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NAD + and NR have the same protective effect against FK866-induced cortical neurodegeneration. A) Schematic representation of FK866 effect on NAD + metabolism. B) NAD + level measured on cortical neurons cultured on plates exposed to 10 mM FK866 for 24, 48, and 72 h (n = 3-4). C ) Quantification of somatic status and AxD in cortical neurons exposed to 10 mM FK866 (n = 4). D) Fluorescence microscopic analysis of somatic status and AxD after somatodendritic 10 mM FK866 treatment in the presence of 50 mM NAD + or 50 mM NR in both compartments (72 h). Left: the somatodendritic compartment stained with anti-MAP2 (red) and Hoechst 33342 (blue); right: the axonal compartment stained with anti-b3-tubulin. Scale bars, 20 mm. E, F ) Effect of NR or NAD + on neuronal death and AxD in presence of FK866: cortical neurons where treated in both chambers with 50 mM NR or NAD + at the same time (0 h) or 24-48 h after 10 mM FK866 treatment for 72 h. E ) Quantification of somatic status by percentage of condensed nuclei after Hoechst staining (n = 3). F) Quantification of AxD after b-tubulin staining (n = 3). *P , 0.05, **P , 0.01, ***P , 0.001.
Source publication
NAD(+) depletion is a common phenomenon in neurodegenerative pathologies. Excitotoxicity occurs in multiple neurologic disorders and NAD(+) was shown to prevent neuronal degeneration in this process through mechanisms that remained to be determined. The activity of nicotinamide riboside (NR) in neuroprotective models and the recent description of e...
Contexts in source publication
Context 1
... excitotoxicity and SARM1 activation induce NAD + depletion in a manner that can be protected by NR and NAD + , we tested whether pharmacological inhibition of NAD + homeostasis causes AxD. FK866, a specific inhibitor of Nampt (46), which salvages NAM for resynthesis of NAD + (Fig. 6A), was used to induce NAD + depletion. Addition of 10 mM FK866 to the somatodendritic com- partment of cortical neurons induced a rapid decrease of NAD + levels after 24 h of treatment (Fig. 6B). At 72 h, this drop in NAD + induced somatodendritic degeneration, nuclear condensation, and AxD (Fig. 6C, D). Cotreatment of cortical neurons ...
Context 2
... whether pharmacological inhibition of NAD + homeostasis causes AxD. FK866, a specific inhibitor of Nampt (46), which salvages NAM for resynthesis of NAD + (Fig. 6A), was used to induce NAD + depletion. Addition of 10 mM FK866 to the somatodendritic com- partment of cortical neurons induced a rapid decrease of NAD + levels after 24 h of treatment (Fig. 6B). At 72 h, this drop in NAD + induced somatodendritic degeneration, nuclear condensation, and AxD (Fig. 6C, D). Cotreatment of cortical neurons with 10 mM FK866 and 50 mM NAD + or NR fully prevented these effects (Fig. 6D-F). Notably, the protective concentrations of NAD + and NR were lower than those used in the NMDA-induced neuro- ...
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... which salvages NAM for resynthesis of NAD + (Fig. 6A), was used to induce NAD + depletion. Addition of 10 mM FK866 to the somatodendritic com- partment of cortical neurons induced a rapid decrease of NAD + levels after 24 h of treatment (Fig. 6B). At 72 h, this drop in NAD + induced somatodendritic degeneration, nuclear condensation, and AxD (Fig. 6C, D). Cotreatment of cortical neurons with 10 mM FK866 and 50 mM NAD + or NR fully prevented these effects (Fig. 6D-F). Notably, the protective concentrations of NAD + and NR were lower than those used in the NMDA-induced neuro- degeneration model (50 mM for both in the FK866 model and 5 mM NAD + or 1 mM NR in the NMDA model) (Figs. 2A-D ...
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... to the somatodendritic com- partment of cortical neurons induced a rapid decrease of NAD + levels after 24 h of treatment (Fig. 6B). At 72 h, this drop in NAD + induced somatodendritic degeneration, nuclear condensation, and AxD (Fig. 6C, D). Cotreatment of cortical neurons with 10 mM FK866 and 50 mM NAD + or NR fully prevented these effects (Fig. 6D-F). Notably, the protective concentrations of NAD + and NR were lower than those used in the NMDA-induced neuro- degeneration model (50 mM for both in the FK866 model and 5 mM NAD + or 1 mM NR in the NMDA model) (Figs. 2A-D and 6D-F). NAD + and NR remained fully pro- tective when applied 24 h after treatment, at a time when NAD + ...
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... than those used in the NMDA-induced neuro- degeneration model (50 mM for both in the FK866 model and 5 mM NAD + or 1 mM NR in the NMDA model) (Figs. 2A-D and 6D-F). NAD + and NR remained fully pro- tective when applied 24 h after treatment, at a time when NAD + depletion was already observed, but dropped to 20% protection when applied 48 h later (Fig. 6E, F). These findings highlight the existence of a temporal window in which neuronal integrity can be rescued after a neurotoxic insult. Taken together, these data show that NAD + and NR have the same neuroprotective effect against FK866- induced NAD + ...
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Citations
... The resultant decline in NAD+ levels has been casually implicated with the development of mitochondrial dysfunction, the biological hallmarks of aging, and may contribute to age-associated disorders and abnormalities, such as neurodegeneration, hypertension, and chronic inflammation (Fang et al., 2017;Covarrubias et al., 2021). NAD+ homeostasis is also disturbed in conditions of metabolic stress, including heart failure, diabesity, central and peripheral neurodegeneration, mitochondrial disease, alcoholic liver disease, postpartum, coronavirus infection (Samuel A.J. Trammell et al., 2016;Hamity et al., 2017;Vaur et al., 2017;Diguet et al., 2018;Liu et al., 2018;Ear et al., 2019;Parker et al., 2020;Pirinen et al., 2020;Heer et al., 2021). On the other hand, interventions that boost NAD+ availability have repeatedly been demonstrated to rescue defects associated with the loss of NAD+ homeostasis and improve physiological function (Cantó et al., 2012;Zhang et al., 2016;Martens et al., 2018;Elhassan et al., 2019). ...
Background
Nicotinamide riboside (NR) is a promising compound for augmenting the intracellular NAD+ pool, potentially mitigating age-related decline and associated conditions. While oral NR supplementation has demonstrated safety and bioavailability in multiple animal and human studies, the effects of intravenous NR (NR IV) are far less understood. Until now, pharmaceutical grade NR was not available for injection research.
Objectives
Given that intravenous administration may offer advantages in certain conditions and contexts, a systematic investigation of the clinical effects of NR IV is warranted.
Methods
The present randomized, double-blinded, placebo-controlled, pilot clinical study was initiated with the primary aim of investigating the safety, tolerability, and the blood NAD+-boosting efficacy of an acute, single dose of NR IV (500 mg, test), NAD+ IV (500 mg, active comparator), oral NR (500 mg, bridge), and saline IV (placebo control) in generally healthy adult participants. The study consisted of two parts; data from 37 and 16 participants in the first and second phases, respectively, were analyzed.
Results
No significant differences in vital signs were detected across groups. In comparison to NAD+ IV, NR IV was associated with fewer and less severe adverse experiences during the infusion; no attributable adverse events were reported through the 14-day follow-up period for any treatment groups. Further, the mean tolerable infusion time for NR IV was 75% less than that of NAD+ IV. No clinically meaningful changes in blood chemistry markers were described in the NR IV condition, whereas an increase in white blood cell counts and neutrophils was observed in the NAD+ IV condition, suggesting the presence of an inflammatory response. Finally, NR IV appeared to promote the most robust increases in NAD+ concentration as measured by dried blood spot analyses, with peak NAD+ levels increasing by 20.7% relative to baseline, and acutely outperforming NAD+ IV (p <0.01) and oral NR (p<0.01) at the 3-hr timepoint.
Conclusion
This is the first study to clinically evaluate NR IV. Overall, acute intravenous infusions of 500 mg NR were safe in the study participants with no attributable adverse events and only minor and transient infusion-related experiences. In comparison to NAD+ IV, NR IV had a faster infusion time with superior tolerability. At 3 hours post-infusion, blood NAD+ levels were significantly higher in the NR IV group compared to the NAD+ IV group. Future studies in larger populations are needed to validate these results.
... NR has been shown to be a superior neuroprotective agent to NAD + in excitotoxicityinduced axonal degeneration [34] and can effectively promote neuronal survival [35]. Synapses are fundamental to neuronal activity [36]. ...
... Currently, NR is emerging as a leading drug candidate compared to other precursors (NAM/NMN) due to its high bioavailability, safety, and strong ability to increase NAD + levels [41,42]. Therapeutic strategies to maintain or increase NAD + early after injury may reduce the progression of secondary injury and tissue damage [24,34]. This study showed that in mice after SCI, there was a depletion of NAD + in the lesional spinal cord tissue. ...
... It has been confirmed in in vivo and in vitro models that NAD + is crucial for energy metabolism, oxidative stress, DNA damage repair, lifespan regulation, and some signaling processes, and can prevent neurodegeneration [24] and enhance axonal protection [34]. In the spinal cord ischemia-reperfusion injury model, Xie et al. confirmed that supplementing NAD + reduce oxidative stress and neuronal apoptosis [16,44]. ...
Changes in intracellular nicotinamide adenine dinucleotide (NAD+) levels have been observed in various disease states. A decrease in NAD+ levels has been noted following spinal cord injury (SCI). Nicotinamide riboside (NR) serves as the precursor of NAD+. Previous research has demonstrated the anti-inflammatory and apoptosis-reducing effects of NR supplements. However, it remains unclear whether NR exerts a similar role in mice after SCI. The objective of this study was to investigate the impact of NR on these changes in a mouse model of SCI. Four groups were considered: (1) non-SCI without NR (Sham), (2) non-SCI with NR (Sham +NR), (3) SCI without NR (SCI), and (4) SCI with NR (SCI + NR). Female C57BL/6J mice aged 6–8 weeks were intraperitoneally administered with 500 mg/kg/day NR for a duration of one week. The supplementation of NR resulted in a significant elevation of NAD+ levels in the spinal cord tissue of mice after SCI. In comparison to the SCI group, NR supplementation exhibited regulatory effects on the chemotaxis/recruitment of leukocytes, leading to reduced levels of inflammatory factors such as IL-1β, TNF-α, and IL-22 in the injured area. Moreover, NR supplementation notably enhanced the survival of neurons and synapses within the injured area, ultimately resulting in improved motor functions after SCI. Therefore, our research findings demonstrated that NR supplementation had inhibitory effects on leukocyte chemotaxis, anti-inflammatory effects, and could significantly improve the immune micro-environment after SCI, thereby promoting neuronal survival and ultimately enhancing the recovery of motor functions after SCI. NR supplementation showed promise as a potential clinical treatment strategy for SCI.
... For example, a previous study demonstrated that NR attenuated axonal degeneration in dorsal root ganglia neurons [32]. Moreover, another study showed that NR suppressed excitotoxicitymediated axonal degeneration in cortical neurons [33]. A very recent study found that NR can prevent tri-ortho-cresyl phosphate-induced axonal degeneration of the dorsal root ganglia neurons [34]. ...
Nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+), has been studied to support human health against metabolic stress, cardiovascular disease, and neurodegenerative disease. In the present study, we investigated the effects of oral NR on axonal damage in a rat ocular hypertension model. Intraocular pressure (IOP) elevation was induced by laser irradiation and then the rats received oral NR of 1000 mg/kg/day daily. IOP elevation was seen 7, 14, and 21 days after laser irradiation compared with the controls. We confirmed that oral NR administration significantly increased NAD+ levels in the retina. After 3-week oral administration of NR, morphometric analysis of optic nerve cross-sections showed that the number of axons was protected compared with that in the untreated ocular hypertension group. Oral NR administration significantly prevented retinal ganglion cell (RGC) fiber loss in retinal flat mounts, as shown by neurofilament immunostaining. Immunoblotting samples from the optic nerves showed that oral NR administration augmented the phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK) level in rats with and without ocular hypertension induction. Immunohistochemical analysis showed that some p-AMPK-immunopositive fibers were colocalized with neurofilament immunoreactivity in the control group, and oral NR administration enhanced p-AMPK immunopositivity. Our findings suggest that oral NR administration protects against glaucomatous RGC axonal degeneration with the possible upregulation of p-AMPK.
... 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]. ...
Many studies have suggested that the oxidized form of nicotinamide adenine dinucleotide (NAD+) is involved in an extensive spectrum of human pathologies, including neurodegenerative disorders, cardiomyopathy, obesity, and diabetes. Further, healthy aging and longevity appear to be closely related to NAD+ and its related metabolites, including nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). As a dietary supplement, NR appears to be well tolerated, having better pharmacodynamics and greater potency. Unfortunately, NR is a reactive molecule, often unstable during its manufacturing, transport, and storage. Recently, work related to prebiotic chemistry discovered that NR borate is considerably more stable than NR itself. However, immediately upon consumption, the borate dissociates from the NR borate and is lost in the body through dilution and binding to other species, notably carbohydrates such as fructose and glucose. The NR left behind is expected to behave pharmacologically in ways identical to NR itself. This review provides a comprehensive summary (through Q1 of 2023) of the literature that makes the case for the consumption of NR as a dietary supplement. It then summarizes the challenges of delivering quality NR to consumers using standard synthesis, manufacture, shipping, and storage approaches. It concludes by outlining the advantages of NR borate in these processes.
... Both NAR and NAD + prevented neuronal death due to the axonal stress. However, NAR exhibited better neuroprotection than NAD + at the level of cortical neurons [48]. ...
NAD+ is known classically as a metabolite that participates in catabolic and anabolic pathways throughout the metabolism that is taught to students in introductory biochemistry courses. However, non-classical studies starting over a decade ago found that NAD+ is also involved in higher order functions, in part because of its involvement in the activation of SIRTs and the support of the mitochondrial unfolded protein response. Many studies since have suggested that NAD+ is involved in an extensive spectrum of human pathologies, including neurodegenerative disorders, cardiomyopathy, obesity, and diabetes, Further, healthy aging and longevity appear to be closely related to NAD+ and its related metabolites, including NAR and NMN. Together, these studies show that this system has value as a dietary supplement to improve general health overall, as well as mitigating specific disease conditions. Accordingly, many are now recommending the consumption of materials in this system as dietary supplements. Nicotinamide riboside (NAR) appears to have special value in this regard. It appears to be better tolerated than other molecules in this system, as well as better pharmacodynamics and greater potency. Unfortunately, NAR is a reactive molecule, often unstable during its manufacturing, transport, and storage. Indeed, HPLC analyses of many commercial samples of NAR shows that they contain substantial amounts of material that are not, in fact, NAR. In some of these commercial preparations, NAR is a minority component. Therefore, more stable derivatives of NAR that are easily converted upon consumption into NAR are therefore desired. Recently work related to prebiotic chemistry provided the borate derivative of NAR. NARB is considerably more stable than NAR itself. However, immediately upon consumption, the borate dissociates from NARB, and is lost in the body through dilution and binding to other species, notably carbohydrates such as fructose and glucose. The NAR left behind is expected to behave pharmacologically in ways identical to NAR itself. This review provides a comprehensive summary (through Q1 of 2023) of literature that makes the case for the consumption of NAR as a dietary supplement. It then summarizes the challenges of delivering quality NAR to consumers using standard synthesis, manufacture, shipping, and storage approaches. It concludes by outlining the advantages of NAR-borate in these processes.
... In addition to mutated genes, a balance between biosynthesis and degradation of a major mitochondrial redox substrate NAD+ (vitamin B3 derivative) has a significant role in axonal degeneration [15,16]. The link between the NAD+ levels and CMT disease is supported by reduced levels of NAD+ in the blood of CMT patients vs. healthy subjects [17]. ...
... The positive action of the administration of different NAD+ precursors is known in a number of pathologies with neurological manifestations [81,82]. In particular, one NAD+ precursor, nicotinamide riboside, has been shown to counteract excitotoxicity-induced neurodegeneration [15]. Thus, the available data suggest vitamin B3 and its derivatives to be of therapeutic potential in CMT disease. ...
Understanding the molecular mechanisms of neurological disorders is necessary for the development of personalized medicine. When the diagnosis considers not only the disease symptoms, but also their molecular basis, treatments tailored to individual patients may be suggested. Vitamin-responsive neurological disorders are induced by deficiencies in vitamin-dependent processes. These deficiencies may occur due to genetic impairments of proteins whose functions are involved with the vitamins. This review considers the enzymes encoded by the DHTKD1, PDK3 and PDXK genes, whose mutations are observed in patients with Charcot–Marie–Tooth (CMT) disease. The enzymes bind or produce the coenzyme forms of vitamins B1 (thiamine diphosphate, ThDP) and B6 (pyridoxal-5′-phosphate, PLP). Alleviation of such disorders through administration of the lacking vitamin or its derivative calls for a better introduction of mechanistic knowledge to medical diagnostics and therapies. Recent data on lower levels of the vitamin B3 derivative, NAD+, in the blood of patients with CMT disease vs. control subjects are also considered in view of the NAD-dependent mechanisms of pathological axonal degeneration, suggesting the therapeutic potential of vitamin B3 in these patients. Thus, improved diagnostics of the underlying causes of CMT disease may allow patients with vitamin-responsive disease forms to benefit from the administration of the vitamins B1, B3, B6, their natural derivatives, or their pharmacological forms.
... In multiple ischemic stroke models, the combination of NAD with a small dose of NADPH has a more potent neuroprotective effect by increasing ATP levels and decreasing ROS levels [63]. However, in an NMDA-induced excitotoxicityrelated axon degeneration model, direct supplementation of NAD was found to have a weaker protective effect than NR supplementation [75]. ...
... A recent phase I clinical trial on PD patients found that oral NR supplementation is safe and results in mild clinical improvement [118]. In several preclinical studies, NR showed protective effects against various nervous system diseases or damage, including AD [71][72][73], NMDA-induced brain damage [75], retinal ganglion cell damage [76], and an hSOD1-linked ALS mouse disease [77]. In a mouse brain ischemia model, the NR salt NRC was found to increase the energy supply and promote cognitive function recovery [79]. ...
As the aging population continues to grow rapidly, age-related diseases are becoming an increasing burden on the healthcare system and a major concern for the well-being of elderly individuals. While aging is an inevitable process for all humans, it can be slowed down and age-related diseases can be treated or alleviated. Nicotinamide adenine dinucleotide (NAD) is a critical coenzyme or cofactor that plays a central role in metabolism and is involved in various cellular processes including the maintenance of metabolic homeostasis, post-translational protein modifications, DNA repair, and immune responses. As individuals age, their NAD levels decline, and this decrease has been suggested to be a contributing factor to the development of numerous age-related diseases, such as cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. In pursuit of healthy aging, researchers have investigated approaches to boost or maintain NAD levels. Here, we provide an overview of NAD metabolism and the role of NAD in age-related diseases and summarize recent progress in the development of strategies that target NAD metabolism for the treatment of age-related diseases, particularly neurodegenerative diseases.
... NAD confers neuroprotection through an improvement in mitochondrial biogenesis and function in a neuronal primary culture bath with glutamate [148]. In addition to NAD, NR was particularly associated with protection against excitotoxicity-induced axon degeneration and conferred better protection than NAD supplementation [149]. ...
Excitotoxicity is classically defined as the neuronal damage caused by the excessive release of glutamate, and subsequent activation of excitatory plasma membrane receptors. In the mammalian brain, this phenomenon is mainly driven by excessive activation of glutamate receptors (GRs). Excitotoxicity is common to several chronic disorders of the Central Nervous System (CNS) and is considered the primary mechanism of neuronal loss of function and cell death in acute CNS diseases (e.g. ischemic stroke). Multiple mechanisms and pathways lead to excitotoxic cell damage including pro-death signaling cascade events downstream of glutamate receptors, calcium (Ca2+) overload, oxidative stress, mitochondrial impairment, excessive glutamate in the synaptic cleft as well as altered energy metabolism. Here, we review the current knowledge on the molecular mechanisms that underlie excitotoxicity, emphasizing the role of Nicotinamide Adenine Dinucleotide (NAD) metabolism. We also discuss novel and promising therapeutic strategies to treat excitotoxicity, highlighting recent clinical trials. Finally, we will shed light on the ongoing search for stroke biomarkers, an exciting and promising field of research, which may improve stroke diagnosis, prognosis and allow better treatment options.
... In addition to mutated genes, a balance in biosynthesis and degradation of a major mitochondrial redox substrate NAD+ (vitamin B3 derivative) has a significant role in axonal degeneration [15,16]. The link between the NAD+ levels and CMT disease is supported by reduced levels of NAD+ in the blood of CMT patients vs healthy subjects [17]. ...
... Positive action of the administration of different NAD+ precursors is known in a number of pathologies with neurological manifestations [64,65]. In particular, NAD+ precursor, nicotinamide riboside, is shown to protect from excitotoxicity-induced neurodegeneration [15]. Thus, the available data suggest vitamin B3 and its derivatives to be of therapeutic potential in CMT disease. ...
Understanding molecular mechanisms of neurological disorders is required for development of personalized medicine. When the diagnosis considers not only the disease symptoms, but also their molecular basis, the treatments tailored for individual patients may be suggested. The vitamins-responsive neurological disorders are induced by deficiencies in the vitamin-dependent processes. The deficiencies may occur due to genetic impairments of proteins whose functions are involved with the vitamins. This review considers the enzymes encoded by DHTKD1, PDK3 and PDXK genes, whose mutations are observed in patients with Charcot-Marie-Tooth (CMT) disease. The enzymes bind or produce the coenzyme forms of vitamins B1 (thiamine diphosphate, ThDP) and B6 (pyridoxal-5’-phosphate, PLP). Alleviation of such disorders by administration of the lacking vitamin or its derivative calls upon a better introduction of the mechanistic knowledge to medical diagnostics and therapies. Recent data on lower levels of the vitamin B3 derivative, NAD+, in the blood of patients with CMT disease, compared to the control subjects, are also considered in view of the NAD-dependent mechanisms of pathological axonal degeneration, suggesting therapeutic potential of vitamin B3. Thus, improved diagnostics of the underlying causes of the CMT disease may allow the patients with the vitamin-responsive disease forms to benefit from the administration of the vitamins B1, B3, B6, their natural derivatives or pharmacological forms.
... In a variety of tissue culture and disease models, NAD + supplementation results in cytoprotection (Alano et al., 2010;Alano et al., 2004;Belenky et al., 2007;Brown et al., 2014;Canto et al., 2012;Gong et al., 2013;Hamity et al., 2017;Harlan et al., 2016;Hou et al., 2018;Khan et al., 2014;Liu et al., 2019;Sasaki et al., 2006;Sasaki et al., 2009;Trammell et al., 2016b;Vaur et al., 2017;Xie et al., 2017a;Xie et al., 2017b;Zhang et al., 2016;Zheng et al., 2019). NAD + can be effectively increased in culture and in the nervous system in vivo by exogenous application of NAD + , NAD + precursors (e.g., NAM, NMN, NR), or supplementation or manipulation of the enzymes involved in NAD + synthesis (e.g., NMNAT, NAMPT) (Brown et al., 2014;Sasaki et al., 2006;Zhou et al., 2015). ...
... Application of NAD + precursors to increase cellular NAD + levels is particularly effective. Their administration attenuates cell death (Hou et al., 2018), reduces lesion volume (Vaur et al., 2017), counteracts astrocyte toxicity and reactivity (Harlan et al., 2016;Hou et al., 2018), reduces inflammation (Hou et al., 2018;Zhang et al., 2016), modulates oxidative stress (Wei et al., 2017), protects axons and reduces axonal dysfunction (Brown et al., 2014;Gong et al., 2013;Hamity et al., 2017;Hou et al., 2018;Kitaoka et al., 2020;Vaur et al., 2017), stimulates neurogenesis (Hou et al., 2018;Zhou et al., 2020), and reduces cell senescence (Zhang et al., 2016). The ability of NAD + augmentation in other injury/disease models to modify these cellular processes, along with demonstration that exogenous administration of NAD + protects neurons against cell death in ischemic SCI (Xie et al., 2017a;Xie et al., 2017b), led us to examine whether elevating spinal cord NAD + could be an effective treatment for SCI. ...
... Application of NAD + precursors to increase cellular NAD + levels is particularly effective. Their administration attenuates cell death (Hou et al., 2018), reduces lesion volume (Vaur et al., 2017), counteracts astrocyte toxicity and reactivity (Harlan et al., 2016;Hou et al., 2018), reduces inflammation (Hou et al., 2018;Zhang et al., 2016), modulates oxidative stress (Wei et al., 2017), protects axons and reduces axonal dysfunction (Brown et al., 2014;Gong et al., 2013;Hamity et al., 2017;Hou et al., 2018;Kitaoka et al., 2020;Vaur et al., 2017), stimulates neurogenesis (Hou et al., 2018;Zhou et al., 2020), and reduces cell senescence (Zhang et al., 2016). The ability of NAD + augmentation in other injury/disease models to modify these cellular processes, along with demonstration that exogenous administration of NAD + protects neurons against cell death in ischemic SCI (Xie et al., 2017a;Xie et al., 2017b), led us to examine whether elevating spinal cord NAD + could be an effective treatment for SCI. ...
Spinal cord injury (SCI)-induced tissue damage spreads to neighboring spared cells in the hours, days and weeks following injury leading to exacerbation of tissue damage and functional deficits. Among the biochemical changes is the rapid reduction of cellular nicotinamide adenine dinucleotide (NAD ⁺ ), an essential coenzyme for energy metabolism and an essential cofactor for non-redox NAD ⁺ -dependent enzymes with critical functions in sensing and repairing damaged tissue. NAD ⁺ depletion propagates tissue damage. Augmenting NAD ⁺ by exogenous application of NAD ⁺ , its synthesizing enzymes or its cellular precursors mitigates tissue damage. Among the NAD ⁺ precursors, nicotinamide riboside (NR) appears to be particularly well-suited for clinical translation. It safely and effectively augments cellular NAD ⁺ synthesis in a variety of species, including rats and humans, and in a variety of preclinical models, elicits tissue protection. Evidence of NR’s efficacy in the context of SCI repair, however, is currently lacking. These studies tested the hypothesis that administration of NR can effectively enhance NAD ⁺ in the injured spinal cord and that augmenting spinal cord NAD ⁺ protects spinal cord tissue from injury and leads to improvements in locomotor recovery. The results show that intraperitoneal administration of NR (500 mg/kg), administered four days prior to and two weeks following a mid-thoracic contusion-SCI injury, doubles spinal cord NAD ⁺ levels in Long-Evans rats. NR administration preserves spinal cord tissue after injury including neurons and axons, as determined by gray and white matter sparing, and enhances motor function, as assessed by the BBB subscore and missteps on the horizontal ladderwalk. Collectively, the findings demonstrate that administration of the NAD ⁺ precursor, NR, to elevate NAD ⁺ within the injured spinal cord mitigates the tissue damage and functional decline that occurs following SCI.
HIGHLIGHTS
Nicotinamide Riboside augments spinal cord nicotinamide adenine dinucleotide (NAD ⁺ ).
Elevating NAD ⁺ protects spinal cord tissue from spinal cord injury (SCI).
Elevating NAD ⁺ enhances motor recovery following SCI.
