## 2 Effects of Nicotinamide Riboside on Several Organs and Systems  
### Nicotinamide Riboside and the Nervous System  
The effects of NR on energy metabolism and neuroprotection were highlighted with the first research about this compound. In yeast and mammals, NR is metabolized by two main pathways: (i) degradative processes from which NAM results; (ii) synthetic processes exploiting NR kinases (NRK1, NRK2), resulting in increased tissue NAD\({}^{+}\). This increase is reported to increase insulin sensitivity, MT biogenesis, and SIRT functions. Thus, in experimental models of Alzheimer's disease (AD), NR in larger amounts than is found naturally in food leads to brain-protective effects by the stimulation of NAD\({}^{+}\) anabolism [7]. NR is a neuroprotective factor that improves cognition after brain injuries, such as acute ischemia. In an experimental model, 300 mg/kg NRCl was i.p. administered, 20 min after reperfusion, in mice with middle cerebral artery (MCA) occlusion. The NRCl-treated group exhibited better memory function and recovery of learning in the Morris water maze test. Following acute treatment with NRCl, apoptosis in the hippocampus, neuronal loss, and hippocampal infarct volume were decreased. NRCl also increased the measured amounts of NAD\({}^{+}\) and ATP, and stimulated adenosine 5\({}^{\prime}\)-monophosphate (AMP)-activated protein kinase and SIRT1, as observed by high-performance liquid chromatography (HPLC) and Western blot assays [43]. Moreover, the clinical phenotype and T-cell survival/function were improved by S-adenosylmethionine (SAM) and NR co-administration for patients with phosphoribosyl pyrophosphate synthetase 1 (PRPS1) deficiency ([PERSON] syndrome, manifested by serious neurological and immunological deficiencies especially in males) [44]. NR is reported to be beneficial in other neurological syndromes. For example, Gulf War illness (GWI) is a chronic neuropsychiatric disorder characterized by neurocognitive deficits arising from OXS, neuroinflammation, and neuronal damage. Currently, no effective treatment of GWI is known [45]. However, in a GWI experimental model, NR-mediated SIRT1 activation restored brain MT bioenergetics dysfunction (following astroglia activation) and reduced neuroinflammation. Here, NR was administered as a dietary supplement, 100 ug/kg daily for two months. In the brain of NR-treated GWI mice, a decrease in lipid peroxidation and proinflammatory cytokines was closely correlated to the increase in deacetylation of the peroxisome proliferatorator-activated receptor gamma coactivator-1 alpha (PGC-1\(\alpha\)) and nuclear factor-kappaB (NF-\(\kappa\)B) p65 subunit [46]. Many central nervous system (CNS) disorders arise from dysfunctionalities in the gut microbiota-brain axis. In the mice brain, NRS provided protection against alcohol-induced depressive behavior and decreased the level of anti-inflammatory (interleukin (IL)-10 and transforming growth factor (TGF)-\(\beta\)) and proinflammatory (IL-1\(\beta\), IL-6, and tumor necrosis factor (TNF)-\(\alpha\)) cytokines. In the hippocampus, NR significantly reduced the number of activated microglia and the inhibition of the protein kinase B (AKT)/glycogen synthase kinase 3 beta (GSK3\(\beta\))/\(\beta\)-catenin signaling pathway and increased the brain-derived neurotrophic factor (BDNF). Similar with donor mice, in recipient mice, fecal microbiota transplantation (FMT) improved the microglial activity, the level of BDNF and cytokines, the activation of AKT/GSK3\(\beta\)/\(\beta\)-catenin signaling pathway, and cognitive behavior [47]. Intracortical administration of NR protects against excitotoxicity-induced axonal degeneration (AxD) and decreases the brain damage provoked by injection of \(N\)-methyl-D-aspartate (NMDA). Both NR and NAD\({}^{+}\) prevented neuronal death due to the axonal stress. However, NR exhibited better neuroprotection than NAD\({}^{+}\) at the level of cortical neurons [48].