Global and item-level MADRS differences between melancholic and unspecified depressive symptoms under rTMS: an exploratory analysis.

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway and plays an important role in maintaining NAD homeostasis. Recently, growing evidence has linked NAD to neuroinflammatory processes in neurodegenerative diseases (). Studies have shown that changes in NAD levels not only affect cellular energy metabolism but also participate in regulating inflammatory responses. In particular, in inflammation-related cells such as microglia, NAD metabolic remodeling has been closely associated with inflammatory activation (). Previous studies have shown that depletion of NAD in microglia can significantly ameliorate the progression of inflammation-mediated diseases (). In addition, NAMPT has been implicated in microglial activation and neuroinflammatory processes in mouse models of ischemic neural injury, whereas inhibition of NAMPT has been shown to alleviate neuroinflammation (). These findings suggest that NAMPT is not merely a metabolic enzyme required for maintaining NAD supply but may also represent an important regulatory node linking metabolic homeostasis to neuroinflammatory responses. Based on the role of NAMPT in inflammatory regulation, FK866, a specific inhibitor of NAMPT, has recently received considerable attention in studies related to neural injury. Previous studies have shown that FK866 can attenuate glial activation and reduce the release of inflammatory cytokines in models of traumatic brain injury and cryoinjury, suggesting its potential anti-inflammatory effects (, ). However, as the key rate-limiting enzyme for NAD biosynthesis, NAMPT is widely involved in multiple cellular processes, including DNA repair, neuroinflammation, immune regulation, and mitochondrial energy metabolism. Studies have also shown that, while inhibiting NAMPT, FK866 may reduce intracellular NAD levels, further induce mitochondrial dysfunction and disturbances in energy metabolism, and even contribute to neurodegenerative changes (). Therefore, the effects of FK866 are not limited to the suppression of inflammation-related metabolic processes but may also interfere with physiological NAD requirements, thereby limiting its clinical application. Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by increased Aβ plaque deposition and progressive decline in learning and memory ability (). Recent studies have shown that AD pathology is also accompanied by persistent neuroinflammatory activation and impaired energy metabolism (). Accumulating evidence has demonstrated that neuroinflammation plays an important role in the pathogenesis of AD. Cluster of differentiation 38 (CD38) and poly(ADP-ribose) polymerase 1 (PARP1) are important NAD-consuming enzymes involved in the regulation of NAD homeostasis. Studies have also shown that suppressing CD38- and PARP1-associated NAD depletion can ameliorate neuroinflammatory responses in the AD brain (–), suggesting that targeting NAD metabolism may represent a promising therapeutic strategy for improving neuroinflammation in AD. Notably, decreased NAD levels in the AD brain are closely associated with mitochondrial dysfunction and neuronal damage. Previous studies have shown that a decline in brain NAD levels may reduce the activity of mitochondrial respiratory chain complexes, decrease ATP production, aggravate oxidative stress, and disrupt mitochondrial membrane integrity, thereby leading to mitochondrial damage (). Previous work has shown that long-term FK866 treatment reduced neuronal NAD levels and aggravated AD pathology. These findings suggest that maintaining NAD at an appropriate level is critical for the treatment of AD. Therefore, reducing the adverse effects associated with NAMPT inhibition may be of considerable importance for the clinical translation of NAMPT-targeted strategies in AD.