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  • Review Article
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Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity

Key Points

  • Nitric oxide (NO) is a gaseous signalling molecule that is involved in the regulation of the cardiovascular, immune and nervous systems.

  • In the CNS, NO is involved in many processes, including the regulation of synaptic plasticity, the sleep–wake cycle, neurosecretion, fluid balance and reproductive processes. In the PNS, NO is an inhibitory neurotransmitter that mediates the non-adrenergic, non-cholinergic relaxation of smooth muscle in both the gastrointestinal and urogenital tracts.

  • NO exerts its effect on an array of functions through the activation of several intracellular signalling pathways. One key pathway is the soluble guanylyl cyclase–cyclic GMP–protein kinase G system.

  • Physiological amounts of NO are neuroprotective, owing to S-nitrosylation of NMDA (N-methyl-D-aspartate) receptor subunits or of the active sites of caspases. Furthermore, NO activates Akt and CREB (cyclic AMP-responsive-element-binding protein), which are involved in two important survival pathways. NO also induces haem oxygenase 1, a key enzyme in the cellular stress response.

  • If it is produced in excess, or if a cell is under conditions of oxidative stress, NO becomes noxious and may undergo an oxidative–reductive reaction to form toxic compounds known as reactive nitrogen species (RNS), which cause cell damage. Both NO and RNS have a pathogenetic role in the onset and development of neurodegenerative disorders.

  • Although drugs that act on the NO–cGMP pathway are commonly used to treat impotence, lung diseases and pulmonary hypertension, their use for the prevention of neurodegenerative disorders is unlikely. The use of natural antioxidants, such as polyphenols, has been proposed for the prevention or treatment of Alzheimer's disease because of their in vitro ability to counteract NO-induced damage. However, the pharmacokinetics of these substances may limit their use in humans, and so more effort would be required to make these natural substances efficient in the treatment of neurodegenerative disorders.

Abstract

At the end of the 1980s, it was clearly demonstrated that cells produce nitric oxide and that this gaseous molecule is involved in the regulation of the cardiovascular, immune and nervous systems, rather than simply being a toxic pollutant. In the CNS, nitric oxide has an array of functions, such as the regulation of synaptic plasticity, the sleep–wake cycle and hormone secretion. Particularly interesting is the role of nitric oxide as a Janus molecule in the cell death or survival mechanisms in brain cells. In fact, physiological amounts of this gas are neuroprotective, whereas higher concentrations are clearly neurotoxic.

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Figure 1: Nitric oxide in the CNS and PNS.
Figure 2: The metabolic pathway that leads to nitric oxide formation.
Figure 3: Nitric oxide activates soluble guanylyl cyclase.
Figure 4: Neuroprotective effects of nitric oxide.
Figure 5: Neurotoxic effects of nitric oxide.

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References

  1. Guix, F. X., Uribesalgo, I., Coma, M. & Munoz, F. J. The physiology and pathophysiology of nitric oxide in the brain. Prog. Neurobiol. 76, 126–152 (2005). A comprehensive review of NO functions in the brain.

    CAS  PubMed  Google Scholar 

  2. Rivier, C. Role of gaseous neurotransmitters in the hypothalamic–pituitary–adrenal axis. Ann. NY Acad. Sci. 933, 254–264 (2001). A useful paper for understanding the controversial action of NO in the regulation of the stress axis.

    CAS  PubMed  Google Scholar 

  3. McCann, S. M. The nitric oxide hypothesis of brain aging. Exp. Gerontol. 32, 431–440 (1997).

    CAS  PubMed  Google Scholar 

  4. Toda, N., Ayajiki, K. & Okamura, T. Nitric oxide and penile erectile function. Pharmacol. Ther. 106, 233–266 (2005).

    CAS  PubMed  Google Scholar 

  5. Takahashi, T. Pathophysiological significance of neuronal nitric oxide synthase in the gastrointestinal tract. J. Gastroenterol. 38, 421–430 (2003).

    CAS  PubMed  Google Scholar 

  6. Currò, D. & Preziosi, P. Non-adrenergic non-cholinergic relaxation of the rat stomach. Gen. Pharmacol. 31, 697–703 (1998).

    PubMed  Google Scholar 

  7. Pacher, P., Beckman, J. S. & Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87, 315–424 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hirst, D. G. & Robson T. Nitrosative stress in cancer therapy. Front. Biosci. 12, 3406–3418 (2007).

    CAS  PubMed  Google Scholar 

  9. Ridnour, L. A. et al. The chemistry of nitrosative stress induced by nitric oxide and reactive nitrogen oxide species. Putting perspective on stressful biological situations. Biol. Chem. 385, 1–10 (2004).

    CAS  PubMed  Google Scholar 

  10. Sultana R. et al. Identification of nitrated proteins in Alzheimer's disease brain using a redox proteomics approach. Neurobiol. Dis. 22, 76–87 (2006).

    CAS  PubMed  Google Scholar 

  11. Castegna A. et al. Proteomic identification of nitrated proteins in Alzheimer's disease brain. J. Neurochem. 85, 1394–1401 (2003). This was the first proteomics study to identify nitrated proteins in the brain of patients with Alzheimer's disease.

    CAS  PubMed  Google Scholar 

  12. Bredt, D. S. Endogenous nitric oxide synthesis: biological functions and pathophysiology. Free Radic. Res. 31, 577–596 (1999).

    CAS  PubMed  Google Scholar 

  13. Dawson, T. M. & Snyder, S. H. Gases as biological messengers: nitric oxide and carbon monoxide in the brain. J. Neurosci. 14, 5147–5159 (1994). This paper provides details on the distribution of nNOS in the CNS and PNS.

    CAS  PubMed  Google Scholar 

  14. Rodrigo, J. et al. Localization of nitric oxide synthase in the adult rat brain. Philos. Trans. R. Soc. Lond. B Biol. Sci. 345, 175–221 (1994).

    CAS  PubMed  Google Scholar 

  15. Vincent, S. R. & Kimura, H. Histochemical mapping of nitric oxide synthase in the rat brain. Neuroscience 46, 755–784 (1992).

    CAS  PubMed  Google Scholar 

  16. Bredt, D. S. et al. Nitric oxide synthase protein and mRNA are discretely localized in neuronal populations of the mammalian CNS together with NADPH diaphorase. Neuron 7, 615–624 (1991).

    CAS  PubMed  Google Scholar 

  17. De Giorgio, R. et al. Nitric oxide producing neurons in the monkey and human digestive system. J. Comp. Neurol. 342, 619–627 (1994).

    CAS  PubMed  Google Scholar 

  18. Magee, T. et al. Cloning of a novel neuronal nitric oxide synthase expressed in penis and lower urinary tract. Biochem. Biophys. Res. Commun. 226, 145–151 (1996).

    CAS  PubMed  Google Scholar 

  19. Calabrese, V., Butterfield, D. A., Scapagnini, G., Stella, A. M. & Maines, M. D. Redox regulation of heat shock protein expression by signaling involving nitric oxide and carbon monoxide: relevance to brain aging, neurodegenerative disorders, and longevity. Antioxid. Redox Signal. 8, 444–477 (2006).

    CAS  PubMed  Google Scholar 

  20. Colasanti, M. et al. Expression of a NOS-III-like protein in human astroglial cell culture. Biochem. Biophys. Res. Commun. 252, 552–555 (1998).

    CAS  PubMed  Google Scholar 

  21. Rajasekaran, M. et al. Ex vivo expression of nitric oxide synthase isoforms (eNOS/iNOS) and calmodulin in human penile cavernosal cells. J. Urol. 160, 2210–2215 (1998).

    CAS  PubMed  Google Scholar 

  22. Arnold, W. P., Mittal, C. K., Katsuki, S. & Murad, F. Nitric oxide activates guanylate cyclase and increases guanosine 3′-5′-cyclic monophosphate levels in various tissue preparations. Proc. Natl Acad. Sci. USA 74, 3203–3207 (1977). A milestone paper about the ability of NO to activate sGC.

    CAS  PubMed  Google Scholar 

  23. Krumenacker, J. S., Hanafy, K. A. & Murad, F. Regulation of nitric oxide and soluble guanylyl cyclase. Brain Res. Bull. 62, 505–515 (2004).

    CAS  PubMed  Google Scholar 

  24. Nakane, M. Soluble guanylyl cyclase: physiological role as an NO receptor and the potential molecular target for therapeutic application. Clin. Chem. Lab. Med. 41, 865–870 (2003).

    CAS  PubMed  Google Scholar 

  25. Uretsky, A. D., Weiss, B. L., Yunker, W. K. & Chang, J. P. Nitric oxide produced by a novel nitric oxide synthase isoform is necessary for gonadotropin-releasing hormone-induced growth hormone secretion via a cGMP-dependent mechanism. J. Neuroendocrinol. 15, 667–676 (2003).

    CAS  PubMed  Google Scholar 

  26. Mollace, V., Muscoli, C., Masini, E., Cuzzocrea, S. & Salvemini, D. Modulation of prostaglandin biosynthesis by nitric oxide and nitric oxide donors. Pharmacol. Rev. 57, 217–252 (2005).

    CAS  PubMed  Google Scholar 

  27. Motterlini, R., Green, C. J. & Foresti, R. Regulation of heme oxygenase-1 by redox signals involving nitric oxide. Antioxid. Redox Signal. 4, 615–624 (2002).

    CAS  PubMed  Google Scholar 

  28. Contestabile, A. & Ciani, E. Role of nitric oxide in the regulation of neuronal proliferation, survival and differentiation. Neurochem. Int. 45, 903–914 (2004).

    CAS  PubMed  Google Scholar 

  29. Riccio, A. et al. A nitric oxide signaling pathway controls CREB-mediated gene expression in neurons. Mol. Cell 21, 283–294 (2006). This study demonstrates that the NO pathway controls CREB–DNA binding and CRE-mediated gene expression.

    CAS  Google Scholar 

  30. Foster, M. W., McMahon, T. J. & Stamler, J. S. S-nitrosylation in health and disease. Trends Mol. Med. 9, 160–168 (2003).

    CAS  PubMed  Google Scholar 

  31. Garthwaite, J., Charles, S. L. & Chess-Williams, R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature 336, 385–388 (1988). A landmark paper that demonstrates that EDRF, the early name given to NO, is involved in neurotransmission.

    CAS  PubMed  Google Scholar 

  32. Palmer, R. M., Ferrige, A. G. & Moncada, S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327, 524–526 (1987).

    CAS  Google Scholar 

  33. Ignarro, L. J., Buga, G. M., Wood, K. S., Byrns, R. E. & Chaudhuri, G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc. Natl Acad. Sci. USA 84, 9265–9269 (1987). A milestone paper that reveals the identity of EDRF as NO.

    CAS  PubMed  Google Scholar 

  34. Garthwaite, J. & Boulton, C. L. Nitric oxide signaling in the central nervous system. Annu. Rev. Physiol. 57, 683–706 (1995).

    CAS  PubMed  Google Scholar 

  35. Sanders, K. M. & Ward, S. M. Nitric oxide as a mediator of nonadrenergic noncholinergic neurotransmission. Am. J. Physiol. 262, G379–G392 (1992).

    CAS  PubMed  Google Scholar 

  36. Prast, H., Tran, M. H., Fischer, H. & Philippu, A. Nitric oxide-induced release of acetylcholine in the nucleus accumbens: role of cyclic GMP, glutamate, and GABA. J. Neurochem. 71, 266–273 (1998).

    CAS  PubMed  Google Scholar 

  37. Getting, S. J., Segieth, J., Ahmad, S., Biggs, C. S. & Whitton, P. S. Biphasic modulation of GABA release by nitric oxide in the hippocampus of freely moving rats in vivo. Brain Res. 717, 196–199 (1996).

    CAS  PubMed  Google Scholar 

  38. Ohkuma, S., Katsura, M., Chen, D. Z., Narihara, H. & Kuriyama, K. Nitric oxide-evoked [3H]γ-aminobutyric acid release is mediated by two distinct release mechanisms. Brain Res. Mol. Brain Res. 36, 137–144 (1996).

    CAS  PubMed  Google Scholar 

  39. Lonart, G., Wang, J. & Johnson, K. M. Nitric oxide induces neurotransmitter release from hippocampal slices. Eur. J. Pharmacol. 220, 271–272 (1992).

    CAS  PubMed  Google Scholar 

  40. Lorrain, D. S. & Hull, E. M. Nitric oxide increases dopamine and serotonin release in the medial preoptic area. Neuroreport 5, 87–89 (1993).

    CAS  PubMed  Google Scholar 

  41. Kaehler, S. T., Singewald, N., Sinner, C. & Philippu, A. Nitric oxide modulates the release of serotonin in the rat hypothalamus. Brain Res. 835, 346–349 (1999).

    CAS  PubMed  Google Scholar 

  42. Bon, C. L. & Garthwaite, J. On the role of nitric oxide in hippocampal long-term potentiation. J. Neurosci. 23, 1941–1948 (2003).

    CAS  PubMed  Google Scholar 

  43. Boulton, C. L., Southam, E. & Garthwaite, J. Nitric oxide-dependent long-term potentiation is blocked by a specific inhibitor of soluble guanylyl cyclase. Neuroscience 69, 699–703 (1995).

    CAS  PubMed  Google Scholar 

  44. Chien, W. L. et al. Enhancement of long-term potentiation by a potent nitric oxide–guanylyl cyclase activator, 3-(5-hydroxymethyl-2-furyl)-1-benzyl-indazole. Mol. Pharmacol. 63, 1322–1328 (2003).

    CAS  PubMed  Google Scholar 

  45. Hars, B. Endogenous nitric oxide in the rat pons promotes sleep. Brain Res. 816, 209–219 (1999).

    CAS  PubMed  Google Scholar 

  46. Datta, S., Patterson, E. H. & Siwek, D. F. Endogenous and exogenous nitric oxide in the pedunculopontine tegmentum induces sleep. Synapse 27, 69–78 (1997).

    CAS  PubMed  Google Scholar 

  47. Cavas, M. & Navarro, J. F. Effects of selective neuronal nitric oxide synthase inhibition on sleep and wakefulness in the rat. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 56–67 (2006).

    CAS  PubMed  Google Scholar 

  48. Stern, J. E. Nitric oxide and homeostatic control: an intercellular signalling molecule contributing to autonomic and neuroendocrine integration? Prog. Biophys. Mol. Biol. 84, 197–215 (2004).

    CAS  PubMed  Google Scholar 

  49. Toni, R., Malaguti, A., Benfenati, F. & Martini L. The human hypothalamus: a morpho-functional perspective. J. Endocrinol. Invest. 27, 73–94 (2004).

    CAS  PubMed  Google Scholar 

  50. Tsigos, C. & Chrousos, G. P. Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. J. Psychosom. Res. 53, 865–871 (2002).

    PubMed  Google Scholar 

  51. Barberis, C. & Tribollet, E. Vasopressin and oxytocin receptors in the central nervous system. Crit. Rev. Neurobiol. 10, 119–154 (1996).

    CAS  PubMed  Google Scholar 

  52. Tringali, G., Aubry, J. M., Navarra, P. & Pozzoli, G. Lamotrigine inhibits basal and Na+-stimulated, but not Ca2+-stimulated, release of corticotropin-releasing hormone from the rat hypothalamus. Psychopharmacology (Berl.) 188, 386–392 (2006).

    CAS  Google Scholar 

  53. Costa, A., Trainer, P., Besser, M. & Grossman, A. Nitric oxide modulates the release of corticotropin-releasing hormone from the rat hypothalamus in vitro. Brain Res. 605, 187–192 (1993).

    CAS  PubMed  Google Scholar 

  54. Yasin, S. et al. Nitric oxide modulates the release of vasopressin from rat hypothalamic explants. Endocrinology 133, 1466–1469 (1993).

    CAS  PubMed  Google Scholar 

  55. Nguyen, K. T. et al. Exposure to acute stress induces brain interleukin-1β protein in the rat. J. Neurosci. 18, 2239–2246 (1998).

    CAS  PubMed  Google Scholar 

  56. Karanth, S., Lyson, K. & McCann, S. M. Role of nitric oxide in interleukin 2-induced corticotropin-releasing factor release from incubated hypothalami. Proc. Natl Acad. Sci. USA 90, 3383–3387 (1993).

    CAS  PubMed  Google Scholar 

  57. Rivier, C. Role of nitric oxide in regulating the rat hypothalamic–pituitary–adrenal axis response to endotoxemia. Ann. NY Acad. Sci. 992, 72–85 (2003).

    CAS  PubMed  Google Scholar 

  58. Kadekaro, M. Nitric oxide modulation of the hypothalamo-neurohypophyseal system. Braz. J. Med. Biol. Res. 37, 441–450 (2004).

    CAS  PubMed  Google Scholar 

  59. Brann, D. W., Bhat, G. K., Lamar, C. A. & Mahesh, V. B. Gaseous transmitters and neuroendocrine regulation. Neuroendocrinology 65, 385–395 (1997).

    CAS  PubMed  Google Scholar 

  60. Argiolas, A. & Melis, M. R. Central control of penile erection: role of the paraventricular nucleus of the hypothalamus. Prog. Neurobiol. 76, 1–21 (2005).

    CAS  PubMed  Google Scholar 

  61. Mancuso, C. Heme oxygenase and its products in the nervous system. Antioxid. Redox Signal. 6, 878–887 (2004).

    CAS  PubMed  Google Scholar 

  62. Mancuso, C. et al. Inhibition of heme oxygenase in the central nervous system potentiates endotoxin-induced vasopressin release in the rat. J. Neuroimmunol. 99, 189–194 (1999).

    CAS  PubMed  Google Scholar 

  63. Mancuso, C. et al. Activation of heme oxygenase and consequent carbon monoxide formation inhibits the release of arginine vasopressin from rat hypothalamic explants. Molecular linkage between heme catabolism and neuroendocrine function. Brain Res. Mol. Brain Res. 50, 267–276 (1997). This was the first paper to provide direct evidence that carbon monoxide is involved in the regulation of vasopressin release from rat hypothalamic explants.

    CAS  PubMed  Google Scholar 

  64. Pozzoli, G. et al. Carbon monoxide as a novel neuroendocrine modulator: inhibition of stimulated corticotropin-releasing hormone release from acute rat hypothalamic explants. Endocrinology 135, 2314–2317 (1994).

    CAS  PubMed  Google Scholar 

  65. Jaffrey, S. R., Erdjument-Bromage, H., Ferris, C. D., Tempst, P. & Snyder, S. H. Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nature Cell Biol. 3, 193–197 (2001).

    CAS  PubMed  Google Scholar 

  66. Choi, Y. B. et al. Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nature Neurosci. 3, 15–21 (2000).

    CAS  PubMed  Google Scholar 

  67. Lipton, S. A., Singel, D. J. & Stamler, J. S. Nitric oxide in the central nervous system. Prog. Brain Res. 103, 359–364 (1994).

    CAS  PubMed  Google Scholar 

  68. Mungrue, I. N. & Bredt, D. S. nNOS at a glance: implications for brain and brawn. Cell Sci. 117, 2627–2629 (2004).

    CAS  Google Scholar 

  69. Melino, G. et al. S-nitrosylation regulates apoptosis. Nature 388, 432–433 (1997).

    CAS  PubMed  Google Scholar 

  70. Liu, L. & Stamler, J. S. NO: an inhibitor of cell death. Cell Death Differ. 6, 937–942 (1999).

    CAS  PubMed  Google Scholar 

  71. Mannick, J. B. et al. S-Nitrosylation of mitochondrial caspases. J. Cell Biol. 154, 1111–1116 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Tenneti, L., D'Emilia, D. M. & Lipton, S. A. Suppression of neuronal apoptosis by S-nitrosylation of caspases. Neurosci. Lett. 236, 139–142 (1997).

    CAS  PubMed  Google Scholar 

  73. Zhou, P., Qian, L. & Iadecola, C. Nitric oxide inhibits caspase activation and apoptotic morphology but does not rescue neuronal death. J. Cereb. Blood Flow Metab. 25, 348–357 (2005).

    CAS  PubMed  Google Scholar 

  74. Kitamura, Y. et al. In vitro and in vivo induction of heme oxygenase-1 in rat glial cells: possible involvement of nitric oxide production from inducible nitric oxide synthase. Glia 22, 138–148 (1998).

    CAS  PubMed  Google Scholar 

  75. Mancuso, C., Bonsignore, A., Di Stasio, E., Mordente, A. & Motterlini, R. Bilirubin and S-nitrosothiols interaction: evidence for a possible role of bilirubin as a scavenger of nitric oxide. Biochem. Pharmacol. 66, 2355–2363 (2003). In this paper, the authors describe the ability of bilirubin to interact with S -nitrosothiols.

    CAS  PubMed  Google Scholar 

  76. Good, P. F., Hsu, A., Werner, P., Perl, D. P. & Olanow, C. W. Protein nitration in Parkinson's disease. J. Neuropathol. Exp. Neurol. 57, 338–342 (1998).

    CAS  PubMed  Google Scholar 

  77. Mancuso, C. et al. Mitochondrial dysfunction, free radical generation and cellular stress response in neurodegenerative disorders. Front. Biosci. 12, 1107–1123 (2007).

    CAS  PubMed  Google Scholar 

  78. Dalle-Donne, I., Scaloni, A. & Butterfield, D. A. (Eds) Redox Proteomics: From Protein Modifications to Cellular Dysfunctions and Diseases (John Wiley & Sons, New Jersey, 2006). A comprehensive treatise on the identification of oxidatively modified proteins in health and disease.

    Google Scholar 

  79. Castegna, A. et al. Proteomic identification of oxidatively modified proteins in Alzheimer's disease brain. Part II: dihydropyrimidinase-related protein 2, α-enolase and heat shock cognate 71. J. Neurochem. 82, 1524–1532 (2002).

    CAS  PubMed  Google Scholar 

  80. Messier, C. & Gagnon, M. Glucose regulation and brain aging. J. Nutr. Health Aging 4, 208–213 (2000).

    CAS  PubMed  Google Scholar 

  81. Vanhanen, M. & Soininen, H. Glucose intolerance, cognitive impairment and Alzheimer's disease. Curr. Opin. Neurol. 11, 673–677 (1998).

    CAS  PubMed  Google Scholar 

  82. Ojika, K., Tsugu, Y., Mitake, S., Otsuka, Y. & Katada, E. NMDA receptor activation enhances the release of a cholinergic differentiation peptide (HCNP) from hippocampal neurons in vitro. Brain Res. Dev. Brain Res. 106, 173–180 (1998).

    CAS  PubMed  Google Scholar 

  83. Rossor, M. N. et al. The substantia innominata in Alzheimer's disease: an histochemical and biochemical study of cholinergic marker enzymes. Neurosci. Lett. 28, 217–222 (1982).

    CAS  PubMed  Google Scholar 

  84. Giacobini, E. Cholinergic function and Alzheimer's disease. Int. J. Geriatr. Psychiatry 18, S1–S5 (2003).

    PubMed  Google Scholar 

  85. Sun, M. K. & Alkon, D. L. Carbonic anhydrase gating of attention: memory therapy and enhancement. Trends Pharmacol. Sci. 23, 83–89 (2002).

    CAS  PubMed  Google Scholar 

  86. Chuang, D. M., Hough, C. & Senatorov, V. V. Glyceraldehyde-3-phosphate dehydrogenase, apoptosis, and neurodegenerative diseases. Annu. Rev. Pharmacol. Toxicol. 45, 269–290 (2005).

    CAS  PubMed  Google Scholar 

  87. Browne, S. E. & Beal, M. F. Oxidative damage in Huntington's disease pathogenesis Antioxid. Redox Signal. 8, 2061–2073 (2006).

    CAS  PubMed  Google Scholar 

  88. Gu, Z. et al. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297, 1186–1190 (2002).

    CAS  Google Scholar 

  89. Yong, V. W., Power, C., Forsyth, P. & Edwards, D. R. Metalloproteinases in biology and pathology of the nervous system. Nature Rev. Neurosci. 2, 502–511 (2001).

    CAS  Google Scholar 

  90. Yao, D. et al. Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proc. Natl Acad. Sci. USA 101, 10810–10814 (2004).

    CAS  PubMed  Google Scholar 

  91. Chung, K. K. et al. S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. Science 304, 1328–1331 (2004).

    CAS  PubMed  Google Scholar 

  92. Hara, M. R. et al. Neuroprotection by pharmacologic blockade of the GAPDH death cascade. Proc. Natl Acad. Sci. USA 103, 3887–3889 (2006). This paper describes a GAPDH–SIAH1-mediated pathway for cell death and unravels a new mechanism of action for selegiline, a drug used in the treatment of Parkinson's disease.

    CAS  PubMed  Google Scholar 

  93. Uehara, T. et al. S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441, 513–517 (2006).

    CAS  PubMed  Google Scholar 

  94. Burnett, A. L. The role of nitric oxide in erectile dysfunction: implications for medical therapy. J. Clin. Hypertens. (Greenwich) 8 (Suppl. 4), 53–62 (2006).

    CAS  Google Scholar 

  95. Redington, A. E. Modulation of nitric oxide pathways: therapeutic potential in asthma and chronic obstructive pulmonary disease. Eur. J. Pharmacol. 533, 263–276 (2006).

    CAS  PubMed  Google Scholar 

  96. Griffiths, M. J. & Evans, T. W. Inhaled nitric oxide therapy in adults. N. Engl. J. Med. 353, 2683–2695 (2005).

    CAS  PubMed  Google Scholar 

  97. Hemnes, A. R. & Champion, H. C. Sildenafil, a PDE5 inhibitor, in the treatment of pulmonary hypertension. Expert Rev. Cardiovasc. Ther. 4, 293–300 (2006).

    CAS  PubMed  Google Scholar 

  98. Butterfield D. et al. Nutritional approaches to combat oxidative stress in Alzheimer's disease. J. Nutr. Biochem. 13, 444 (2002).

    CAS  PubMed  Google Scholar 

  99. Scapagnini, G. et al. Curcumin activates defensive genes and protects neurons against oxidative stress. Antioxid. Redox Signal. 8, 395–403 (2006).

    CAS  PubMed  Google Scholar 

  100. Kanski, J., Aksenova, M., Stoyanova, A. & Butterfield, D. A. Ferulic acid antioxidant protection against hydroxyl and peroxyl radical oxidation in synaptosomal and neuronal cell culture systems in vitro: structure-activity studies. J. Nutr. Biochem. 13, 273–281 (2002).

    CAS  PubMed  Google Scholar 

  101. Kim, H. S. et al. Inhibitory effects of long-term administration of ferulic acid on microglial activation induced by intracerebroventricular injection of β-amyloid peptide (1–42) in mice. Biol. Pharm. Bull. 27, 120–121 (2004).

    CAS  PubMed  Google Scholar 

  102. Sultana, R., Ravagna, A., Mohmmad-Abdul, H., Calabrese, V. & Butterfield, D. A. Ferulic acid ethyl ester protects neurons against amyloid β-peptide(1–42)-induced oxidative stress and neurotoxicity: relationship to antioxidant activity. J. Neurochem. 92, 749–758 (2005).

    CAS  PubMed  Google Scholar 

  103. Calabrese, V., Giuffrida Stella, A. M., Calvani, M. & Butterfield, D. A. Acetylcarnitine and cellular stress response: roles in nutritional redox homeostasis and regulation of longevity genes. J. Nutr. Biochem. 17, 73–88 (2006).

    CAS  PubMed  Google Scholar 

  104. Calabrese, V. et al. Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: evidence for a protective role of acetylcarnitine. Neurochem. Res. 28, 1321–1328 (2003).

    CAS  PubMed  Google Scholar 

  105. Abdul, H. M., Calabrese, V., Calvani, M. & Butterfield, D. A. Acetyl-L-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-β peptide 1–42-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease. J. Neurosci. Res. 84, 398–408 (2006).

    CAS  PubMed  Google Scholar 

  106. De Marchis, S., Modena, C., Peretto, P., Giffard, C. & Fasolo, A. Carnosine-like immunoreactivity in the central nervous system of rats during postnatal development. J. Comp. Neurol. 426, 378–390 (2000).

    CAS  PubMed  Google Scholar 

  107. Calabrese, V. et al. Protective effect of carnosine during nitrosative stress in astroglial cell cultures. Neurochem. Res. 30, 797–807 (2005).

    CAS  PubMed  Google Scholar 

  108. Preston, J. E., Hipkiss, A. R., Himsworth, D. T., Romero, I. A. & Abbott, J. N. Toxic effects of β-amyloid (25–35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and β-alanine. Neurosci. Lett. 242, 105–108 (1998).

    CAS  PubMed  Google Scholar 

  109. Hipkiss, A. R. et al. Pluripotent protective effects of carnosine, a naturally occurring dipeptide. Ann. NY Acad. Sci. 854, 37–53 (1998).

    CAS  PubMed  Google Scholar 

  110. Fontana, M., Pinnen, F., Lucente, G. & Pecci, L. Prevention of peroxynitrite-dependent damage by carnosine and related sulphonamido pseudodipeptides. Cell. Mol. Life Sci. 59, 546–551 (2002).

    CAS  PubMed  Google Scholar 

  111. Joshi, G. et al. Glutathione elevation by γ-glutamylcysteine ethyl ester as a potential therapeutic strategy towards preventing oxidative stress in brain mediated by in vivo administration of adriamycin: implications for chemobrain. J. Neurosci. Res. 85, 497–503 (2007).

    CAS  PubMed  Google Scholar 

  112. Tangpong, J. et al. Adriamycin-induced, TNF-α-mediated central nervous system toxicity. Neurobiol. Dis. 23, 127–139 (2006).

    CAS  PubMed  Google Scholar 

  113. Tangpong, J. et al. Adriamycin mediated nitration of manganese superoxide dismutase in the central nervous system: insight into the mechanism of chemobrain. J. Neurochem. 100, 191–201 (2007).

    CAS  PubMed  Google Scholar 

  114. Silverman, D. H. et al. Altered frontocortical, cerebellar, and basal ganglia activity in adjuvant-treated breast cancer survivors 5–10 years after chemotherapy. Breast Cancer Res. Treat. 103, 303–311 (2007).

    CAS  PubMed  Google Scholar 

  115. Rahman, I., Biswas, S. K. & Kirkham, P. A. Regulation of inflammation and redox signalling by dietary polyphenols. Biochem. Pharmacol. 72, 1439–1452 (2006).

    CAS  PubMed  Google Scholar 

  116. Sultana, R. et al. Proteomic identification of nitrated brain proteins in amnestic mild cognitive impairment: a regional study. J. Cell. Mol. Med. 11, 839–851 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Butterfield, D. A. et al. Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer's disease. Neurobiol. Dis. 22, 223–232 (2006). This was the first paper to describe proteomics-identified oxidatively modified brain proteins in mild cognitive impairment, a precursor to Alzheimer's disease.

    CAS  PubMed  Google Scholar 

  118. Salerno, L., Sorrenti, V., Di Giacomo, C., Romeo, G. & Siracusa, M. A. Progress in the development of selective nitric oxide synthase (NOS) inhibitors. Curr. Pharm. Des. 8, 177–200 (2002). This paper provides useful information about the selectivity of several NOS inhibitors.

    CAS  PubMed  Google Scholar 

  119. Mejia-Garcia, T. A. & Paes-de-Carvalho, R. Nitric oxide regulates cell survival in purified cultures of avian retinal neurons: involvement of multiple transduction pathways. J. Neurochem. 100, 382–394 (2007).

    CAS  PubMed  Google Scholar 

  120. Privalle, C., Talarico, T., Keng, T. & DeAngelo, J. Pyridoxalated hemoglobin polyoxyethylene: a nitric oxide scavenger with antioxidant activity for the treatment of nitric oxide-induced shock. Free Radic. Biol. Med. 28, 1507–1517 (2000).

    CAS  PubMed  Google Scholar 

  121. Kaur, H. et al. Interaction of bilirubin and biliverdin with reactive nitrogen species. FEBS Lett. 543, 113–119 (2003).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from Ministero dell'Università e della Ricerca Cofin 2000, Progetti di Ricerca di Interesse Nazionale 2005, Fondo per gli Investimenti della Ricerca di Base RBNE01ZK8F and by National Institutes of Health grant AG-10836; AG-05119.

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Correspondence to Vittorio Calabrese.

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Calabrese, V., Mancuso, C., Calvani, M. et al. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 8, 766–775 (2007). https://doi.org/10.1038/nrn2214

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