Nicotinamide phosphoribosyltransferase inhibitor ameliorates mouse aging-induced cognitive impairment

Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme for the synthesis of nicotinamide adenine dinucleotide (NAD) in the salvaging pathway. Though NAMPT inhibitors such as FK866 were originally developed as anti-cancer drugs, they also display neuroprotective effects. Here we show that the administration of FK866 at 0.5 mg/kg (ip, qod) for four weeks, i.e., ∼1% of the dose used for the treatment of cancer, significantly alleviates the aging-induced impairment of cognition and locomotor activity. Mechanistically, FK866 enhanced autophagy, reduced protein aggregation, and inhibited neuroinflammation indicated by decreasing TNFα, IL-6, GFAP, and Iba1 levels in the aged mouse brain. Though FK866 did not affect the total NAD and nicotinamide mononucleotide (NMN) levels in the mouse brain at the dose we used, FK866 increased nicotinamide (NAM) level in the young mouse brain and decreased NAM level in the aged mouse brain. On the other hand, FK866 did not affect the serum glucose, cholesterol, and triglyceride of young and aged mice and exhibited no effects on the various indices of young mice. Thus, the NAMPT inhibitor can be repurpose to counteract the cognitive impairment upon aging. We also envision that NAMPT inhibitor can be used for the treatment of age-related neurodegenerative diseases.

mTOR‐mediated autophagy in the hippocampus is involved in perioperative neurocognitive disorders in diabetic rats

“…Neuroinflammation can lead to impairment of autophagy that exacerbates neurodegeneration, and conversely, a disruption of autophagy during pathological conditions can initiate or intensify neuroinflammation. 45,54,55 Although the interaction between neuroinflammation and autophagy is complicated and controversial, this issue warrants further investigation in future work. Third, The MWM is a common and reliable test to assess hippocampal-dependent spatial learning and memory in rodents undergoing tibial fracture surgery, some other behavioral experiments, such as the Y-maze and fear conditioning tests, are needed to better evaluate the role of mTOR signaling in neurocognitive disorders.…”

“…43,44 Autophagy is essential for the maintenance of cell homeostasis, as it clears damaged organelles and misfolded/toxic proteins, and autophagy dysfunction is involved in many neurodegenerative diseases. 18,45 P62, LC3, and Beclin-1 are widely considered to be markers of autophagy. The LC3-II/LC3-I ratio and beclin-1 levels directly correlate with autophagic activity, while the P62 levels inversely correlate with autophagy activity.…”

Preoperative plasma visfatin may have a dual effect on the occurrence of postoperative delirium

“…The relationship between the visfatin level in blood and cognitive function remains controversial. Some studies showed that elevated blood visfatin levels are associated with a cognitive decline ( 12 , 14 , 31 ). However, some studies indicated that loss of visfatin may harm neurons and impair cognitive function ( 18 ).…”

From Rate-Limiting Enzyme to Therapeutic Target: The Promise of NAMPT in Neurodegenerative Diseases

“…Great efforts have been made on exploring the therapeutic potential of NSCs in PD ( Zhang et al, 2017 ). A growing number of evidence has shown that NSCs suffer cell senescence under various stresses ( Zeng et al, 2021 ). iNAMPT is particularly important for the proliferation, self-renewal, and differentiation of NSPCs.…”