternative electron carrier in the mitochondrial electron transport chain, activating the Nrf2/antioxidant response element (ARE) pathway, suppressing microglia-mediated neuroinflammation, inhibiting tau protein aggregation, and preserving blood-brain barrier integrity. Recent randomized controlled trials demonstrate that single-dose intraoperative intravenous MB (2 mg/kg) significantly reduces POD incidence (from 24% to 7%, number needed to treat = 6) in elderly patients undergoing major non-cardiac surgery. Biomarker studies confirm attenuated neuronal injury (reduced serum S100β) and decreased systemic inflammation following MB administration.Conclusion: MB represents a mechanism-based therapeutic strategy targeting the mitochondrial and inflammatory core of PND pathophysiology. Large-scale, multicenter randomized controlled trials with extended neurocognitive follow-up are warranted to establish MB’s definitive role in perioperative neuroprotection and to optimize dosing protocols for high-risk populations.