Nursing & Health

Permanent URI for this collectionhttps://research.avondale.edu.au/handle/123456789/457

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    A Pilot Study Investigating Changes in the Human Plasma and Urine NAD+ Metabolome During a 6 Hour Intravenous Infusion of NAD+
    (2019-09-12) Watson, James; Broom, Susan; Bennett, James; Braidy, Nady; Mestayer, Richard; Berg, Jade; Grant, Ross

    Accumulating evidence suggests that active maintenance of optimal levels of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+) is beneficial in conditions of either increased NAD+ turnover or inadequate synthesis, including Alzheimer’s disease and other neurodegenerative disorders and the aging process. While studies have documented the efficacy of some NAD+ precursors such as nicotinamide riboside (NR) in raising plasma NAD+, no data are currently available on the fate of directly infused NAD+ in a human cohort. This study, therefore, documented changes in plasma and urine levels of NAD+ and its metabolites during and after a 6 h 3 μmol/min NAD+ intravenous (IV) infusion. Surprisingly, no change in plasma (NAD+) or metabolites [nicotinamide, methylnicotinamide, adenosine phosphoribose ribose (ADPR) and nicotinamide mononucleotide (NMN)] were observed until after 2 h. Increased urinary excretion of methylnicotinamide and NAD+ were detected at 6 h, however, no significant rise in urinary nicotinamide was observed. This study revealed for the first time that: (i) at an infusion rate of 3 μmol/min NAD+ is rapidly and completely removed from the plasma for at least the first 2 h; (ii) the profile of metabolites is consistent with NAD+ glycohydrolase and NAD+ pyrophosphatase activity; and (iii) urinary excretion products arising from an NAD+ infusion include NAD+ itself and methyl nicotinamide (meNAM) but not NAM.

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    A Case of Parkinson’s Disease Symptom Reduction with Intravenous NAD+
    (2019-04-05) Happel, Michael; Gibson, Susan B.; Grigoryev, Yevgeniy; Grant, Ross; Mestayer, Richard F.; Gadol, Erin

    Neurological deterioration in Parkinson’s disease (PD) and resulting motor dysfunction arises from Lewy body formation and dopaminergic neuronal death in the substantia nigra. Two factors contributing to PD-related apoptosis and subsequent motor dysfunction involve improper cellular metabolism of reactive oxygen species (ROS) and impaired mitochondrial functionality. The co-factor Nicotinamide Adenine Dinucleotide (NAD+), reduction of which has been implicated in the development of neurodegenerative disease, is a critical player in maintaining cellular redox metabolism and mitochondrial function. We present a case study of a PD patient who has become near asymptomatic through the use of intravenous (I.V.) NAD+. This report documents the patient’s initial symptom changes while receiving I.V. NAD+ over the course of eight treatment days, with two non-treatment days in between. The treatment entailed 1500 mg. I.V. NAD+ on day one, 1000 mg. I.V. NAD+ on day two, and 750 mg. I.V. NAD+ on day three. Symptoms were documented by medical staff for the next two days of non-treatment. Following this, 750 mg. I.V. NAD+ was administered on treatment days four and five, 500 mg. I.V. NAD+ on treatment days six and seven, and 750 mg. I.V. NAD+ on treatment day eight. Over the course of treatment, the patient’s hand tremors decreased to a mild level, permitting coordinated use of a pen and utensils. Hand tremors were absent on days one and six. Visual hallucinations were absent on days two through seven. To maintain tremors at a tolerable level, aftercare involved I.V. NAD+ every four to six weeks, with a daily regimen of 300 mg/ml NAD+ nasal spray. Moreover, the patient discontinued PD-related medication, thereby preventing visual hallucination side effects. Although more research on NAD+ in clinical use is needed, the evidence obtained from these symptom improvements indicates NAD+ as having the potential for clinical use in at least a subset of PD sufferers.

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    Nicotinamide Adenine Dinucleotide and its Related Precursors for the Treatment of Alzheimer's Disease
    (2018-03-01) Sachdev, Perminder; Grant, Ross; Braidy, Nady

    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.

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    Indoleamine 2,3-Dioxygenase Activity Increases NAD+ Production in IFN-γ–Stimulated Human Primary Mononuclear Cells
    (2018-01-08) Grant, Ross

    IFN-γ activation of mononuclear phagocytes significantly increases indoleamine 2,3-dioxygenase (IDO) and flux through the kynurenine pathway (KP). However, the effect of IDO on NAD+ synthesis, the end product of KP metabolism, is unknown. To investigate this, primary human peripheral blood mononuclear cells were cultured up to 10 days and activated with IFN-γ in the presence or absence of a poly(ADP-ribose) polymerase (PARP) inhibitor. Day 10 macrophages had significantly higher NAD+ levels compared with monocytes. IFN-γ activation of macrophages resulted in the highest induction of IDO but decreased intracellular NAD+ concentrations at both 24 and 48 hours. However, IFN-γ activation of both day 6 and day 10 macrophages in the presence of a PARP inhibitor resulted in significantly higher intracellular NAD+ levels at 24 hours. This study provides evidence for the first time that an immune-mediated increase in IDO activity increases NAD+ biosynthesis concomitantly with an increase in NAD+ catabolism in primary human macrophages.

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    Neuroprotective Effects of Naturally Occurring Polyphenols on Quinolinic Acid-induced Excitotoxicity in Human Neurons
    (2010-01-01) Guillemin, Gilles; Adams, Seray; Grant, Ross; Braidy, Nady

    Quinolinic acid (QUIN) excitotoxicity is mediated by elevated intracellular Ca2+ levels, and nitric oxide-mediated oxidative stress, resulting in DNA damage, poly(ADP-ribose) polymerase (PARP) activation, NAD+ depletion and cell death. We evaluated the effect of a series of polyphenolic compounds [i.e. epigallocatechin gallate (EPCG), catechin hydrate, curcumin, apigenin, naringenin and gallotannin] with antioxidant properties on QUIN-induced excitotoxicity on primary cultures of human neurons. We showed that the polyphenols, EPCG, catechin hydrate and curcumin can attenuate QUIN-induced excitotoxicity to a greater extent than apigenin, naringenin and gallotannin. Both EPCG and curcumin were able to attenuate QUIN-induced Ca2+ influx and neuronal nitric oxide synthase (nNOS) activity to a greater extent compared with apigenin, naringenin and gallotannin. Although Ca2+ influx was not attenuated by catechin hydrate, nNOS activity was reduced, probably through direct inhibition of the enzyme. All polyphenols reduced the oxidative effects of increased nitric oxide production, thereby reducing the formation of 3-nitrotyrosine and poly (ADP-ribose) polymerase activity and, hence, preventing NAD+ depletion and cell death. In addition to the well-known antioxidant properties of these natural phytochemicals, the inhibitory effect of some of these compounds on specific excitotoxic processes, such as Ca2+ influx, provides additional evidence for the beneficial health effects of polyphenols in excitable tissue, particularly within the central nervous system.

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    Cerebrospinal Fluid Levels of Inflammation, Oxidative Stress and NAD+ are Linked to Differences in Plasma Carotenoid Concentrations
    (2014-07-01) Bilgin, Ayse; Croft, Kevin D.; Mori, Trevor A.; Garg, Manohar; Grant, Ross; Guest, Jade

    Background: The consumption of foods rich in carotenoids that possess significant antioxidant and inflammatory modulating properties has been linked to reduced risk of neuropathology. The objective of this study was to evaluate the relationship between plasma carotenoid concentrations and plasma and cerebrospinal fluid (CSF) markers of inflammation, oxidative stress and nicotinamide adenine dinucleotide (NAD+) in an essentially healthy human cohort.

    Methods: Thirty-eight matched CSF and plasma samples were collected from consenting participants who required a spinal tap for the administration of anaesthetic. Plasma concentrations of carotenoids and both plasma and cerebrospinal fluid (CSF) levels of NAD(H) and markers of inflammation (IL-6, TNF-α) and oxidative stress (F2-isoprostanes, 8-OHdG and total antioxidant capacity) were quantified.

    Results: The average age of participants was 53 years (SD = 20, interquartile range = 38). Both α-carotene (P = 0.01) and β-carotene (P < 0.001) correlated positively with plasma total antioxidant capacity. A positive correlation was observed between α-carotene and CSF TNF-α levels (P = 0.02). β-cryptoxanthin (P = 0.04) and lycopene (P = 0.02) inversely correlated with CSF and plasma IL-6 respectively. A positive correlation was also observed between lycopene and both plasma

    (P < 0.001) and CSF (P < 0.01) [NAD(H)]. Surprisingly no statistically significant associations were found between the most abundant carotenoids, lutein and zeaxanthin and either plasma or CSF markers of oxidative stress.

    Conclusion: Together these findings suggest that consumption of carotenoids may modulate inflammation and enhance antioxidant defences within both the central nervous system (CNS) and systemic circulation. Increased levels of lycopene also appear to moderate decline in the essential pyridine nucleotide [NAD(H)] in both the plasma and the CSF.

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    The Effect of Antioxidant Supplementation on Fatigue During Exercise: Potential Role for NAD+(H)
    (2010-03-01) Bentley, David J.; Grant, Ross; Dank, Steve; Midgley, Adrian W.; Mach, John

    This study compared serum pyridine levels (NAD+ /NADH) in trained (n = 6)and untrained (n = 7) subjects after continuous progressive exercise at 50%, 70% then 95% of physical work capacity until fatigue (TTF) after consuming a placebo or antioxidant (AO) cocktail (Lactaway ©). An increase of 17% in TTF was observed in AO as compared to placebo (p = 0.032). This was accompanied by a significant increase in serum NAD+ levels (p = 0.037) in the AO supplemented group post exercise. The increases in NAD+ and improved endurance reflect lower oxidative stress-induced suppression of aerobic respiration.

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    Promotion of Cellular NAD+ Anabolism: Therapeutic Potential for Oxidative Stress in Ageing and Alzheimer’s Disease
    (2008-01-01) Grant, Ross; Guillemin, Gilles; Braidy, Nady

    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 peroxidation, 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 signalling, 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.