The NAD⁺ Precursor Nicotinamide Governs Neuronal Survival During Oxidative Stress Through Protein Kinase B Coupled to FOXO3a and Mitochondrial Membrane Potential

Abstract

Summary:Nicotinamide, a ß-nicotinamide adenine dinucleotide (NAD +

Relative efficacy of nicotinamide treatment of a mouse model of infantile Niemann-Pick C1 disease

“…Nicotinamide can prevent apoptosis in toxicity-induced neurodegeneration (Klaidman, et al 1996) and multiple roles are involved. It protects cells from apoptotic genomic DNA fragmentation and membrane phosphatidyl serine exposure to ROS (Chong, et al, 2004). These protective effects require activation of the Akt1 signalling pathway while alterations in mitochondrial potential and inhibition of FOX03a phosphorylation are also involved (Chong, et al, 2004).…”

“…It protects cells from apoptotic genomic DNA fragmentation and membrane phosphatidyl serine exposure to ROS (Chong, et al, 2004). These protective effects require activation of the Akt1 signalling pathway while alterations in mitochondrial potential and inhibition of FOX03a phosphorylation are also involved (Chong, et al, 2004). The role of NAD + , for which nicotinamide is a precursor, in both pathways is recently and thoroughly reviewed by Canto, et al (2015).…”

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

“…In addition to the neuroprotective attributes of nicotinamide [91][92][93], one potential pathway to consider for the protective capacity of nicotinamide in DM involves the maintenance of vascular integrity [11,42,64]. For example, nicotinamide can protect the function of the blood brain barrier [94,95], influence arteriolar dilatation and blood flow [96], potentially lead to decreased atherosclerotic plaque through inhibition of poly(ADP-ribose) polymerase [97], and promote platelet production through megakaryocyte maturation [98].…”

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

“…Akt inhibition of FOXO3a requires its phosphorylation that results in the association of FOXO3a with 14−3−3 protein and retention of FOXO3a in the cytoplasm, rendering it ineffective to target genes in the nucleus and thus blocking apoptosis. During periods of oxidative stress in the nervous system, an initial inhibitory phosphorylation of FOXO3a at regulatory phosphorylation sites (Thr 32 and Ser 253 ) [27,185] can occur [47]. However, loss of phosphorylated FOXO3a expression appears to subsequently result over a 12-h period, possibly by caspase degradation, which can potentially enhance the vulnerability of neurons to apoptotic injury during neuro-degenerative disorders, such as Alzheimer's disease [47].…”

“…In fact, recent work that employs transcriptional profiling of the human frontal cortex in the aging brain suggests that altered expression of a variety of genes may promote oxidative stress, DNA damage, and impaired mitochondrial function [133]. If one examines the aging process on more specific cellular terms, agents such as nicotinamide, an NAD + precursor that is intimately tied to cell survival during acute apoptotic injury [47,120,140,144], may negatively influence the life span of cells through the regulation of the Sir2 gene [126]. The Sir2 gene belongs to a family of genes which is a highly conserved group in the genomes of organisms ranging from archaebacteria to eukaryotes [74,232].…”