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

BACKGROUND

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.