Nicotinamide supplementation mitigates synaptic plasticity impairment and cognitive decline after tibial fracture surgery in aging mice

Post-operative delirium (POD) in elderly patients is associated with increased cognitive decline, morbidity, and mortality. Neuroinflammation and NAD+ imbalance contribute to POD. We investigated the imbalance of NAD+-consuming enzymes, particularly sirtuins and CD38, associated with neuroinflammation. Additionally, we examined Nicotinamide (NAM), a precursor of NAD+, for its potential to alleviate neuroinflammation and metabolic imbalance.Female C57BL/6J mice aged 20-22 months underwent tibial fracture surgery and received pre- and post-surgery NAM treatment. Neuroinflammation, synaptic plasticity, and cognition were assessed 72 hours post-surgery via rtPCR, WB, LTP, dendritic spine counting, and behavioral tests (open field maze and Y-maze).Tibial fracture surgery increased hippocampal levels of the inflammatory markers IL-1beta mRNA, CD38, and SIRT1 protein, and induced a decline in LTP, dendritic spine loss, and hippocampal-dependent memory function. Pretreatment with NAM prevented all these changes. Considering the observed effects on LTP and dendritic spines and the known role of CD38 in calcium signaling, S-glutathionylation of RyR calcium channels and BDNF protein levels were assessed. The results revealed that tibial fracture is associated with increased S-glutathionylation of RyR-calcium channels and decreased BDNF protein levels, which can be prevented with NAM treatment. Moreover, the NAD+ level assays indicated that while there's no decline post-surgery, treatment with NAM boosts hippocampal levels.NAM supplementation prevents cognitive decline and synaptic plasticity deficits post-surgery by reducing inflammation and lowering IL-1beta and CD38 protein levels. Mechanistically, these findings suggest that NAM pretreatment's protective effect in POD mice may involve regulation of the CD38 signaling pathway and enhancement of NAD+ levels.