Abstract
Our study investigated the role of nicotinamide adenine dinucleotide phosphate (NADPH) in neuroinflammation-associated depression-like behaviors. Using a lipopolysaccharide (LPS)-induced mouse model of depression, we found that NADPH significantly alleviated depressive-like behaviors, including reduced immobility time and increased sucrose preference. Mechanistic exploration revealed that NADPH suppressed microglial activation, downregulated pro-inflammatory cytokine expression (e.g., IL-1β, TNF-α, IFN-γ), and mitigated oxidative stress in the hippocampus, thereby ameliorating neuroinflammation. Furthermore, NADPH preserved myelin integrity, inhibited microglial phagocytosis of myelin and synapses, and preserved synaptic integrity. These findings provide experimental evidence supporting NADPH as a potential antidepressant agent and highlight its critical role in modulating neuroinflammation via dual suppression of cytokine release and microglial hyperactivation.