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Braidy N.,University of Sydney | Guillemin G.J.,University of Sydney | Guillemin G.J.,St Vincents Center For Applied Medical Research | Mansour H.,University of Sydney | And 3 more authors.
FEBS Journal | Year: 2011

The kynurenine pathway of tryptophan catabolism plays an important role in several biological systems affected by aging. We quantified tryptophan and its metabolites kynurenine (KYN), kynurenine acid (KYNA), picolinic acid (PIC) and quinolinic acid (QUIN), and activity of the kynurenine pathway enzymes indoleamine 2,3-dioxygenase (IDO), tryptophan 2,3-dioxygenase (TDO) and quinolinic acid phosphoribosyltransferase (QPRTase), in the brain, liver and kidney of young, middle-aged and old female Wistar rats. Tryptophan levels and TDO activity decreased in all tissues with age. In contrast, brain IDO activity increased with age, while liver and kidney IDO activity decreased with age. The levels of KYN, KYNA, QUIN and PIC in brain all increased with age, while the levels of KYN in the liver and kidney showed a tendency to decrease. The levels of KYNA in the liver did not change, but the levels of KYNA in the kidney increased. The levels of PIC and QUIN increased significantly in the liver but showed a tendency to decrease in the kidney. QPRTase activity in both brain and liver decreased with age but was elevated in the kidney in middle-aged (12-month-old) rats. These age-associated changes in tryptophan metabolism have the potential to impact upon major biological processes, including lymphocyte function, pyridine (NAD(P)(H)) synthesis and N-methyl-d-aspartate (NMDA)-mediated synaptic transmission, and may therefore contribute to several degenerative changes of the elderly. The kynurenine pathway (KP) plays an important role in several biological systems affected by aging. In this study, the levels of several KP metabolites, and the activities of important KP enzymes have been examined in the brain, liver and kidney of physiologically aged female wistar rats. These age-related changes can impact upon biological processes associated with aging © 2011 The Authors Journal compilation © 2011 FEBS. Source


Braidy N.,University of New South Wales | Guillemin G.J.,University of New South Wales | Guillemin G.J.,St Vincents Center For Applied Medical Research | Grant R.,University of New South Wales | Grant R.,Australasian Research Institute
International Journal of Tryptophan Research | Year: 2011

The kynurenine pathway (KP) is the principle route of L-Tryptophan (TRP) metabolism, producing several neurotoxic and neuroprotective metabolic precursors before complete oxidation to the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD +). KP inhibition may prove therapeutic in central nervous system (CNS) inflammation by reducing the production of excitotoxins such as quinolinic acid (QUIN). However, KP metabolism may also be cytoprotective through the de novo synthesis of intracellular NAD +. We tested the hypothesis that the KP is directly involved in the maintenance of intracellular NAD + levels and SIRT1 function in primary astrocytes and neurons through regulation of NAD + synthesis. Competitive inhibition of indoleamine 2,3 dioxygenase (IDO), and quinolinic acid phosphoribosyltransferase (QPRT) activities with 1-methyl-L-Tryptophan (1-MT), and phthalic acid (PA) respectively, resulted in a dose-dependent decrease in intracellular NAD + levels and sirtuin deacetylase-1 (SIRT1) activity, and correlated directly with reduced cell viability. These results support the hypothesis that the primary role of KP activation during neuroinflammation is to maintain NAD + levels through de novo synthesis from TRP. Inhibition of KP metabolism under these conditions can compromise cell viability, NAD-dependent SIRT1 activity and CNS function, unless alternative precursors for NAD + synthesis are made available. © the author(s). Source


Guest J.,Australasian Research Institute | Guest J.,University of New South Wales | Grant R.,University of New South Wales | Grant R.,University of Sydney | And 2 more authors.
PLoS ONE | Year: 2014

An extensive body of evidence indicates that oxidative stress and inflammation play a central role in the degenerative changes of systemic tissues in aging. However a comparatively limited amount of data is available to verify whether these processes also contribute to normal aging within the brain. High levels of oxidative damage results in key cellular changes including a reduction in available nicotinamide adenine dinucleotide (NAD+), an essential molecule required for a number of vital cellular processes including DNA repair, immune signaling and epigenetic processing. In this study we quantified changes in [NAD(H)] and markers of inflammation and oxidative damage (F2-isoprostanes, 8-OHdG, total antioxidant capacity) in the cerebrospinal fluid (CSF) of healthy humans across a wide age range (24-91 years). CSF was collected from consenting patients who required a spinal tap for the administration of anesthetic. CSF of participants aged >45 years was found to contain increased levels of lipid peroxidation (F2-isoprostanes) (p = 0.04) and inflammation (IL-6) (p = 0.00) and decreased levels of both total antioxidant capacity (p = 0.00) and NAD(H) (p = 0.05), compared to their younger counterparts. A positive association was also observed between plasma [NAD(H)] and CSF NAD(H) levels (p = 0.03). Further analysis of the data identified a relationship between alcohol intake and CSF [NAD(H)] and markers of inflammation. The CSF of participants who consumed >1 standard drink of alcohol per day contained lower levels of NAD(H) compared to those who consumed no alcohol (p<0.05). An increase in CSF IL-6 was observed in participants who reported drinking >0-1 (p<0.05) and >1 (p<0.05) standard alcoholic drinks per day compared to those who did not drink alcohol. Taken together these data suggest a progressive age associated increase in oxidative damage, inflammation and reduced [NAD(H)] in the brain which may be exacerbated by alcohol intake. © 2014 Guest et al. Source


Braidy N.,University of Sydney | Grant R.,University of Sydney | Grant R.,Australasian Research Institute | Adams S.,University of Sydney | And 2 more authors.
FEBS Journal | Year: 2010

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. © 2009 FEBS. Source


Braidy N.,University of New South Wales | Guillemin G.J.,University of New South Wales | Guillemin G.J.,St Vincents Center For Applied Medical Research | Mansour H.,University of Sydney | And 4 more authors.
PLoS ONE | Year: 2011

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. © 2011 Braidy et al. Source

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