Nicotinamide, a beta-nicotinamide adenine dinucleotide (NAD) precursor and an essential nutrient for cell growth and function, may offer critical insights into the specific cellular mechanisms that determine neuronal survival, since this agent significantly impacts upon both neuronal and vascular integrity in the central nervous system. The authors show that nicotinamide provides broad, but concentration-specific, protection against apoptotic genomic DNA fragmentation and membrane phosphatidylserine exposure during oxidative stress to secure cellular integrity and prevent phagocytic cellular demise. Activation of the protein kinase B (Akt1) pathway is a necessary requirement for nicotinamide protection, because transfection of primary hippocampal neurons with a plasmid encoding a kinase-deficient dominant-negative Akt1 as well as pharmacologic inhibition of phosphatidylinositol-3-kinase phosphorylation of Akt1 eliminates cytoprotection by nicotinamide. Nicotinamide fosters neuronal survival through a series of intimately associated pathways. At one level, nicotinamide directly modulates mitochondrial membrane potential and pore formation to prevent cytochrome c release and caspase-3-and 9-like activities through mechanisms that are independent of the apoptotic protease activating factor-1. At a second level, nicotinamide maintains an inhibitory phosphorylation of the forkhead transcription factor FOXO3a at the regulatory sites of Thr and Ser and governs a unique regulatory loop that prevents the degradation of phosphorylated FOXO3a by caspase-3. Their work elucidates some of the unique neuro-protective pathways used by the essential cellular nutrient nicotinamide that may direct future therapeutic approaches for neurodegenerative disorders.