Advertisement

NeuroMolecular Medicine

, Volume 11, Issue 1, pp 28–42 | Cite as

Nicotinamide Prevents NAD+ Depletion and Protects Neurons Against Excitotoxicity and Cerebral Ischemia: NAD+ Consumption by SIRT1 may Endanger Energetically Compromised Neurons

  • Dong Liu
  • Robert Gharavi
  • Michael Pitta
  • Marc Gleichmann
  • Mark P. Mattson
Original Paper
First Online:
Received:
Accepted:

Abstract

Neurons require large amounts of energy to support their survival and function, and are therefore susceptible to excitotoxicity, a form of cell death involving bioenergetic stress that may occur in several neurological disorders including stroke and Alzheimer’s disease. Here we studied the roles of NAD+ bioenergetic state, and the NAD+-dependent enzymes SIRT1 and PARP-1, in excitotoxic neuronal death in cultured neurons and in a mouse model of focal ischemic stroke. Excitotoxic activation of NMDA receptors induced a rapid decrease of cellular NAD(P)H levels and mitochondrial membrane potential. Decreased NAD+ levels and poly (ADP-ribose) polymer (PAR) accumulation in nuclei were relatively early events (<4 h) that preceded the appearance of propidium iodide- and TUNEL-positive cells (markers of necrotic cell death and DNA strand breakage, respectively) which became evident by 6 h. Nicotinamide, an NAD+ precursor and an inhibitor of SIRT1 and PARP1, inhibited SIRT1 deacetylase activity without affecting SIRT1 protein levels. NAD+ levels were preserved and PAR accumulation and neuronal death induced by excitotoxic insults were attenuated in nicotinamide-treated cells. Treatment of neurons with the SIRT1 activator resveratrol did not protect them from glutamate/NMDA-induced NAD+ depletion and death. In a mouse model of focal cerebral ischemic stroke, NAD+ levels were decreased in both the contralateral and ipsilateral cortex 6 h after the onset of ischemia. Stroke resulted in dynamic changes of SIRT1 protein and activity levels which varied among brain regions. Administration of nicotinamide (200 mg/kg, i.p.) up to 1 h after the onset of ischemia elevated brain NAD+ levels and reduced ischemic infarct size. Our findings demonstrate that the NAD+ bioenergetic state is critical in determining whether neurons live or die in excitotoxic and ischemic conditions, and suggest a potential therapeutic benefit in stroke of agents that preserve cellular NAD+ levels. Our data further suggest that, SIRT1 is linked to bioenergetic state and stress responses in neurons, and that under conditions of reduced cellular energy levels SIRT1 enzyme activity may consume sufficient NAD+ to nullify any cell survival-promoting effects of its deacetylase action on protein substrates.

Keywords

Excitotoxicity Glutamate NMDA NAD+ NADH SIRT1 PARP-1 PAR Nicotinamide MCAO TUNEL 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

We would like to thank Graeme I. Bell for providing us the mouse GLUT3 cDNA clone used for riboprobe preparation and in situ hybridization. This research was supported by the Intramural Research Program of the National Institute on Aging.

References

  1. Alcendor, R. R., Gao, S., Zhai, P., Zablocki, D., Holle, E., Yu, X., et al. (2007). Sirt1 regulates aging and resistance to oxidative stress in the heart. Circulation Research, 100, 1512–1521. doi: 10.1161/01.RES.0000267723.65696.4a.PubMedCrossRefGoogle Scholar
  2. Anderson, R. M., Latorre-esteves, M., Neves, A. R., Lavu, S., Medvedik, O., Taylor, C., et al. (2003). Yeast life-span extension by calorie restriction is independent of NAD+ fluctuation. Science, 302, 2124–2126. doi: 10.1126/science.1088697.PubMedCrossRefGoogle Scholar
  3. Ankarcrona, M., Dypbukt, J. M., Bonfoco, E., Zhivotovsky, B., Orrenius, S., Lipton, S. A., et al. (1995). Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function. Neuron, 15, 961–973. doi: 10.1016/0896-6273(95)90186-8.PubMedCrossRefGoogle Scholar
  4. Antzoulatos, E. G., & Byrne, J. H. (2004). Learning insights transmitted by glutamate. Trends in Neurosciences, 27, 555–560. doi: 10.1016/j.tins.2004.06.009.PubMedCrossRefGoogle Scholar
  5. Araki, T., Sasaki, Y., & Milbrandt, J. (2004). Increased nuclear NAD+ biosynthesis and SIRT1 activation prevent axonal degeneration. Science, 305, 1010–1013. doi: 10.1126/science.1098014.PubMedCrossRefGoogle Scholar
  6. Beal, M. F. (1992). Mechanisms of excitotoxicity in neurological diseases. The FASEB Journal, 6, 3338–3344.PubMedGoogle Scholar
  7. Belenky, P., Bogan, K. L., & Brenner, C. (2006). NAD+ metabolism in health and disease. Trends in Biochemical Sciences, 32, 12–19. doi: 10.1016/j.tibs.2006.11.006.PubMedCrossRefGoogle Scholar
  8. Bieganowski, P., & Brenner, C. (2004). Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-handler independent route to NAD+ in fungi and humans. Cell, 117, 495–502. doi: 10.1016/S0092-8674(04)00416-7.PubMedCrossRefGoogle Scholar
  9. Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M., & Sinclair, D. A. (2002). Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast Sir2 and human SIRT1. The Journal of Biological Chemistry, 277, 45099–45107. doi: 10.1074/jbc.M205670200.PubMedCrossRefGoogle Scholar
  10. Blander, G., & Guarente, L. (2004). The Sir2 family of protein deacetylases. Annual Review of Biochemistry, 73, 417–435. doi: 10.1146/annurev.biochem.73.011303.073651.PubMedCrossRefGoogle Scholar
  11. Boulares, A. H., Yakovlev, A. G., Ivanova, V., Stoica, B. A., Wang, G., Iyer, S., et al. (1999). Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis: Caspase 3-resistant parp mutant increases rates of apoptosis in transfected cells. The Journal of Biological Chemistry, 274, 22932–22940. doi: 10.1074/jbc.274.33.22932.PubMedCrossRefGoogle Scholar
  12. Brennan, A. M., Connor, J. A., & Shuttleworth, C. W. (2006). NAD(P)H fluorescence transients after synaptic activity in brain slices: predominant role of mitochondrial function. Journal of Cerebral Blood Flow and Metabolism, 26, 1389–1406. doi: 10.1038/sj.jcbfm.9600292.PubMedCrossRefGoogle Scholar
  13. Brunet, A., Sweeney, L. B., Sturgill, J. F., Chua, K. F., Greer, P. L., Lin, Y., et al. (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science, 303, 2011–2015. doi: 10.1126/science.1094637.PubMedCrossRefGoogle Scholar
  14. Butler, R., & Bates, G. P. (2006). Histone deacetylase inhibitors as therapeutics for polyglutamine disorders. Nature Reviews. Neuroscience, 7, 784–796. doi: 10.1038/nrn1989.PubMedCrossRefGoogle Scholar
  15. Cai, A. L., Zipfel, G. J., & Sheline, C. T. (2006). Zinc neurotoxicity is dependent on intracellular NAD+ levels and the sirtuin pathway. The European Journal of Neuroscience, 24, 2169–2176. doi: 10.1111/j.1460-9568.2006.05110.x.PubMedCrossRefGoogle Scholar
  16. Choi, D. W., & Koh, J. Y. (1998). Zinc and brain injury. Annual Review of Neuroscience, 21, 347–375. doi: 10.1146/annurev.neuro.21.1.347.PubMedCrossRefGoogle Scholar
  17. Clement, M. V., Hirpara, J. L., Chawdhury, S. H., & Pervaiz, S. (1998). Chemopreventive agent resveratrol, a natural product derived from grapes, triggers CD95 signaling-dependent apoptosis in human tumor cells. Blood, 92, 996–1002.PubMedGoogle Scholar
  18. Cohen, H. Y., Miller, C., Bitterman, K. J., Wal, N. R., Hekking, B., Kessler, B., et al. (2004). Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science, 305, 390–392. doi: 10.1126/science.1099196.PubMedCrossRefGoogle Scholar
  19. Dawson, V. L., & Dawson, T. M. (2004). Deadly conversations: Nuclear-mitochondrial cross-talk. Journal of Bioenergetics and Biomembranes, 36, 287–294. doi: 10.1023/B:JOBB.0000041755.22613.8d.PubMedCrossRefGoogle Scholar
  20. Du, L., Zhang, X., Han, Y. Y., Burke, N. A., Kochanek, P. M., Watkins, S. C., et al. (2003). Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress. The Journal of Biological Chemistry, 278, 18426–18433. doi: 10.1074/jbc.M301295200.PubMedCrossRefGoogle Scholar
  21. Eng, J., Lynch, R. M., & Balaban, R. S. (1989). Nicotinamide adenine dinucleotide fluorescence spectroscopy and imaging of isolated myocytes. Biophysical Journal, 55, 621–630. doi: 10.1016/S0006-3495(89)82859-0.PubMedCrossRefGoogle Scholar
  22. Fabrizio, P., Gattazzo, C., Battistella, L., Wei, M., Cheng, C., McGrew, K., et al. (2005). Sir2 blocks extreme life-span extension. Cell, 18, 655–667. doi: 10.1016/j.cell.2005.08.042.CrossRefGoogle Scholar
  23. Feng, Y., Paul, I. A., & LeBlanc, M. H. (2006). Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat. Brain Research Bulletin, 69, 117–122. doi: 10.1016/j.brainresbull.2005.11.011.PubMedCrossRefGoogle Scholar
  24. Gao, X., Xu, Y. X., Divine, G., Janakiraman, N., Chapman, R. A., & Gautam, S. C. (2002). Disparate in vitro and in vivo antileukemic effects of resveratrol, a natural polyphenolic compound found in grapes. The Journal of Nutrition, 132, 2076–2081.PubMedGoogle Scholar
  25. Gill, R., Andine, P., Hillerd, L., Persson, L., & Hagberg, H. (1992). The effect of MK-801 on cortical spreading depression in the penumbral zone following focal ischemia in the rat. Journal of Cerebral Blood Flow and Metabolism, 12, 371–379.PubMedGoogle Scholar
  26. Green, K. N., Steffan, J. S., Martinez-Coria, H., Sun, X., Schreiber, S. S., Thompson, L. M., et al. (2008). Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. Journal of Neuroscience, 28, 11500–11510. doi: 10.1523/JNEUROSCI.3203-08.2008.PubMedCrossRefGoogle Scholar
  27. Greene, J. G., & Greenamyre, J. T. (1996). Bioenergetics and glutamate excitotoxicity. Progress in Neurobiology, 48, 613–634. doi: 10.1016/0301-0082(96)00006-8.PubMedCrossRefGoogle Scholar
  28. Grubisha, O., Smith, B. C., & Denu, J. M. (2005). Small molecule regulation of sir2 protein deacetylase. FEBS, 272, 4607–4616. doi: 10.1111/j.1742-4658.2005.04862.x.CrossRefGoogle Scholar
  29. Ha, H. C., & Snyder, S. H. (2000). Poly(ADP-ribose) polymerase-1 in the nervous system. Neurobiology of Disease, 7, 225–239. doi: 10.1006/nbdi.2000.0324.PubMedCrossRefGoogle Scholar
  30. Hata, R., Maeda, K., Hermann, D., Mies, G., & Hossmann, K. A. (2000). Dynamics of regional brain metabolism and gene expression after middle cerebral artery occlusion. Journal of Cerebral Blood Flow and Metabolism, 20, 306–315. doi: 10.1097/00004647-200002000-00012.PubMedGoogle Scholar
  31. Herceg, Z., & Wang, Z. Q. (1999). Failure of poly(ADP-ribose) polymerase cleavage by caspases leads to induction of necrosis and enhanced apoptosis. Molecular and Cellular Biology, 19, 5124–5133.PubMedGoogle Scholar
  32. Hinz, M., Katsilambros, N., Maier, V., Schatz, H., & Pfeiffer, E. F. (1973). Significance of streptozotocin induced nicotinamide-adenine-dinucleotide (NAD+) degradation in mouse pancreatic islets. FEBS Letters, 30, 225–230. doi: 10.1016/0014-5793(73)80656-8.PubMedCrossRefGoogle Scholar
  33. Hossmann, K. A. (2003). Glutamate hypothesis of stroke. Fortschritte der Neurologie, Psychiatrie, und ihrer Grenzgebiete, 71(Suppl 1), S10. doi: 10.1055/s-2003-40500.Google Scholar
  34. Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., & Wood, J. G. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 425, 191–196. doi: 10.1038/nature01960.PubMedCrossRefGoogle Scholar
  35. Hyun, D. H., Hunt, N. D., Emerson, S. S., Hernandez, J. O., Mattson, M. P., & de Cabo, R. (2007). Up-regulation of plasma membrane-associated redox activities in neuronal cells lacking functional mitochondria. Journal of Neurochemistry, 100, 1364–1374. doi: 10.1111/j.1471-4159.2006.04411.x.PubMedCrossRefGoogle Scholar
  36. Imai, S., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000). Transcriptional silencing and longevity protein Sir2 is an NAD+-dependent histone deacetylase. Nature, 403, 795–800. doi: 10.1038/35001622.PubMedCrossRefGoogle Scholar
  37. Kaufmann, S. H., Desnoyers, S., Ottaviano, Y., Davidson, N. E., & Poirier, G. G. (1993). Specific cleavage of poly(ADP-ribose) polymerase: An early marker of chemotherapy-induced apoptosis. Cancer Research, 53, 3976–3985.PubMedGoogle Scholar
  38. Kauppinen, T. M., & Swanson, R. A. (2007). The role of poly(ADP-ribose) polymerase-1 in CNS disease. Neuroscience, 145, 1267–1272. doi: 10.1016/j.neuroscience.2006.09.034.PubMedCrossRefGoogle Scholar
  39. Klaidman, L., Morales, M., Kem, S., Yang, J., Chang, M. L., & Adams, J. D. (2003). Nicotinamide offers multiple protective mechanisms in stroke as a precursor for NAD+, as a PARP inhibitor and by partial restoration of mitochondrial function. Pharmacology, 69, 150–157. doi: 10.1159/000072668.PubMedCrossRefGoogle Scholar
  40. Kobayashi, Y., Furukawa-Hibi, Y., Chen, C., Horio, Y., Isobe, K., Ikeda, K., et al. (2005). SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress. International Journal of Molecular Medicine, 16, 237–243.PubMedGoogle Scholar
  41. Kolthur-Seetharam, U., Dantzer, F., McBurney, M. W., de Murcia, G., & Sassone-Corsi, P. (2006). Control of AIF-mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage. Cell Cycle, 5, 873–877.PubMedGoogle Scholar
  42. Landry, J., Sutton, A., Tafrov, S. T., Heller, R. C., Stebbins, J., Pillus, L., et al. (2000). The silencing protein SIR2 and its homologs are NAD+-dependent protein deacetylases. Proceedings of the National Academy of Sciences of the United States of America, 97, 5807–5811. doi: 10.1073/pnas.110148297.PubMedCrossRefGoogle Scholar
  43. Langley, B., Gensert, J. M., Beal, M. F., & Ratan, R. R. (2005). Remodeling chromatin and stress resistance in the central nervous system: histone deacetylase inhibitors as novel and broadly effective neuroprotective agents. Current Drug Targets. CNS Neurological Disorders, 4, 41–50.PubMedCrossRefGoogle Scholar
  44. Lee, J. B., Grabb, M. C., Zipfel, G. J., & Choi, D. W. (2000). Brain tissue responses to ischemia. The Journal of Clinical Investigation, 106, 723–731. doi: 10.1172/JCI11003.PubMedCrossRefGoogle Scholar
  45. Lisa, F. D., Menabo, R., Canton, M., Baria, M., & Bernardi, P. (2001). Opening of the mitochondrial permeability transition pore causes depletion of mitochondrial and cytosolic NAD+ and is a causative event in the death of myocytesin postischemic reperfusion of the heart. The Journal of Biological Chemistry, 276, 2571–2575. doi: 10.1074/jbc.M006825200.PubMedCrossRefGoogle Scholar
  46. Liu, D., Chan, S. L., de Souza-Pinto, N. C., Slevin, J. R., Wersto, R. P., Zhan, M., et al. (2006). Mitochondrial UCP4 mediates an adaptive shift in energy metabolism and increases the resistance of neurons to metabolic and oxidative stress. Neuromolecular Medicine, 8, 389–414. doi: 10.1385/NMM:8:3:389.PubMedCrossRefGoogle Scholar
  47. Liu, D., Lu, C., Wan, R., Auyeung, W. W., & Mattson, M. P. (2002). Activation of mitochondrial ATP-dependent potassium channels protects neurons against ischemia-induced death by a mechanism involving suppression of Bax translocation and cytochrome C. Journal of Cerebral Blood Flow and Metabolism, 22, 431–433. doi: 10.1097/00004647-200204000-00007.PubMedGoogle Scholar
  48. Liu, D., Pitta, M., & Mattson, M. (2008). Preventing NAD+ depletion protects neurons against excitotoxicity: Bioenergetic effects of mild mitochondrial uncoupling, caloric restriction. Annals of the New York Academy of Sciences, 1147, 275–282.PubMedCrossRefGoogle Scholar
  49. Liu, D., Smith, C. L., Barone, F. C., Ellison, J. A., Lysko, P. G., Li, K., et al. (1999). Astrocytic demise precedes delayed neuronal death in focal ischemic rat brain. Molecular Brain Research, 68, 29–41. doi: 10.1016/S0169-328X(99)00063-7.PubMedCrossRefGoogle Scholar
  50. Matthews, R. T., Ferrante, R. J., Klivenyi, P., Yang, L., Klein, A. M., Mueller, G., et al. (1999). Creatine and cyclocreatine attenuate MPTP neurotoxicity. Experimental Neurology, 157, 142–149. doi: 10.1006/exnr.1999.7049.PubMedCrossRefGoogle Scholar
  51. Matthews, R. T., Yang, L., Jenkins, B. G., Ferrante, R. J., Rosen, B. R., Kaddurah-Daouk, R., et al. (1998). Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington’s disease. Journal of Neuroscience, 18, 156–163.PubMedGoogle Scholar
  52. Mattson, M. P. (2003). Excitotoxic and excitoprotective mechanisms: Abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromolecular Medicine, 3, 65–94. doi: 10.1385/NMM:3:2:65.PubMedCrossRefGoogle Scholar
  53. Mattson, M. P., Barger, S. W., Begley, J. G., & Mark, R. J. (1995). Calcium, free radicals, and excitotoxic neuronal death in primary cell culture. Methods in Cell Biology, 46, 187–216. doi: 10.1016/S0091-679X(08)61930-5.PubMedCrossRefGoogle Scholar
  54. Mattson, M. P., & Liu, D. (2002). Energetics and oxidative stress in synaptic plasticity and neurodegenerative disorders. Neuromolecular Medicine, 2, 215–231. doi: 10.1385/NMM:2:2:215.PubMedCrossRefGoogle Scholar
  55. McBurney, M. W., Yang, X., Jardine, K., Hixon, M., Boekelheide, K., Webb, J. R., et al. (2003). The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis. Molecular and Cellular Biology, 23, 38–54. doi: 10.1128/MCB.23.1.38-54.2003.PubMedCrossRefGoogle Scholar
  56. Ohsawa, S., & Miura, M. (2006). Caspase-mediated changes in Sir2α during apoptosis. FEBS Letters, 580, 5875–5879. doi: 10.1016/j.febslet.2006.09.051.PubMedCrossRefGoogle Scholar
  57. Pieper, A. A., Blackshaw, S., Clements, E. E., Daniel, J., Brat, D. J., Krug, D. K., et al. (2000). Poly(ADP-ribosyl)ation basally activated by DNA strand breaks reflects glutamate-nitric oxide neurotransmission. Proceedings of the National Academy of Sciences of the United States of America, 97, 1845–1850. doi: 10.1073/pnas.97.4.1845.PubMedCrossRefGoogle Scholar
  58. Pillai, J. B., Isbatan, A., Imai, S., & Gupta, M. P. (2005). Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced sir2α deacetylase activity. The Journal of Biological Chemistry, 280, 43121–43130. doi: 10.1074/jbc.M506162200.PubMedCrossRefGoogle Scholar
  59. Raval, A. P., Dave, K. R., & Perez-Pinzon, M. A. (2006). Resveratrol mimics ischemic preconditioning in the brain. Journal of Cerebral Blood Flow and Metabolism, 26, 1141–1147.PubMedGoogle Scholar
  60. Rodgers, J. T., Lerin, C., Haas, W., Gygi, S. P., Spiegelman, B. M., & Puigserver, P. (2005). Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature, 434, 113–118. doi: 10.1038/nature03354.PubMedCrossRefGoogle Scholar
  61. Sadanaga-Akiyoshi, F., Yao, H., Tanuma, S., Nakahara, T., Hong, J. S., Ibayashi, S., et al. (2003). Nicotinamide attenuates focal ischemic brain injury in rats: With special reference to changes in nicotinamide and NAD+ levels in ischemic core and penumbra. Neurochemical Research, 28, 1227–1234. doi: 10.1023/A:1024236614015.PubMedCrossRefGoogle Scholar
  62. Sauve, A. A., Moir, R. M., Schramm, V. L., & Willis, I. M. (2005). Chemical activation of sir2-dependent silencing by relief of nicotinamide inhibition. Molecular Cell, 17, 595–601. doi: 10.1016/j.molcel.2004.12.032.PubMedCrossRefGoogle Scholar
  63. Schmidt, M. T., Smith, B. C., Jackson, M. D., & Denu, J. M. (2004). Coenzyme specificity of Sir2 protein deacetylases: Implications for physiological regulation. The Journal of Biological Chemistry, 279, 40122–40129. doi: 10.1074/jbc.M407484200.PubMedCrossRefGoogle Scholar
  64. Schulz, J. B., Henshaw, D. R., Matthews, R. T., & Beal, M. F. (1995). Coenzyme Q10 and nicotinamide and a free radical spin trap protect against MPTP neurotoxicity. Experimental Neurology, 132, 279–283. doi: 10.1016/0014-4886(95)90033-0.PubMedCrossRefGoogle Scholar
  65. Sheline, C. T., Behrens, M. M., & Choi, D. W. (2000). Zinc-induced cortical neuronal death: contribution of energy failure attributable to loss of NAD+ and inhibition of glycolysis. The Journal of Neuroscience, 20, 3139–3146.PubMedGoogle Scholar
  66. Soane, L., Kahraman, S., Kristian, T., & Fiskum, G. (2007). Mechanisms of impaired mitochondrial energy metabolism in acute and chronic neurodegenerative disorders. Journal of Neuroscience Research, 85, 3407–3415. doi: 10.1002/jnr.21498.PubMedCrossRefGoogle Scholar
  67. Sullivan, P. G., Geiger, J. D., Mattson, M. P., & Scheff, S. W. (2000). Dietary supplement creatine protects against traumatic brain injury. Annals of Neurology, 48, 723–729. doi: 10.1002/1531-8249(200011)48:5<723::AID-ANA5>3.0.CO;2-W.PubMedCrossRefGoogle Scholar
  68. Tanner, K. G., Landry, J., Sternglanz, R., & Denu, J. M. (2000). Silent information regulator 2 family of NAD-dependent histone/protein deacetylases generates a unique product, 1-O-acetyl-ADP-ribose. Proceedings of the National Academy of Sciences of the United States of America, 97, 14178–14182. doi: 10.1073/pnas.250422697.PubMedCrossRefGoogle Scholar
  69. Tarnopolsky, M. A., & Beal, M. F. (2001). Potential for creatine and other therapies targeting cellular energy dysfunction in neurological disorders. Annals of Neurology, 49, 561–574. doi: 10.1002/ana.1028.PubMedCrossRefGoogle Scholar
  70. Virag, L., & Szabo, C. (2002). The therapeutic potential of poly (ADP-ribose) polymerase inhibitors. Pharmacological Reviews, 54, 375–429. doi: 10.1124/pr.54.3.375.PubMedCrossRefGoogle Scholar
  71. Winfree, C. J., Baker, C. J., Connoly, E. S., Fiore, A. J., & Solomon, R. A. (1996). Mild hypothermia reduces penumbral glutamate levels in the rat permanent focal cerebral ischemia model. Neurosurgery, 38, 1216–1222. doi: 10.1097/00006123-199606000-00034.PubMedCrossRefGoogle Scholar
  72. Woodley, C. L., & Gupta, N. K. (1971). New enzyme cycling method for determination of oxidized and reduced nicotinamide adenine dinucleotide. Analytical Biochemistry, 43, 341–348.PubMedCrossRefGoogle Scholar
  73. Yang, J., Klaidman, L. K., Chang, M. L., Kem, S., Sugawara, T., Chan, P., et al. (2002). Nicotinamide therapy protects against both necrosis and apoptosis in a stroke model. Pharmacology, Biochemistry, and Behavior, 73, 901–910. doi: 10.1016/S0091-3057(02)00939-5.PubMedCrossRefGoogle Scholar
  74. Yang, T., & Sauve, A. A. (2006). NAD+ metabolism and sirtuins: Metabolic regulation of protein deacetylation in stress and toxicity. The AAPS Journal, 8, 632–643. doi: 10.1208/aapsj080472.CrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Dong Liu
    • 1
  • Robert Gharavi
    • 1
  • Michael Pitta
    • 1
  • Marc Gleichmann
    • 1
  • Mark P. Mattson
    • 1
  1. 1.Laboratory of NeurosciencesNational Institute on Aging, Intramural Research ProgramBaltimoreUSA

Personalised recommendations

Cite article

Buy options