D-mannose alleviates neurological deficits and inhibits NLRP3 inflammasome activation via the AMPK-mitophagy signaling pathway after traumatic brain injury.

Traumatic brain injury (TBI) represents one of the most common and severe central nervous system (CNS) disorders, contributing significantly to the global health burden However, effective clinical strategies to mitigate TBI-induced secondary damage remain limited. The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome plays a pivotal role in secondary neuroinflammation following the primary insult of TBI. D-mannose, a C-2 epimer of glucose and a major monosaccharide component of N-glycans, has recently been reported as a potential therapeutic agent for neurological disorders. Nevertheless, its protective effects against neuroinflammation and neurological deficits after TBI have not been fully elucidated. In this study, we investigated whether D-mannose attenuates secondary injury by suppressing NLRP3 inflammasome activation. Our findings demonstrated that D-mannose treatment significantly reduced neuronal apoptosis and blood-brain barrier (BBB) disruption, while promoting motor function recovery. Furthermore, D-mannose suppressed the activation of pro-inflammatory microglia and neurotoxic astrocytes. Mechanistically, we propose that D-mannose exerts neuroprotection by activating AMP-activated protein kinase (AMPK), thereby promoting mitophagy and suppressing NLRP3 inflammasome activation. D-mannose markedly increased AMPK phosphorylation, enhanced mitophagy, and reduced the expression of NLRP3-related proteins in the peritraumatic cortex. Notably, pharmacological inhibition of AMPK abolished these effects. Collectively, these findings highlight AMPK-mitophagy signaling as a critical pathway through which D-mannose confers neuroprotection after TBI.