Nitric oxide and multiple sclerosis

  • Juan Manuel Encinas
  • Louis Manganas
  • Grigori Enikolopov


Nitric oxide (NO) is a free radical signaling molecule with remarkably complex biochemistry. Its involvement in multiple sclerosis (MS) had been postulated soon after the discovery of the critical role NO plays in inflammation. However, the extent of NO’s contribution to MS is not yet understood, party due to the often opposing roles that NO can play in cellular processes. This review briefly covers new developments in the area of NO that may be relevant to MS. It also describes recent progress in understanding the role of NO in MS, new potential targets of the action of NO in the cell, and prospects for NO-based therapies.


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References and Recommended Reading

  1. 1.
    Smith KJ, Lassmann H: The role of nitric oxide in multiple sclerosis. Lancet Neurol 2002, 1:232–241. This is a detailed review of the contribution of NO to MS and EAE and of potential NO-based therapies.PubMedCrossRefGoogle Scholar
  2. 2.
    Parkinson JF, Mitrovic B, Merrill JE: The role of nitric oxide in multiple sclerosis. J Mol Med 1997, 75:174–186.PubMedCrossRefGoogle Scholar
  3. 3.
    Smith KJ, Kapoor R, Felts PA: Demyelination: the role of reactive oxygen and nitrogen species. Brain Pathol 1999, 9:69–92.PubMedCrossRefGoogle Scholar
  4. 4.
    Willenborg DO, Staykova MA, Cowden WB: Our shifting understanding of the role of nitric oxide in autoimmune encephalomyelitis: a review. J Neuroimmunol 1999, 100:21–35.PubMedCrossRefGoogle Scholar
  5. 5.
    Bredt DS: Endogenous nitric oxide synthesis: biological functions and pathophysiology. Free Radic Res 1999, 31:577–596.PubMedCrossRefGoogle Scholar
  6. 6.
    Ignarro LJ: Nitric Oxide: Biology and Pathobiology, edn 1. San Diego: Academic Press; 2000.Google Scholar
  7. 7.
    Nathan C: Specificity of a third kind: reactive oxygen and nitrogen intermediates in cell signaling. J Clin Invest 2003, 111:769–778.PubMedCrossRefGoogle Scholar
  8. 8.
    Alderton WK, Cooper CE, Knowles RG: Nitric oxide synthases: structure, function and inhibition. Biochem J 2001, 357:593–615.PubMedCrossRefGoogle Scholar
  9. 9.
    Nathan C: Inducible nitric oxide synthase: what difference does it make? J Clin Invest 1997, 100:2417–2423.PubMedCrossRefGoogle Scholar
  10. 10.
    Ridnour LA, Thomas DD, Mancardi D, et al.: The chemistry of nitrosative stress induced by nitric oxide and reactive nitrogen oxide species. Putting perspective on stressful biological situations. Biol Chem 2004, 385:1–10.PubMedCrossRefGoogle Scholar
  11. 11.
    Fang FC: Antimicrobial reactive oxygen and nitrogen species: concepts and controversies. Nat Rev Microbiol 2004, 2:820–832.PubMedCrossRefGoogle Scholar
  12. 12.
    Hess DT, Matsumoto A, Kim SO, et al.: Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol 2005, 6:150–166.PubMedCrossRefGoogle Scholar
  13. 13.
    Chung KK, Thomas B, Li X, et al.: S-nitrosylation of parkin regulates ubiquitination and compromises parkin’s protective function. Science 2004, 304:1328–1331.PubMedCrossRefGoogle Scholar
  14. 14.
    Yao D, Gu Z, Nakamura T, et al.: Nitrosative stress linked to sporadic Parkinson’s disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proc Natl Acad Sci U S A 2004, 101:10810–10814.PubMedCrossRefGoogle Scholar
  15. 15.
    Bryan NS, Rassaf T, Maloney RE, et al.: Cellular targets and mechanisms of nitros(yl)ation: an insight into their nature and kinetics in vivo. Proc Natl Acad Sci U S A 2004, 101:4308–4313. This article documents the presence of large amounts of RNNO compounds in tissues.PubMedCrossRefGoogle Scholar
  16. 16.
    Janero DR, Bryan NS, Saijo F, et al.: Differential nitros(yl)ation of blood and tissue constituents during glyceryl trinitrate biotransformation in vivo. Proc Natl Acad Sci U S A 2004, 101:16958–16963.PubMedCrossRefGoogle Scholar
  17. 17.
    Baker PR, Schopfer FJ, Sweeney S, Freeman BA: Red cell membrane and plasma linoleic acid nitration products: synthesis, clinical identification, and quantitation. Proc Natl Acad Sci U S A 2004, 101:11577–11582. This paper describes endogenous nitroderivatives of fatty acids with anti-inflammatory activity.PubMedCrossRefGoogle Scholar
  18. 18.
    Liu X, Miller MJ, Joshi MS, et al.: Accelerated reaction of nitric oxide with O2 within the hydrophobic interior of biological membranes. Proc Natl Acad Sci U S A 1998, 95:2175–2179.PubMedCrossRefGoogle Scholar
  19. 19.
    Schopfer FJ, Lin Y, Baker PR, et al.: Nitrolinoleic acid: an endogenous peroxisome proliferator-activated receptor (gamma) ligand. Proc Natl Acad Sci U S A 2005, 102:2340–2345.PubMedCrossRefGoogle Scholar
  20. 20.
    Lundberg JO, Weitzberg E, Cole JA, Benjamin N: Nitrate, bacteria and human health. Nat Rev Microbiol 2004, 2:593–602. This is a detailed review of NOS-independent generation of nitrogen oxides.PubMedCrossRefGoogle Scholar
  21. 21.
    Blanco Y, Yague J, Graus F, Saiz A: No association of inducible nitric oxide synthase gene (NOS2A) to multiple sclerosis. J Neurol 2003, 250:598–600.PubMedCrossRefGoogle Scholar
  22. 22.
    Tajouri L, Martin V, Ovcaric M, et al.: Investigation of an inducible nitric oxide synthase gene (NOS2A) polymorphism in a multiple sclerosis population. Brain Res Bull 2004, 64:9–13.PubMedCrossRefGoogle Scholar
  23. 23.
    Tajouri L, Ferreira L, Ovcaric M, et al.: Investigation of a neuronal nitric oxide synthase gene (NOS1) polymorphism in a multiple sclerosis population. J Neurol Sci 2004, 218:25–28.PubMedCrossRefGoogle Scholar
  24. 24.
    Barcellos LF, Begovich AB, Reynolds RL, et al.: Linkage and association with the NOS2A locus on chromosome 17q11 in multiple sclerosis. Ann Neurol 2004, 55:793–800.PubMedCrossRefGoogle Scholar
  25. 25.
    Kanwar JR, Kanwar RK, Krissansen GW: Simultaneous neuroprotection and blockade of inflammation reverses autoimmune encephalomyelitis. Brain 2004, 127:1313–1331. This article demonstrates that a combination of three drugs can reverse EAE. It also shows a concomitant decrease in NOS activity.PubMedCrossRefGoogle Scholar
  26. 26.
    Broholm H, Andersen B, Wanscher B, et al.: Nitric oxide synthase expression and enzymatic activity in multiple sclerosis. Acta Neurol Scand 2004, 109:261–269.PubMedCrossRefGoogle Scholar
  27. 27.
    Hill KE, Zollinger LV, Watt HE, et al.: Inducible nitric oxide synthase in chronic active multiple sclerosis plaques: distribution, cellular expression and association with myelin damage. J Neuroimmunol 2004, 151:171–179.PubMedCrossRefGoogle Scholar
  28. 28.
    Acar G, Idiman F, Idiman E, et al.: Nitric oxide as an activity marker in multiple sclerosis. J Neurol 2003, 250:588–592.PubMedCrossRefGoogle Scholar
  29. 29.
    Danilov AI, Andersson M, Bavand N, et al.: Nitric oxide metabolite determinations reveal continuous inflammation in multiple sclerosis. J Neuroimmunol 2003, 136:112–118.PubMedCrossRefGoogle Scholar
  30. 30.
    Rejdak K, Eikelenboom MJ, Petzold A, et al.: CSF nitric oxide metabolites are associated with activity and progression of multiple sclerosis. Neurology 2004, 63:1439–1445.PubMedGoogle Scholar
  31. 31.
    Garthwaite G, Goodwin DA, Batchelor AM, et al.: Nitric oxide toxicity in CNS white matter: an in vitro study using rat optic nerve. Neuroscience 2002, 109:145–155.PubMedCrossRefGoogle Scholar
  32. 32.
    Hooper DC, Bagasra O, Marini JC, et al.: Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: implications for the treatment of multiple sclerosis. Proc Natl Acad Sci U S A 1997, 94:2528–2533.PubMedCrossRefGoogle Scholar
  33. 33.
    Cross AH, Manning PT, Keeling RM, et al.: Peroxynitrite formation within the central nervous system in active multiple sclerosis. J Neuroimmunol 1998, 88:45–56.PubMedCrossRefGoogle Scholar
  34. 34.
    Liu JS, Zhao ML, Brosnan CF, Lee SC: Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Am J Pathol 2001, 158:2057–2066.PubMedGoogle Scholar
  35. 35.
    Kahl KG, Schmidt HH, Jung S, et al.: Experimental autoimmune encephalomyelitis in mice with a targeted deletion of the inducible nitric oxide synthase gene: increased T-helper 1 response. Neurosci Lett 2004, 358:58–62.PubMedCrossRefGoogle Scholar
  36. 36.
    Touil T, Deloire-Grassin MS, Vital C, et al.: In vivo damage of CNS myelin and axons induced by peroxynitrite. Neuroreport 2001, 12:3637–3644.PubMedCrossRefGoogle Scholar
  37. 37.
    Scott GS, Spitsin SV, Kean RB, et al.: Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors. Proc Natl Acad Sci U S A 2002, 99:16303–16308.PubMedCrossRefGoogle Scholar
  38. 38.
    Scott GS, Virag L, Szabo C, Hooper DC: Peroxynitrite-induced oligodendrocyte toxicity is not dependent on poly(ADP-ribose) polymerase activation. Glia 2003, 41:105–116.PubMedCrossRefGoogle Scholar
  39. 39.
    Takao T, Flint N, Lee L, et al.: 17beta-estradiol protects oligodendrocytes from cytotoxicity induced cell death. J Neurochem 2004, 89:660–673.PubMedCrossRefGoogle Scholar
  40. 40.
    Bizzozero OA, DeJesus G, Howard TA: Exposure of rat optic nerves to nitric oxide causes protein S-nitrosation and myelin decompaction. Neurochem Res 2004, 29:1675–1685. This article describes NO-induced defects to myelin and selective S-nitrosylation of PLP by NO.PubMedCrossRefGoogle Scholar
  41. 41.
    Calabrese V, Scapagnini G, Ravagna A, et al.: Nitric oxide synthase is present in the cerebrospinal fluid of patients with active multiple sclerosis and is associated with increases in cerebrospinal fluid protein nitrotyrosine and S-nitrosothiols and with changes in glutathione levels. J Neurosci Res 2002, 70:580–587.PubMedCrossRefGoogle Scholar
  42. 42.
    Boullerne AI, Rodriguez JJ, Touil T, et al.: Anti-S-nitrosocysteine antibodies are a predictive marker for demyelination in experimental autoimmune encephalomyelitis: implications for multiple sclerosis. J Neurosci 2002, 22:123–132. This article proposes S-nitrosylation as a novel marker for disease progression in MS.PubMedGoogle Scholar
  43. 43.
    Boullerne AI, Petry KG, Meynard M, Geffard M: Indirect evidence for nitric oxide involvement in multiple sclerosis by characterization of circulating antibodies directed against conjugated S-nitrosocysteine. J Neuroimmunol 1995, 60:117–124.PubMedCrossRefGoogle Scholar
  44. 44.
    McDonald JW, Althomsons SP, Hyrc KL, et al.: Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity. Nat Med 1998, 4:291–297.PubMedCrossRefGoogle Scholar
  45. 45.
    Pitt D, Werner P, Raine CS: Glutamate excitotoxicity in a model of multiple sclerosis. Nat Med 2000, 6:67–70.PubMedCrossRefGoogle Scholar
  46. 46.
    Rosin C, Bates TE, Skaper SD: Excitatory amino acid induced oligodendrocyte cell death in vitro: receptor-dependent and -independent mechanisms. J Neurochem 2004, 90:1173–1185.PubMedCrossRefGoogle Scholar
  47. 47.
    Pitt D, Nagelmeier IE, Wilson HC, Raine CS: Glutamate uptake by oligodendrocytes: Implications for excitotoxicity in multiple sclerosis. Neurology 2003, 61:1113–1120.PubMedGoogle Scholar
  48. 48.
    Mander P, Borutaite V, Moncada S, Brown GC: Nitric oxide from inflammatory-activated glia synergizes with hypoxia to induce neuronal death. J Neurosci Res 2005, 79:208–215. This article shows that NO-induced cell death increases 10-fold under hypoxia.PubMedCrossRefGoogle Scholar
  49. 49.
    Lassmann H: Hypoxia-like tissue injury as a component of multiple sclerosis lesions. J Neurol Sci 2003, 206:187–191.PubMedCrossRefGoogle Scholar
  50. 50.
    Aboul-Enein F, Lassmann H: Mitochondrial damage and histotoxic hypoxia: a pathway of tissue injury in inflammatory brain disease? Acta Neuropathol (Berl) 2005, 109:49–55.CrossRefGoogle Scholar
  51. 51.
    Bossy-Wetzel E, Talantova MV, Lee WD, et al.: Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels. Neuron 2004, 41:351–365. This article describes a molecular mechanism of NO/zinc-mediated cell death.PubMedCrossRefGoogle Scholar
  52. 52.
    Kahl KG, Zielasek J, Uttenthal LO, et al.: Protective role of the cytokine-inducible isoform of nitric oxide synthase induction and nitrosative stress in experimental autoimmune encephalomyelitis of the DA rat. J Neurosci Res 2003, 73:198–205. This article shows a protective role of iNOS in EAE and discusses often contradictory results on the benefits of blocking NO production for EAE and MS.PubMedCrossRefGoogle Scholar
  53. 53.
    Staykova MA, Paridaen JT, Cowden WB, Willenborg DO: Nitric oxide contributes to resistance of the Brown Norway rat to experimental autoimmune encephalomyelitis. Am J Pathol 2005, 166:147–157.PubMedGoogle Scholar
  54. 54.
    Okuda Y, Sakoda S, Fujimura H, Yanagihara T: Aminoguanidine, a selective inhibitor of the inducible nitric oxide synthase, has different effects on experimental allergic encephalomyelitis in the induction and progression phase. J Neuroimmunol 1998, 81:201–210.PubMedCrossRefGoogle Scholar
  55. 55.
    O’Brien NC, Charlton B, Cowden WB, Willenborg DO: Inhibition of nitric oxide synthase initiates relapsing remitting experimental autoimmune encephalomyelitis in rats, yet nitric oxide appears to be essential for clinical expression of disease. J Immunol 2001, 167:5904–5912.PubMedGoogle Scholar
  56. 56.
    Xu LY, Yang JS, Link H, Xiao BG: SIN-1, a nitric oxide donor, ameliorates experimental allergic encephalomyelitis in Lewis rats in the incipient phase: the importance of the time window. J Immunol 2001, 166:5810–5816.PubMedGoogle Scholar
  57. 57.
    Imitola J, Snyder EY, Khoury SJ: Genetic programs and responses of neural stem/progenitor cells during demyelination: potential insights into repair mechanisms in multiple sclerosis. Physiol Genomics 2003, 14:171–197. This is a detailed review of the prospects and limitations of stem cell-based therapies for MS.PubMedGoogle Scholar
  58. 58.
    Packer MA, Stasiv Y, Benraiss A, et al.: Nitric oxide negatively regulates mammalian adult neurogenesis. Proc Natl Acad Sci U S A 2003, 100:9566–9571.PubMedCrossRefGoogle Scholar
  59. 59.
    Park C, Sohn Y, Shin KS, et al.: The chronic inhibition of nitric oxide synthase enhances cell proliferation in the adult rat hippocampus. Neurosci Lett 2003, 339:9–12.PubMedCrossRefGoogle Scholar
  60. 60.
    Cheng A, Wang S, Cai J, et al.: Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Dev Biol 2003, 258:319–333.PubMedCrossRefGoogle Scholar
  61. 61.
    Moreno-Lopez B, Romero-Grimaldi C, Noval JA, et al.: Nitric oxide is a physiological inhibitor of neurogenesis in the adult mouse subventricular zone and olfactory bulb. J Neurosci 2004, 24:85–95.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc 2005

Authors and Affiliations

  • Juan Manuel Encinas
  • Louis Manganas
  • Grigori Enikolopov
    • 1
  1. 1.Cold Spring Harbor LaboratoryCold Spring HarborUSA

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