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Background: Alzheimer's disease (AD) is a progressive neurocognitive disorder. There is no cure for AD. Maintenance on intracellular levels of nicotinamide adenine dinucleotide (NAD+) has been reported to be a promising therapeutic strategy for the treatment of AD. NAD+ precursors that represent candidate targets include nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR)., Objective: This systematic review provides insights into the potential therapeutic value of NAD+ precursors including NMN and NR, for the treatment of AD using preclinical and clinical studies published in the last 5 years., Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol was followed to systematically search the literature using two databases., Results: We found 3 studies that used NMN to treat AD in preclinical murine models. However, human clinical trials using NMN as a therapeutic intervention in AD was not available in the current literature. We also found 4 studies that investigated the potential benefits of NR for the treatment of AD in preclinical models. We also found 2 human clinical trials that showed marked improvements in plasma and neuroimaging biomarkers, and cognitive measures following supplementation with NR., Conclusions: Results of preclinical and clinical studies confirm the potential benefits of NAD+ precursors for the treatment of AD. However, further clinical studies are required to confirm the increasingly important value of NAD+ precursors as effective pharmacological interventions in the clinic.

The role of nicotinamide adenine dinucleotide (NAD+) in ageing has emerged as a critical factor in understanding links to a wide range of chronic diseases. Depletion of NAD+, a central redox cofactor and substrate of numerous metabolic enzymes, has been detected in many major age-related diseases. However, the mechanisms behind age-associated NAD+ decline remains poorly understood. Despite limited conclusive evidence, supplements aimed at increasing NAD+ levels are becoming increasingly popular. This review provides renewed insights regarding the clinical utility and benefits of NAD+ precursors, namely nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), in attenuating NAD+ decline and phenotypic characterization of age-related disorders, including metabolic, cardiovascular and neurodegenerative diseases. While it is anticipated that NAD+ precursors can play beneficial protective roles in several conditions, they vary in their ability to promote NAD+ anabolism with differing adverse effects. Careful evaluation of the role of NAD + , whether friend or foe in ageing, should be considered., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Friedreich's ataxia (FA) is due to deficiency of the mitochondrial protein, frataxin, which results in multiple pathologies including a deadly, hypertrophic cardiomyopathy. Frataxin loss leads to deleterious accumulations of redox-active, mitochondrial iron, and suppressed mitochondrial bioenergetics. Hence, there is an urgent need to develop innovative pharmaceuticals. Herein, the activity of the novel compound, 6-methoxy-2-salicylaldehyde nicotinoyl hydrazone (SNH6), was assessed in vivo using the well-characterized muscle creatine kinase (MCK) conditional frataxin knockout (KO) mouse model of FA. The design of SNH6 incorporated a dual-mechanism mediating: (1) NAD + -supplementation to restore cardiac bioenergetics; and (2) iron chelation to remove toxic mitochondrial iron. In these studies, MCK wild-type (WT) and KO mice were treated for 4-weeks from the asymptomatic age of 4.5-weeks to 8.5-weeks of age, where the mouse displays an overt cardiomyopathy. SNH6-treatment significantly elevated NAD + and markedly increased NAD + consumption in WT and KO hearts. In SNH6-treated KO mice, nuclear Sirt1 activity was also significantly increased together with the NAD + -metabolic product, nicotinamide (NAM). Therefore, NAD + -supplementation by SNH6 aided mitochondrial function and cardiac bioenergetics. SNH6 also chelated iron in cultured cardiac cells and also removed iron-loading in vivo from the MCK KO heart. Despite its dual beneficial properties of supplementing NAD + and chelating iron, SNH6 did not mitigate cardiomyopathy development in the MCK KO mouse. Collectively, SNH6 is an innovative therapeutic with marked pharmacological efficacy, which successfully enhanced cardiac NAD + and nuclear Sirt1 activity and reduced cardiac iron-loading in MCK KO mice. No other pharmaceutical yet designed exhibits both these effective pharmacological properties., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD+) is an essential pyridine nucleotide that is present in all living cells. NAD+ acts as an important cofactor and substrate for a multitude of biological processes including energy production, DNA repair, gene expression, calcium-dependent secondary messenger signalling and immunoregulatory roles. The de novo synthesis of NAD+ is primarily dependent on the kynurenine pathway (KP), although NAD+ can also be recycled from nicotinic acid (NA), nicotinamide (NAM) and nicotinamide riboside (NR). NAD+ levels have been reported to decline during ageing and age-related diseases. Recent studies have shown that raising intracellular NAD+ levels represents a promising therapeutic strategy for age-associated degenerative diseases in general and to extend lifespan in small animal models. A systematic review of the literature available on Medline, Embase and Pubmed was undertaken to evaluate the potential health and/or longevity benefits due to increasing NAD+ levels. A total of 1545 articles were identified and 147 articles (113 preclinical and 34 clinical) met criteria for inclusion. Most studies indicated that the NAD+ precursors NAM, NR, nicotinamide mononucleotide (NMN), and to a lesser extent NAD+ and NADH had a favourable outcome on several age-related disorders associated with the accumulation of chronic oxidative stress, inflammation and impaired mitochondrial function. While these compounds presented with a limited acute toxicity profile, evidence is still quite limited and long-term human clinical trials are still nascent in the current literature. Potential risks in raising NAD+ levels in various clinical disorders using NAD+ precursors include the accumulation of putative toxic metabolites, tumorigenesis and promotion of cellular senescence. Therefore, NAD+ metabolism represents a promising target and further studies are needed to recapitulate the preclinical benefits in human clinical trials., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD+) and its related metabolites (NADome) are important endogenous analytes that are thought to play important roles in cellular metabolism, inflammation, oxidative stress, cancer, neurodegeneration, and aging in mammals. However, these analytes are unstable during the collection of biological fluids, which is a major limiting factor for their quantitation. Herein, we describe a highly robust and quantitative method using liquid chromatography coupled to tandem mass spectrometry to quantify the NADome in whole blood, plasma, mononuclear cells, platelets, cerebrospinal fluid (CSF), and urine. This methodology represents a "gold standard" of measure for understanding biological pathways and developing targeted pharmacological interventions to modulate NAD+ biosynthesis and NAD-dependent mediators in health and disease.

Nicotinamide adenine dinucleotide (NAD + ) is an essential pyridine nucleotide that serves as an electron carrier in cellular metabolism and plays a crucial role in the maintenance of balanced redox homeostasis. Quantification of NAD + :NADH and NADP + :NADPH ratios are pivotal to a wide variety of cellular processes, including intracellular secondary messenger signaling by CD38 glycohydrolases, DNA repair by poly(adenosine diphosphate ribose) polymerase (PARP), epigenetic regulation of gene expression by NAD-dependent histone deacetylase enzymes known as sirtuins, and regulation of the oxidative pentose phosphate pathway. We quantified changes in the NAD + metabolome in plasma samples collected from consenting healthy human subjects across a wide age range (20-87 years) using liquid chromatography coupled to tandem mass spectrometry. Our data show a significant decline in the plasma levels of NAD + , NADP + , and other important metabolites such as nicotinic acid adenine dinucleotide (NAAD) with age. However, an age-related increase in the reduced form of NAD + and NADP + -NADH and NADPH-and nicotinamide (NAM), N-methyl-nicotinamide (MeNAM), and the products of adenosine diphosphoribosylation, including adenosine diphosphate ribose (ADPR) was also reported. Whereas, plasma levels of nicotinic acid (NA), nicotinamide mononucleotide (NMN), and nicotinic acid mononucleotide (NAMN) showed no statistically significant changes across age groups. Taken together, our data cumulatively suggest that age-related impairments are associated with corresponding alterations in the extracellular plasma NAD + metabolome. Our future research will seek to elucidate the role of modulating NAD + metabolites in the treatment and prevention of age-related diseases.

Significance: Nicotinamide adenine dinucleotide (NAD + ) is an essential pyridine nucleotide that serves as an essential cofactor and substrate for a number of critical cellular processes involved in oxidative phosphorylation and ATP production, DNA repair, epigenetically modulated gene expression, intracellular calcium signaling, and immunological functions. NAD + depletion may occur in response to either excessive DNA damage due to free radical or ultraviolet attack, resulting in significant poly(ADP-ribose) polymerase (PARP) activation and a high turnover and subsequent depletion of NAD + , and/or chronic immune activation and inflammatory cytokine production resulting in accelerated CD38 activity and decline in NAD + levels. Recent studies have shown that enhancing NAD + levels can profoundly reduce oxidative cell damage in catabolic tissue, including the brain. Therefore, promotion of intracellular NAD + anabolism represents a promising therapeutic strategy for age-associated degenerative diseases in general, and is essential to the effective realization of multiple benefits of healthy sirtuin activity. The kynurenine pathway represents the de novo NAD + synthesis pathway in mammalian cells. NAD + can also be produced by the NAD + salvage pathway. Recent Advances: In this review, we describe and discuss recent insights regarding the efficacy and benefits of the NAD + precursors, nicotinamide (NAM), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide mononucleotide (NMN), in attenuating NAD + decline in degenerative disease states and physiological aging. Critical Issues: Results obtained in recent years have shown that NAD + precursors can play important protective roles in several diseases. However, in some cases, these precursors may vary in their ability to enhance NAD + synthesis via their location in the NAD + anabolic pathway. Increased synthesis of NAD + promotes protective cell responses, further demonstrating that NAD + is a regulatory molecule associated with several biochemical pathways. Future Directions: In the next few years, the refinement of personalized therapy for the use of NAD + precursors and improved detection methodologies allowing the administration of specific NAD + precursors in the context of patients' NAD + levels will lead to a better understanding of the therapeutic role of NAD + precursors in human diseases.

Background: Nicotinamide adenine dinucleotide (NAD + ) is an essential pyridine nucleotide that is currently investigated as an important target to extend lifespan and health span. Age-related NAD+ depletion due to the accumulation of oxidative stress is associated with reduced energy production, impaired DNA repair and genomic instability., Scope of Review: NAD+ levels can be elevated therapeutically using NAD+ precursors or through lifestyle modifications including exercise and caloric restriction. However, high amounts of NAD+ may be detrimental in cancer progression and may have deleterious immunogenic roles., Major Conclusions: Standardized quantitation of NAD+ and related metabolites may therefore represent an important component of NAD+ therapy., General Significance: Quantitation of NAD+ may serve dual roles not only as an ageing biomarker, but also as a diagnostic tool for the prevention of malignant disorders., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

High protein intake and reduced levels of the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+) have both been independently associated with promotion of the ageing phenotype. However, it has not yet been shown whether these two independent observations are biochemically linked. To investigate this possibility, we used a cross-sectional study design of 100 apparently healthy middle-aged males (n = 48) and females, in which we assessed average dietary intakes of multiple components using a validated questionnaire. We also analysed fasting blood levels of urea, NAD+ and its metabolites, and inflammation-linked biomarkers, including interleukin-6 (IL-6), Kynurenine (Kyn), and Tryptophan (Trp). One-way ANOVA and ANCOVA were then performed for statistical analysis. Our results have shown for the first time that plasma levels of NAD+ and Total NAD(H) were lower with increasing protein intake (F (2, 92) = 4.61, P = 0.012; F (2, 92) = 4.55, P = 0.013, respectively). The associated decrease in NAD+ and NAD(H) levels was even stronger with increasing plasma levels of the protein breakdown product urea (F (2, 93) = 25.11, P≤0.001; F (2, 93) = 21.10, P≤0.001). These associations were all independent of age, gender and energy intake. However, no significant association was observed between protein intake or plasma urea, and plasma levels of NAD+ metabolites. We also observed that plasma levels of the inflammatory cytokine IL-6, and both Kyn, and Trp, but not the Kyn/Trp ratio were higher with increasing plasma urea levels (F (2, 94) = 3.30, P = 0.041; F (2, 95) = 7.41, P≤0.001; F (2, 96) = 4.23, P = 0.017, respectively). These associations were dependent on eGFR and energy intake, except for the urea and Trp association that was independent of all. In conclusion, we report for the first time, a novel association between protein intake, its metabolism, and plasma NAD+ levels with a possible link to inflammation. These findings provide further insight into how protein restriction may contribute to the anti-ageing process observed in several studies., Competing Interests: The authors have declared that no competing interests exist.

Purpose of Review: The current review discusses the biology and metabolism of the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+) in the central nervous system. We also review recent work suggesting important neuroprotective effects that may be associated with the promotion of NAD+ levels through NAD+ precursors against Alzheimer's disease., Recent Findings: Perturbations in the physiological homoeostatic state of the brain during the ageing process can lead to impaired cellular function, and ultimately leads to loss of brain integrity and accelerates cognitive and memory decline. Increased oxidative stress has been shown to impair normal cellular bioenergetics and enhance the depletion of the essential nucleotides NAD+ and ATP. NAD+ and its precursors have been shown to improve cellular homoeostasis based on association with dietary requirements, and treatment and management of several inflammatory and metabolic diseases in vivo. Cellular NAD+ pools have been shown to be reduced in the ageing brain, and treatment with NAD+ precursors has been hypothesized to restore these levels and attenuate disruption in cellular bioenergetics., Summary: NAD+ and its precursors may represent an important therapeutic strategy to maintain optimal cellular homoeostatic functions in the brain. NAD+ precursors are available in a variety of foods and may be translated to the clinic in the form of supplements.

Nicotinamide adenine dinucleotide (NAD + ) is an essential redox cofactor and signaling molecule that controls the activity of enzymes involved in metabolism, DNA repair, and cellular survival, such as the PARPs, CD38, and the sirtuins. Here, we describe three methods for measuring the activity of these enzymes: the etheno-NAD + assay measures NAD + hydrolase activity using an NAD + analog to produce a fluorescent product that is measured in real time; the PNC1 assay converts a native product of NAD + hydrolysis, nicotinamide, into a quantitative fluorescent readout; and liquid chromatography tandem mass spectrometry (LC-MS/MS) is used to characterize the entire NAD + metabolome in a sample. These methods will enable new insights into the roles that NAD + and the enzymes that utilize it play in health and disease.

Introduction: Nicotinamide adenine dinucleotide (NAD + ) is an essential pyridine nucleotide that serves as a key hydride transfer coenzyme for several oxidoreductases. It is also the substrate for intracellular secondary messenger signalling by CD38 glycohydrolases, DNA repair by poly(adenosine diphosphate ribose) polymerase, and epigenetic regulation of gene expression by a class of histone deacetylase enzymes known as sirtuins. The measurement of NAD + and its related metabolites (hereafter, the NAD + metabolome) represents an important indicator of cellular function., Objectives: A study was performed to develop a sensitive, selective, robust, reproducible, and rapid method for the concurrent quantitative determination of intracellular levels of the NAD + metabolome in glial and oocyte cell extracts using liquid chromatography coupled to mass spectrometry (LC/MS/MS)., Methods: The metabolites were separated on a versatile amino column using a dual HILIC-RP gradient with heated electrospray (HESI) tandem mass spectrometry detection in mixed polarity multiple reaction monitoring mode., Results: Quantification of 17 metabolites in the NAD + metabolome in U251 human astroglioma cells could be achieved. Changes in NAD + metabolism in U251 cell line, and murine oocytes under different culture conditions were also investigated., Conclusion: This method can be used as a sensitive profiling tool, tailoring chromatography for metabolites that express significant pathophysiological changes in several disease conditions and is indispensable for targeted analysis.

Over the last decade, the importance of NAD(+) has expanded beyond its role as an essential cofactor for energy metabolism. NAD(+) has emerged as a major signalling molecule that serves as the sole substrate for several enzymatic reactions including the DNA repair enzyme, poly(ADP-ribose) polymerase (PARP), NAD-dependent protein deacetylases or CD38, and transcriptional factors by a new class of histone deacetylases known as sirtuins. NAD(+) levels are regulated by the metabolic status and cellular stress caused by oxidative stress and DNA damage. Since a detailed study of NAD(+) metabolism in the healthy ageing mammalian brain is nascent, we examined the effect of ageing on intracellular NAD(+) metabolism in different brain regions in female Wistar rats in young (3 months), middle aged (12 months) and older adults (24 months). Our results are the first to show a significant decline in intracellular NAD(+) levels and NAD:NADH ratio with ageing in the CNS, occurring in parallel to an increase in lipid peroxidation and protein oxidation (o- and m-tyrosine) and a decline in total antioxidant capacity. Hyperphosphorylation of H2AX levels was also observed together with increased PARP-1 and PARP-2 expression, and CD38 activity, concomitantly with reduced NAD(+) and ATP levels and SIRT1 function in the cortex, brainstem, hippocampus and cerebellum. Reduced activity of mitochondrial complex I-IV and impaired maximum mitochondrial respiration rate were also observed in the ageing rat brain. Among the multiple physiological pathways associated with NAD(+) catabolism, our discovery of CD38 as the major regulator of cellular NAD(+) levels in rat neurons indicates that CD38 is a promising therapeutic target for the treatment of age-related neurodegenerative diseases.

The levels of the essential pyridine nucleotide, NAD(+) and its reduced form NADH have not been documented in MS patients. We aimed to investigate NAD(+) and NADH levels in serum in patients with different disease stages and forms of MS. NAD(+) and NADH levels were measured in the serum from 209 patients with relapsing remitting MS (RRMS), 136 with secondary progressive MS (SPMS), 51 with primary progressive MS (PPMS), and 99 healthy controls. All patients were in a clinically stable phase. Serum NAD(+) levels declined by at least 50% in patients with MS compared to controls (17.9 ± 3.2 μg/ml; p=0.0012). Within the MS sub-groups NAD(+) levels were higher in RRMS (9.9 ± 2.9 μg/ml; p=0.001) compared to PPMS (6.3 ± 2.1 μg/ml; p=0.003) and SPMS (7.8 ± 2.0 μg/ml; p=0.005). A two-fold increase in NADH levels (p=0.002) and at least three-fold reduction in the NAD(+)/NADH ratio (p=0.009) were observed in MS patients compared to controls. Serum NAD(+) and NADH levels are may be associated with disease progression in MS. Given the importance of NAD(+) in the maintenance of normal cellular function, it is likely that this molecule is of therapeutic relevance in MS., (© 2013 Elsevier B.V. All rights reserved.)

Nicotinamide adenine dinucleotide (NAD(+)) is an essential electron transporter in mitochondrial respiration and oxidative phosphorylation. In genomic DNA, NAD(+) also represents the sole substrate for the nuclear repair enzyme, poly(ADP-ribose) polymerase (PARP) and the sirtuin family of NAD-dependent histone deacetylases. Age associated increases in oxidative nuclear damage have been associated with PARP-mediated NAD(+) depletion and loss of SIRT1 activity in rodents. In this study, we further investigated whether these same associations were present in aging human tissue. Human pelvic skin samples were obtained from consenting patients aged between 15-77 and newborn babies (0-1 year old) (n = 49) previously scheduled for an unrelated surgical procedure. DNA damage correlated strongly with age in both males (p = 0.029; r = 0.490) and females (p = 0.003; r = 0.600) whereas lipid oxidation (MDA) levels increased with age in males (p = 0.004; r = 0.623) but not females (p = 0.3734; r = 0.200). PARP activity significantly increased with age in males (p<0.0001; r = 0.768) and inversely correlated with tissue NAD(+) levels (p = 0.0003; r = -0.639). These associations were less evident in females. A strong negative correlation was observed between NAD(+) levels and age in both males (p = 0.001; r = -0.706) and females (p = 0.01; r = -0.537). SIRT1 activity also negatively correlated with age in males (p = 0.007; r = -0.612) but not in females. Strong positive correlations were also observed between lipid peroxidation and DNA damage (p<0.0001; r = 0.4962), and PARP activity and NAD(+) levels (p = 0.0213; r = 0.5241) in post pubescent males. This study provides quantitative evidence in support of the hypothesis that hyperactivation of PARP due to an accumulation of oxidative damage to DNA during aging may be responsible for increased NAD(+) catabolism in human tissue. The resulting NAD(+) depletion may play a major role in the aging process, by limiting energy production, DNA repair and genomic signalling.

In the twentieth century, NAD+ research generated multiple discoveries. Identification of the important role of NAD+ as a cofactor in cellular respiration and energy production was followed by discoveries of numerous NAD+ biosynthesis pathways. In recent years, NAD+ has been shown to play a unique role in DNA repair and protein deacetylation. As discussed in this review, there are close interactions between oxidative stress and immune activation, energy metabolism, and cell viability in neurodegenerative disorders and ageing. Profound interactions with regard to oxidative stress and NAD+ have been highlighted in the present work. This review emphasizes the pivotal role of NAD+ in the regulation of DNA repair, stress resistance, and cell death, suggesting that NAD+ synthesis through the kynurenine pathway and/or salvage pathway is an attractive target for therapeutic intervention in age-associated degenerative disorders. NAD+ precursors have been shown to slow down ageing and extend lifespan in yeasts, and protect severed axons from degeneration in animal models neurodegenerative diseases.

The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of metabolism, stress resistance and longevity. Apart from its role as an important redox carrier, NAD+ also serves as the sole substrate for NAD-dependent enzymes, including poly(ADP-ribose) polymerase (PARP), an important DNA nick sensor, and NAD-dependent histone deacetylases, Sirtuins which play an important role in a wide variety of processes, including senescence, apoptosis, differentiation, and aging. We examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female wistar rats. Our results are the first to show a significant decline in intracellular NAD+ levels and NAD:NADH ratio in all organs by middle age (i.e.12 months) compared to young (i.e. 3 month old) rats. These changes in [NAD(H)] occurred in parallel with an increase in lipid peroxidation and protein carbonyls (o- and m- tyrosine) formation and decline in total antioxidant capacity in these organs. An age dependent increase in DNA damage (phosphorylated H2AX) was also observed in these same organs. Decreased Sirt1 activity and increased acetylated p53 were observed in organ tissues in parallel with the drop in NAD+ and moderate over-expression of Sirt1 protein. Reduced mitochondrial activity of complex I-IV was also observed in aging animals, impacting both redox status and ATP production. The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.

Oxidative imbalance is a prominent feature in Alzheimer's disease and ageing. Increased levels of reactive oxygen species (ROS) can result in disordered cellular metabolism due to lipid peroxdation, protein-cross linking, DNA damage and the depletion of nicotinamide adenine dinucleotide (NAD(+)). NAD(+) is a ubiquitous pyridine nucleotide that plays an essential role in important biological reactions., from ATP production and secondary messenger signaling, to transcriptional regulation and DNA repair. Chronic oxidative stress may be associated with NAD(+) depletion and a subsequent decrease in metabolic regulation and cell viability. Hence, therapies targeted toward maintaining intracellular NAD(+) pools may prove efficacious in the protection of age-dependent cellular damage, in general, and neurodegeneration in chronic central nervous system inflammatory diseases such as Alzheimer's disease, in particular.

Ciguatoxin (CTX), is a toxic compound produced by microalgae (dinoflagellate) Gambierdiscus spp., and is bio-accumulated and bio-transformed through the marine food chain causing neurological deficits. To determine the mechanism of CTX-mediated cytotoxicity in human neurons, we measured extracellular lactate dehydrogenase (LDH) activity, intracellular levels of nicotinamide adenine dinucleotide (NAD) and H2AX phosphorylation at serine 139 as a measure for DNA damage in primary cultures of human neurons treated with Pacific (P)-CTX-1B and P-CTX-3C. We found these marine toxins can induce a time and dose-dependent increase in extracellular LDH activity, with a concomitant decline in intracellular NAD levels and increased DNA damage at the concentration range of 5-200 nM. We also showed that pre- and post-treatment with rosmarinic acid (RA), the active constituent of the Heliotropium foertherianum (Boraginaceae) can attenuate CTX-mediated neurotoxicity. These results further highlight the potential of RA in the treatment of CTX-induced neurological deficits. [ABSTRACT FROM AUTHOR]