## 2 Effects of Nicotinamide Riboside on Several Organs and Systems
### Nicotinamide Riboside and the Nervous System
Moreover, in rats with TNF-induced optic nerve degeneration, intravitreal injection of NR showed significant axonal protection. In retina and optic nerve, NR upregulated the levels of SIRT1 ATG pathway, decreased the p62 protein levels and increased the levels of microtubule-associated protein 1A/1B-light chain 3-II (LC3-II) that localizes with the MT inner membrane. The presence of NRK1, upregulated by NR administration, was also evidenced in the retinal and optic nerve fibers and in the retinal ganglion cells (RGCs) [49; 50]. This research continues. For example, [PERSON] et al. (2023) recently showed that NAD\({}^{+}\) depletion mediates cytotoxicity in human neurons with ATG deficiency, leading to cytotoxicity and neurodegeneration. The research was conducted on ATG-deficient (ATG5\({}^{-/-}\)) human embryonic stem cells (hESCs) representing a \"human neuronal platform\". In ATG5\({}^{-/-}\) neurons, NR treatment improved cell viability by the restoration of MT bioenergetics and proteostasis [51]. In experimental (prelimical) models and also in clinical studies, NR improved ataxia scores and immunoglobulin G (IgG) levels in ataxia telangiectasia (A-T). In ATM-deficient mice, which is a model for the A-T phenotype in humans, NR administration improved motor function and prevented neuroinflammation, neurodegeneration, MT dysfunction and cellular senescence [52]. NR dietary supplementation was well tolerated by A-T patients; ataxia, dysarthria, and the quality of life (QoL) were all reportedly improved without adverse effects [53; 54]. In cluster of differentiation (CD) 157 knockout (KO) male mice, oral administration of NR increased the levels of oxytocin (OT) in cerebrospinal fluid (CSF), stimulating the release of this anxiolytic factor during stress, and corrected the fearful and anxiety-like behaviors and the social deficits [55]. A recent study highlighted the remission of social behavior impairment by oral gavage administration of NR for 12 days in CD157, but not in CD38 KO mice [56]. In cell culture (in vitro) and in mouse models of amyotrophic lateral sclerosis (ALS), NR and pterostilbene (PT) supplementation cooperatively delayed motor neuron failure, decreased the levels of neuroinflammation markers in the spinal cord, influenced the muscle metabolism, and increased to a small extent the survival of hSOD1\({}^{G93\text{A}}\) transgenic mice [57]. Further, in SOD1\({}^{G93\text{A}}\) transgenic and wild-type (WT) mice, starting at 50 days of age, oral administration of NR (20 mg/mL) improved MT proteostasis and adult neurogenesis. In the brain of SOD1\({}^{G93\text{A}}\) mice, neural stem cells (NSCs)/neuronal precursor cells (NPCs) proliferation and migration were enhanced following the NRS [58]. A recent clinical trial evidenced that NR and PT co-administration proved to be effective in inhibiting OXS-induced cellular damage, the major pathophysiological mechanism of ALS [59; 60]. In mouse models for Cockayne syndrome (CS) (CSA\({}^{-/-}\) and CSB\({}^{\text{m}/\text{m}}\), modeling human CS), NR is reported to protect from noise-induced hearing loss (NIHLL). The main mechanism of action involves the activation of NAD\({}^{+}\)/SIRT3 pathway, which contributes to the reduction in spiral ganglia neurite degeneration caused by intensive noise exposure (NE). NAD\({}^{+}\) supplementation could prove beneficial for the treatment of CS-related hearing loss at a young age and age-related hearing loss (ARHL) affecting elderly individuals [61; 62; 63]. In Sprague-Dawley female rats, oral administration of NR (200 mg/kg) for four weeks relieved the nociceptive and aversive dimensions of intravenous (i.v.) paclitaxel (PTX)-induced peripheral neuropathy. In addition, NRS increased NAD\({}^{+}\) plasma level by 50% and did not influence the myelosuppressive properties of PTX, the adverse locomotor effects not being observed [64].