Neuroinflammation and demyelination from the point of nitrosative stress as a new target for neuroprotection

Reviews in the Neurosciences

Volumn 26, Issue 1, 2015, Pages 49-73

  Ljubisavljevic, Srdjan ^a,b   Stojanovic, Ivana ^b  

^a CLINICAL CENTER NIS   (Serbia)

^b UNIVERSITY OF NI   (Serbia)

Author keywords

Demyelination; Neuroinflammation; Nitrosative stress

Indexed keywords

ACETYLCYSTEINE; ANTIOXIDANT; BETA INTERFERON; BIOLOGICAL MARKER; CYTOKINE; FUMARIC ACID DIMETHYL ESTER; GLUTAMIC ACID; IMMUNOMODULATING AGENT; INDUCIBLE NITRIC OXIDE SYNTHASE; INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITOR; MYELIN; MYELIN BASIC PROTEIN; MYELIN OLIGODENDROCYTE GLYCOPROTEIN; NITRIC OXIDE; NITRIC OXIDE SYNTHASE; NITRIC OXIDE SYNTHASE INHIBITOR; PERTUSSIS TOXIN; PROTEOLIPID PROTEIN; REACTIVE NITROGEN SPECIES; REACTIVE OXYGEN METABOLITE; UNCLASSIFIED DRUG; NEUROPROTECTIVE AGENT;

AEROBIC METABOLISM; ANTIINFLAMMATORY ACTIVITY; APOPTOSIS; ARTICLE; ASTROCYTE; CENTRAL NERVOUS SYSTEM; CENTRAL NERVOUS SYSTEM DISEASE; CLINICAL TRIAL (TOPIC); CORRELATIONAL STUDY; CYTOKINE PRODUCTION; CYTOTOXICITY; DEMYELINATION; DRUG EFFICACY; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; HUMAN; HYPERBARIC OXYGEN; LIPID PEROXIDATION; MEDIATOR; MONOCYTE; MULTIPLE SCLEROSIS; MYELIN SHEATH; NERVE DEGENERATION; NERVOUS SYSTEM INFLAMMATION; NEUROMODULATION; NEUROPROTECTION; NITROSATIVE STRESS; NONHUMAN; OLIGODENDROGLIA; OXIDATION REDUCTION STATE; OXIDATIVE STRESS; PATHOGENESIS; PATHOPHYSIOLOGY; PRIORITY JOURNAL; RISK FACTOR; ANIMAL; DEMYELINATING DISEASES; DRUG EFFECTS; INFLAMMATION; METABOLISM; PHYSIOLOGICAL STRESS;

ANIMALS; DEMYELINATING DISEASES; HUMANS; INFLAMMATION; NEUROPROTECTIVE AGENTS; NITRIC OXIDE; OXIDATIVE STRESS; STRESS, PHYSIOLOGICAL;

EID: 84924148567     PISSN: 03341763     EISSN: None     Source Type: Journal    
DOI: 10.1515/revneuro-2014-0060     Document Type: Article

References (253)

1. Abo-Krysha, N. and Rashed, L. (2008). The role of iron dysregulation in the pathogenesis of multiple sclerosis: an Egyptian study. Mult. Scler. J. 14, 602-608.
2. Abraham, M., Gola, J., Cometto-Muniz, E., and Cain, W. (2000). The solvation properties of nitric oxide. J. Chem. Soc. Perkin. Trans 2, 2067-2070.
3. Acar, G. (2003). Nitric oxide as an activity marker in multiple sclerosis. J. Neurol. 250, 588-592.
4. Agrawal, S.M., Williamson, J., Sharma, R., Kebir, H., Patel, K., Prat, A., and Yong, V.W. (2013). Extracellular matrix metalloproteinase inducer shows active perivascular cuffs in multiple sclerosis. Brain 136, 1760-1777.
5. Alvarez, B. and Radi, R. (2003). Peroxynitrite reactivity with amino acids and proteins. Amino Acids 25, 295-311.
6. Ames, A.I. (2000). CNS energy metabolism as related to function. Brain Res. Rev. 34, 42-68.
7. Androdias, G., Reynolds, R., Chanal, M., Ritleng, C., Confavreux, C., and Nataf, S. (2010). Meningeal T cells associate with diffuse axonal loss in multiple sclerosis spinal cords. Ann. Neurol. 68, 465-476.
8. Arend, C., Brandmann, M., and Dringen, R. (2013). The antiretroviral protease inhibitor ritonavir accelerates glutathione export from cultured primary astrocytes. Neurochem. Res. 38, 732-741.
9. Argaw, A.T., Asp, L., Zhang, J., Navrazhina, K., Pham, T., Mariani, J.N., Mahase, S., Dutta, D.J., Seto, J., Kramer, E.G., et al. (2012). Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. J. Clin. Invest. 122, 2454-2468.
10. Arnett, H.A., Hellendall, R.P., Matsushima, G.K., Suzuki, K., Laubach, V.E., Sherman, P., and Ting, J.P. (2002). The protective role of nitric oxide in a neurotoxicant-induced demyelinating model. J. Immunol. 168, 427-433.
11. Artemiadis, A.K. and Anagnostouli, M.C. (2010). Apoptosis of oligodendrocytes and post-translational modifications of myelin basic protein in multiple sclerosis: possible role for the early stages of multiple sclerosis. Eur. Neurol. 63, 65-72.
12. Ascherio, A. and Munger, K.L. (2007). Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann. Neurol. 61, 288-299.
13. Ascherio, A. and Munger, K. (2008). Epidemiology of multiple sclerosis: from risk factors to prevention. Semin. Neurol. 28, 17-28.
14. Bachmann, M.F., Kopf, M., and Marsland, B.J. (2006). Chemokines: more than just road signs. Nat. Rev. Immunol. 6, 159-164.
15. Bailey, S.L., Carpentier, P.A., McMahon, E.J., Begolka, W.S., and Miller, S.D. (2006). Innate and adaptive immune responses of the central nervous system. Crit. Rev. Immunol. 26, 149-188.
16. Barnett, M.H., Henderson, A.P., and Prineas, J.W. (2006). The macrophage in MS: just a scavenger after all? Pathology and pathogenesis of the acute MS lesion. Mult. Scler. J. 12, 121-132.
17. Baxter, A.G. (2007). The origin and application of experimental autoimmune encephalomyelitis. Nat. Rev. Immunol. 7, 904-912.
18. Beal, M.F. (2003). Mitochondria, oxidative damage, and inflammation in Parkinson's disease. Ann. N. Y. Acad. Sci. 991, 120-131.
19. Bennett, M. and Heard, R. (2010). Hyperbaric oxygen therapy for multiple sclerosis. CNS Neurosci. Ther. 16, 115-124.
20. Bishop, A., Hobbs, K., Eguchi, A., Jeffrey, S., Smallwood, L., Pennie, C., Anderson, J., and Estevez, A. (2009). Differential sensitivity of oligodendrocytes and motor neurons to reactive nitrogen species: implications for multiple sclerosis. J. Neurochem. 109, 93-104.
21. Bitsch, A., Schuchardt, J., Bunkowski, S., Kuhlmann, T., and Bruck, W. (2000). Acute axonal injury in multiple sclerosis. Correlation with demyelination and inflammation. Brain 123, 1174-1183.
22. Bizzozero, O.A., Ziegler, J.L., De Jesus, G., and Bolognani, F. (2006). Acute depletion of reduced glutathione causes extensive carbonylation of rat brain proteins. J. Neurosci. Res. 83, 656-667.
23. Blanco, S., Molina, F.J., Castro, L., Del Moral, M.L., Hernandez, R., Jimenez, A., Alma Rus, A., Martinez-Lara, E., Siles, E., and Peinado, M.A. (2010). Study of the nitric oxide system in the rat cerebellum during aging. BMC Neurosci. 11, 78.
24. Bo, L., Esiri, M., Evangelou, N., and Kuhlmann, T. (2013). Demyelination and Remyelination in Multiple Sclerosis. Myelin Repair and Neuroprotection in Multiple Sclerosis, pp. 23-45.
25. Boullerne, A.I., Rodrguez, J.J., Touil, T., Brochet, B., Schmidt, S., Abrous, N.R., Le Moal, M., Pua, J.R., Jensen, M.A., Mayo, W., et al. (2002). Anti-S-Nitrosocysteine antibodies are a predictive marker for demyelination in experimental autoimmune encephalomyelitis: implications for multiple sclerosis. J. Neurosci. 22, 123-132.
26. Brea, D., Sobrino, T., Ramos-Cabrer, P., and Castillo, J. (2009). Inflammatory and neuroimmunomodulatory changes in acute cerebral ischemia. Cerebrovasc. Dis. 27, 48-64.
27. Brex, P.A., Miszkiel, K.A., O'Riordan, J.I., Plant, G.T., Moseley, I.F., Thompson, A.J., and Miller, D.H. (2001). Assessing the risk of early multiple sclerosis in patients with clinically isolated syndromes: the role of a follow up MRI. J. Neurol. Neurosurg. Psychiatry 70, 390-393.
28. Broholm, H., Andersen, B., Wanscher, B., Frederiksen, J.L., Rubin, I., Pakkenberg, B., Larsson, H.B.W., and Lauritzen, M. (2004). Nitric oxide synthase expression and enzymatic activity in multiple sclerosis. Acta Neurol. Scand. 109, 261-269.
29. Broniowska, K.A., Diers, A.R., Corbett, J.A., and Hogg, N. (2013). Effect of nitric oxide on naphthoquinone toxicity in endothelial cells: role of bioenergetic dysfunction and poly (ADP-ribose) polymerase activation. Biochemistry 52, 4364-4372.
30. Brown, G.C. and Bal-Price, A. (2003). Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol. Neurobiol. 27, 325-355.
31. Butterfield, D.A. and Sultana, R. (2008). Identification of 3finitrotyrosine-modified brain proteins by redox proteomics. Methods Enzymol. 440, 295-308.
32. Calabrese, V., Scapagnini, G., Ravagna, A., Bella, R., Foresti, R., Bates, T.E., Giuffrida Stella, A.M., and Pennisi, G. (2002). 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 Sfinitrosothiols and with changes in glutathione levels. J. Neurosci. Res. 70, 580-587.
33. Calabrese, V., Colombrita, C., Guagliano, E., Sapienza, M., Ravagna, A., Tomaselli, G., Cardile, V., Scapagnini, G., Butterfield, D.A., Giuffrida Stella, A.M., et al. (2005). Protective effect of carnosine during nitrosative stress in astroglial cell cultures. Neurochem. Res. 30, 797-807.
34. Calabrese, V., Sultana, R., Scapagnini, G., Guagliano, E., Sapienza, M., Bella, R., Kanski, J., Pennisi, G., Mancuso, C., Stella, A.M., et al. (2006). Nitrosative stress, cellular stress response, and thiol homeostasis in patients with Alzheimer's disease. Antioxid. Redox Signal. 8, 1975-1986.
35. Calabrese, V., Mancuso, C., Calvani, M., Rizzarelli, E., Butterfield, D.A., and Giuffrida Stella, A.M. (2007). Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat. Rev. Neurosci. 8, 766-775.
36. Calabrese, V., Cornelius, C., Mancuso, C., Barone, E., Calafato, S., Bates, T., Rizzarelli, E., and Dinkova-Kostova, A.T. (2009). Vitagenes, dietary antioxidants and neuroprotection in neurodegenerative diseases. Front. Biosci. 14, 376-397.
37. Carreras, M.C. and Poderoso, J.J. (2007). Mitochondrial nitric oxide in the signaling of cell integrated responses. Am. J. Physiol. Cell Physiol. 292, 1569-1580.
38. Chaitanya, G.V., Omura, S., Sato, F., Martinez, N.E., Minagar, A., Ramanathan, M., Guttman, B.W., Zivadinov, R., Tsunoda, I., and Alexander, J.S. (2013). Inflammation induces neuro-lymphatic protein expression in multiple sclerosis brain neurovasculature. J. Neuroinflamm. 10, 125.
39. Charil, A. and Filippi, M. (2007). Inflammatory demyelination and neurodegeneration in early multiple sclerosis. J. Neurol. Sci. 259, 7-15.
40. Choi, S.H., Aid, S., and Bosetti, F. (2009). The distinct roles of cyclooxygenase-1 and 2 in neuroinflammation: implications for translational research. Trends Pharmacol. Sci. 30, 174-181.
41. Coffey, M.J., Phare, S.M., and Peters-Golden, M. (2002). Interaction between nitric oxide, reactive oxygen intermediates, and peroxynitrite in the regulation of 5-lipoxygenase metabolism. Biochim. Biophys. Acta 1584, 81-90.
42. Confavreux, C. and Vukusic, S. (2006). Natural history of multiple sclerosis: a unifying concept. Brain 129, 606-616.
43. Contestabile, A. and Ciani, E. (2004). Role of nitric oxide in the regulation of neuronal proliferation, survival and differentiation. Neurochem. Int. 45, 903-914.
44. Contestabile, A., Monti, B., and Polazzi, E. (2012). Neuronal-glial interactions define the role of nitric oxide in neural functional processes. Curr. Neuropharmacol. 10, 303-310.
45. Coote, S., Hogan, N., and Franklin, S. (2013). Falls in people with multiple sclerosis who use a walking aid: prevalence, factors, and effect of strength and balance interventions. Arch. Phys. Med. Rehab. 94, 616-621.
46. Corthals, A.P. (2011). Multiple sclerosis is not a disease of the immune system. Q. Rev. Biol. 86, 287-321.
47. Cox, G.M., Kithcart, A.P., Pitt, D., Guan, Z., Alexander, J., Williams, J.L., Shawler, T., Dagia, N.M., Popovich, P.G., Satoskar, A.R., et al. (2013). Macrophage migration inhibitory factor potentiates autoimmune-mediated neuroinflammation. J. Immunol. 191, 1043-1054.
48. Danilov, A.I., Andersson, M., Bavand, N., Wiklund, N.P., Olsson, T., and Brundin, L. (2003). Nitric oxide metabolite determinations reveal continuous inflammation in multiple sclerosis. J. Neuroimmunol. 136, 112-118.
49. Dasgupta, S., Jana, M., Liu, X., and Pahan, K. (2002). Myelin basic protein-primed T cells induce nitric oxide synthase in microglial cells-implications for multiple sclerosis. J. Biol. Chem. 277, 39327-39333.
50. De Groot, C.J., Ruuls, S.R., Theeuwes, J.W., Dijkstra, C.D., and Van Der Valk, P. (1997). Immunocytochemical characterization of the expression of inducible and constitutive isoforms of nitric oxide synthase in demyelinating multiple sclerosis lesions. J. Neuropathol. Exp. Neurol. 56, 10-20.
51. Dedon, P.C. and Tannenbaum, S.R. (2004). Reactive nitrogen species in the chemical biology of inflammation. Arch. Biochem. Biophys. 423, 12-22.
52. Dincic, E., Zivkovic, M., Stankovic, A., Obradovic, D., Alavantic, D., Kostic, V., and Raicevic, R. (2006). Association of polymorphisms in CTLA-4, IL-1ra and IL-1beta genes with multiple sclerosis in Serbian population. J. Neuroimmunol. 177, 146-150.
53. Dinkova-Kostova, A.T. and Talalay, P. (2008). Direct and indirect antioxidant properties of inducers of cytoprotective proteins. Mol. Nutr. Food Res. 52, 128-138.
54. Dutra, R.C., Bento, A.F., Leite, D.F., Manjavachi, M.N., Marcon, R., Bicca, M.A., Pesquero, J.B. and Calixto, J.B. (2013). The role of kinin B1 and B2 receptors in the persistent pain induced by experimental autoimmune encephalomyelitis (EAE) in mice: evidence for the involvement of astrocytes. Neurobiol. Dis. 54, 82-93.
55. Dutta, R., McDonough, J., Yin, X., Peterson, J., Chang, A., Torres, T., Gudz, T., Macklin, W.B., Lewis, D.A., Fox, R.J., et al. (2006). Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients Ann. Neurol. 59, 478-489.
56. Elfering, S.L., Sarkela, T.M., and Giulivi, C. (2002). Biochemistry of mitochondrial nitric-oxide synthase. J. Biol. Chem. 277, 38079-38086.
57. Fancy, S.P., Kotter, M.R., Harrington, E.P., Huang, J.K., Zhao, C., Rowitch, D.H., and Franklin, R.J. (2010). Overcoming remyelination failure in multiple sclerosis and other myelin disorders. Exp. Neurol. 225, 18-23.
58. Farias, A.S., de la Hoz, C., Castro, F.R., Oliveira, E.C., Ribeiro dos Reis, J.R., Silva, J.S., Langone, F., and Santos, L.M. (2007). Nitric oxide and TNFa effects in experimental autoimmune encephalomyelitis demyelination. Neuroimmunomodulation 14, 32-38.
59. Fernandez-Fernandez, S., Almeida, A., and Bolaños, J.P. (2012). Antioxidant and bioenergetic coupling between neurons and astrocytes. Biochem. J. 443, 3-11.
60. Ferretti, G., Bacchetti, T., Principi, F., Di Ludovico, F., Viti, B., Angeleri, V.A., Danni, M., and Provinciali, L. (2005). Increased levels of lipid hydroperoxides in plasma of patients with multiple sclerosis: a relationship with paraoxonase activity. Mult. Scler. J. 11, 677-682.
61. Flynn, R.W., MacWalter, R.S., and Doney, A.S. (2008). The cost of cerebral ischaemia. Neuropharmacology 55, 250-256.
62. Forman, H.J., Fukuto, J.M., and Torres, M. (2004). Redox signaling: thiol chemistry defines which reactive oxygen and nitrogen species can act as second messengers. Am. J. Physiol. Cell Physiol. 287, 246-256.
63. Foster, M.W., McMahon, T.J., and Stamler, J.S. (2003). Sfinitrosylation in health and disease. Trends Mol. Med. 9, 160-168.
64. Frischer, J.M., Bramow, S., Dal-Bianco, A., Lucchinetti, C.F., Rauschka, H., Schmidbauer, M., Laursen, H., Sorensen, P.S., and Lassmann, H. (2009). The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132, 1175-1189.
65. Frohman, T.C., Davis, S.L., Beh, S., Greenberg, B.M., Remington, G., and Frohman, E.M. (2013). Uhthoff's phenomena in MS clinical features and pathophysiology. Nat. Rev. Neurol. 9, 535-540.
66. Fukuda, M., Kanou, F., Shimada, N., Sawabe, M., Saito, Y., Murayama, S., Hashimoto, M., Maruyama, N., and Ishigami, A. (2009). Elevated levels of 4-hydroxynonenal-histidine Michael adduct in the hippocampi of patients with Alzheimer's disease. Biomed. Res. 30, 227-233.
67. Garden, G.A. and Moller, T. (2006). Microglia biology in health and disease. J. Neuroimmun. Pharmacol. 1, 127-137.
68. Gaston, B.M., Carver, J., Doctor, A., and Palmer, L.A. (2003). Sfinitrosylation signaling in cell biology. Mol. Interv. 3, 253-263.
69. Gilgun-Sherki, Y., Melamed, E., and Offen, D. (2004). The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J. Neurol. 251, 261-268.
70. Gilgun-Sherki, Y., Barhum, Y., Atlas, D., Melamed, E., and Offen, D. (2005). Analysis of gene expression in MOG-induced experimental autoimmune encephalomyelitis after treatment with a novel brain-penetrating antioxidant. J. Mol. Neurosci. 27, 125-135.
71. Glass, C., Saijo, K., Winner, B., Marchetto, M., and Gage, F. (2010). Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918-934.
72. Gold, R. and Wolinsky, J.S. (2011). Pathophysiology of multiple sclerosis and the place of teriflunomide. Acta Neurol. Scand. 124, 75-84.
73. Gold, R., Hartung, H.P., and Toyka, K.V. (2000). Animal models for autoimmune demyelinating disorders of the nervous system. Mol. Med. Today 6, 88-91.
74. Gold, R., Linington, C., and Lassmann, H. (2006). Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129, 1953-1971.
75. Gonsette, R.E. (2008). Neurodegeneration in multiple sclerosis: the role of oxidative stress and excitotoxicity. J. Neurol. Sci. 274, 48-53.
76. Gonsette, R.E. (2010). Endogenous neuroprotection in multiple sclerosis. Acta Neurol. Belg. 110, 26-35.
77. Graber, J.J. and Dhib-Jalbut, S. (2011). Biomarkers of disease activity in multiple sclerosis. J. Neurol. Sci. 305, 1-10.
78. Graeber, M.B. and Christie, M.J. (2012). Multiple mechanisms of microglia: a gatekeeper's contribution to pain states. Exp. Neurol. 234, 255-261.
79. Griffin, W.S. (2006). Inflammation and neurodegenerative diseases. Am. J. Clin. Nutr. 83, 470S-474S.
80. Guix, F.X., Uribesalgo, I., Coma, M., and Munoz, F.J. (2005). The physiology and pathophysiology of nitric oxide in the brain. Prog. Neurobiol. 76, 126-152.
81. Gulyaeva, N.V., Onufriev, M.V., and Stepanichev, M.Y. (1994). NO synthase and free radical generation in brain regions of old rats: correlations with individual behaviour. NeuroReport 6, 94-96.
82. Hafler, D.A. (2004). Multiple sclerosis. J. Clin. Invest. 113, 788-794.
83. Haider, L., Fischer, M.T., Frischer, J.M., Bauer, J., Hoftberger, R., Botond, G., Esterbauer, H., Binder, C.J., Witztum, J.L., and Lassmann, H. (2011). Oxidative damage in multiple sclerosis lesions. Brain 134, 1914-1924.
84. Han, M.H., Hwang, S.I., Roy, D.B., Lundgren, D.H., Price, J.V., Ousman, S.S., Fernald, G.H., Gerlitz, B., Robinson, W.H., Baranzini, S.E., et al. (2008). Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 451, 1076-1081.
85. Henderson, A., Barnett, M., Parratt, J., and Prineas, J. (2009). Multiple sclerosis: distribution of inflammatory cells in newly forming lesions. Ann. Neurol. 66, 739-753.
86. Hendrickx, D.A., Koning, N., Schuurman, K.G., van Strien, M.E., van Eden, C.G., Hamann, J., and Huitinga, I. (2013). Selective upregulation of scavenger receptors in and around demyelinating areas in multiple sclerosis. J. Neuropathol. Exp. Neurol. 72, 106-118.
87. Hill, K.E., Zollinger, L.V., Watt, H.E., Carlson, N.G., and Rose, J.W. (2004). Inducible nitric oxide synthase in chronic active multiple sclerosis plaques: distribution, cellular expression and association with myelin damage. J. Neuroimmunol. 151, 171-179.
88. Hohlfeld, R. (2009). ECTRIMS lecture: future challenges in MS. Mult. Scler. J. 15, S8-S9.
89. Hohlfeld, R. and Wekerle, H. (2001). Immunological update on multiple sclerosis. Curr. Opin. Neurol. 14, 299-304.
90. Hooper, D.C., Scott, G.S., Zborek, A., Mikheeva, T., Kean, R.B., Koprowski, H., and Spitsin, S.V. (2000). Uric acid, a peroxynitrite scavenger, inhibits CNS inflammation, blood-CNS barrier permeability changes, and tissue damage in a mouse model of multiple sclerosis. FASEB J. 14, 691-698.
91. Howell, O.W., Rundle, J.L., Garg, A., Komada, M., Brophy, P.J., and Reynolds, R. (2010). Activated microglia mediate axoglial disruption that contributes to axonal injury in multiple sclerosis. J. Neuropathol. Exp. Neurol. 69, 1017-1033.
92. Hua, K.F., Wang, S.H., Dong, W.C., Lin, C.Y., Ho, C.L., and Wu, T.H. (2012). High glucose increases nitric oxide generation in lipopolysaccharide-Activated macrophages by enhancing activity of protein kinase C-?/?and NF-?B. Inflamm. Res. 61, 1107-1116.
93. Jack, C., Ruffini, F., Bar-Or, A., and Antel, J.P. (2005). Microglia and multiple sclerosis. J. Neurosci. Res. 81, 363-373.
94. Jack, C., Ante, J., Brück, W., and Kuhlmann, T. (2007). Contrasting potential of nitric oxide and peroxynitrite to mediate oligodendrocyte injury in multiple sclerosis. Glia 55, 926-934.
95. Jaffrey, S.R., Erdjument-Bromage, H., Ferris, C.D., Tempst, P., and Snyder, S.H. (2001). Protein Sfinitrosylation: a physiological signal for neuronal nitric oxide. Nat. Cell. Biol. 3, 193-197.
96. Jana, A., Hogan, E.L., and Pahan, K. (2009). Ceramide and neurodegeneration: susceptibility of neurons and oligodendrocytes to cell damage and death. J. Neurol. Sci. 278, 5-15.
97. Janssen-Heininger, Y.M., Mossman, B.T., Heintz, N.H., Forman, H.J., Kalyanaraman, B., Finkel, T., Stamler, J.S., Rhee, S.G., and van der Vliet, A. (2008). Redox-based regulation of signal transduction: principles, pitfalls, and promises. Free Radic. Biol. Med. 45, 1-17.
98. Jha, M.K., Jeon, S., and Suk, K. (2012). Glia as a link between neuroinflammation and neuropathic pain. Immune Netw. 12, 41-47.
99. Jia, W., Jackson-Cook, C., and Graf, M.R. (2010). Tumor-infiltrating, myeloid-derived suppressor cells inhibit T cell activity by nitric oxide production in an intracranial rat glioma + vaccination model. J. Neuroimmunol. 223, 20-30.
100. Jolivalt, C.G., Howard, R.B., Chen, L.S., Mizisin, A.P., and Lai, C.S. (2003). A novel nitric oxide scavenger in combination with cyclosporine A ameliorates experimental autoimmune encephalomyelitis progression in mice. J. Neuroimmunol. 138, 56-64.
101. Jung, W.K., Ahn, Y.W., Lee, S.H., Choi, Y.H., Kim, S.K., Yea, S.S., Choi, I., Park, S.G., Seo, S.K., Lee, S.W., et al. (2009). Ecklonia cava ethanolic extracts inhibit lipopolysaccharide-induced cyclooxygenase-2 and inducible nitric oxide synthase expression in BV2 microglia via the MAP kinase and NF-kappaB pathways. Food Chem. Toxicol. 47, 410-417.
102. Kahl, K.G., Zielasek, J., Uttenthal, L.O., Rodrigo, J., Toyka, K.V., and Schmidt, H.H. (2003). 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. 73, 198-205.
103. Kamboj, S.S. and Sandhir, R. (2011). Protective effect of N-Acetylcysteine supplementation on mitochondrial oxidative stress and mitochondrial enzymes in cerebral cortex of streptozotocin-treated diabetic rats. Mitochondrion 11, 214-222.
104. Kang, B.H., Chen, T.C., Huang, K.L., and Wan, F.J. (2012). Effects of hyperbaric oxygen in a murine model of allergic lung inflammation. J. Med. Sci. 32, 81-87.
105. Kapoor, R., Davies, M., Blaker, P.A., Hall, S.M., and Smith, K.J. (2003). Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration. Ann. Neurol. 53, 174-180.
106. Khan, H.A. (2012). Nfinitro-L-Arginine, a nitric oxide synthase inhibitor, aggravates iminodipropionitrile-induced neurobehavioral and vestibular toxicities in rats. Exp. Toxicol. Pathol. 64, 791-796.
107. Kieseier, B.C., Tani, M., Mahad, D., Oka, N., Ho, T., Woodroofe, N., Griffin, J.W., Toyka, K.V., Ransohoff, R.M., and Hartung, H.P. (2002). Chemokines and chemokine receptors in inflammatory demyelinating neuropathies: a central role for IP-10. Brain 125, 823-834.
108. Kim, S., Moon, C., Wie, M.B., Kim, H., Tanuma, N., Matsumoto, Y., and Shin, T. (2000). Enhanced expression of constitutive and inducible forms of nitric oxide synthase in autoimmune encephalomyelitis. J. Vet. Sci. 1, 11-17.
109. Kim, J.H., Budde, M.D., Liang, H.F., Klein, R.S., Russell, J.H., Cross, A.H., and Song, S.K. (2006). Detecting axon damage in spinal cord from a mouse model of multiple sclerosis. Neurobiol. Dis. 21, 626-632.
110. Kim, S.U., Park, Y.H., Min, J.S., Sun, H.N., Han, Y.H., Hua, J.M., Lee, T.H., Lee, S.R., Chang, K.T., Kang, S.W., et al. (2013). Peroxiredoxin I is a ROS/p38 MAPK-dependent inducible antioxidant that regulates NF-?B-mediated iNOS induction and microglial activation. J. Neuroimmunol. 259, 26-36.
111. Knoferle, J., Koch, J.C., Ostendorf, T., Michel, U., Planchamp, V., Vutova, P., Tönges, L., Stadelmann, C., Brück, W., Bähr, M., et al. (2010). Mechanisms of acute axonal degeneration in the optic nerve in vivo. Proc. Natl. Acad. Sci. USA 107, 6064-6069.
112. Knott, A.B. and Bossy-Wetzel, E. (2009). Nitric oxide in health and disease of the nervous system. Antioxid. Redox Signal. 11, 541-553.
113. Koch, M., Ramsaransing, G.S., Arutjunyan, A.V., Stepanov, M., Teelken, A., Heersema, D.J., and De Keyser, J. (2006). Oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of multiple sclerosis. J. Neurol. 253, 483-487.
114. Kone, B.C., Kuncewicz, T., Zhang, W., and Yu, Z.Y. (2003). Protein interactions with nitric oxide synthases: controlling the right time, the right place, and the right amount of nitric oxide. Am. J. Physiol. Renal Physiol. 285, 178-190.
115. Koritschoner, R.S. and Schweinburg, F. (1925). Induktion van Paralyse und Ruckenmarksentzundung durch Immunisierung van Kaninchen met meschlichem Ruckenmarksgewebe. Z. Immun. Exp. Ther. 42, 217-283.
116. Kornek, B., Storch, M., Weissert, R., Wallstroem, E., Stefferl, A., Olsson, T., Linington, C., Schmidbauer, M., and Lassmann, H. (2000). Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive and remyelinated lesions. Am. J. Pathol. 157, 267-276.
117. Krishnan, A.V. and Kiernan, M.C. (2013). Sustained-release fampridine and the role of ion channel dysfunction in multiple sclerosis. Mult. Scler. J. 19, 385-391.
118. Kruger, R., Hardt, C., Tschentscher, F., Jackel, S., Kuhn, W., Muller, T., Werner, J., Woitalla, D., Berg, D., Kuhnl, N., et al. (2000). Genetic analysis of immunomodulating factors in sporadic Parkinson's disease. J. Neural Transm. 107, 553-562.
119. Kurtzke, J.F. (2005). Epidemiology and etiology of multiple sclerosis. Phys. Med. Rehabil. Clin. N. Am. 16, 327-349.
120. Ladeby, R., Wirenfeldt, M., Garcia-Ovejero, D., Fenger, C., Dissing-Olesen, L., Dalmau, I., and Finsen, B. (2005). Microglial cell population dynamics in the injured adult central nervous system. Brain Res. Rev. 48, 196-206.
121. Lambeth, J.D. (2004). NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 4, 181-189.
122. Lameu, C., Trujillo, C.A., Schwindt, T.T., Negraes, P.D., Pillat, M.M., Morais, K.L.P., Lebrun, I., and Ulrich, H. (2012). Interactions between the NO-citrulline cycle and brain-derived neurotrophic factor in differentiation of neural stem cells. J. Biol. Chem. 287, 29690-29701.
123. Lassmann, H. (2003). Axonal injury in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 74, 695-697.
124. Lassmann, H. and van Horssen, J. (2011). The molecular basis of neurodegeneration in multiple sclerosis. FEBS Lett. 585, 3715-3723.
125. Laurila, J.P., Laatikainen, L.E., Castellone, M.D., and Laukkanen, M.O. (2009). SOD3 reduces inflammatory cell migration by regulating adhesion molecule and cytokine expression. PLoS One 4, e5786.
126. Leiper, J. and Nandi, M. (2011). The therapeutic potential of targeting endogenous inhibitor of nitric oxide synthesis. Nat. Rev. Drug Discov. 10, 277-291.
127. Leung, G., Sun, W., Zheng, L., Brookes, S., Tully, M., and Shi, R. (2011). Anti-Acrolein treatment improves behavioral outcome and alleviates myelin damage in experimental autoimmune encephalomyelitis mouse. Neuroscience 173, 150-155.
128. Ley, K., Laudanna, C., Cybulsky, M.I., and Nourshargh, S. (2007). Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 7, 678-689.
129. Li, J., Baud, O., Vartanian, T., Volpe, J.J., and Rosenberg, P.A. (2005). Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc. Natl. Acad. Sci. 102, 9936-9941.
130. Lipton, S.A., Choi, Y.B., Takahashi, H., Zhang, D., Li, W., Godzik, A., and Bankston, L.A. (2002). Cysteine regulation of protein function: as exemplified by NMDA-receptor modulation. Trends Neurosci. 25, 474-80.
131. Liu, J.S., Zhao, M.L., Brosnan, C.F., and Lee, S.C. (2001). Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Am. J. Pathol. 158, 2057-2066.
132. Liu, B., Gao, H.M., Wang, J.Y., Jeohn, G.H., Cooper, C.L., and Hong, J.S. (2002). Role of nitric oxide in inflammation-mediated neurodegeneration. Ann. N. Y. Acad. Sci. 962, 318-331.
133. Liversidge, J., Dick, A., and Gordon, S. (2002). Nitric oxide mediates apoptosis through formation of peroxynitrite and Fas/Fasligand interactions in experimental autoimmune uveitis. Am. J. Pathol. 160, 905-916.
134. Ljubisavljevic, S., Stojanovic, I., Pavlovic, D., Sokolovic, D., and Stevanovic, I. (2011). Aminoguanidine and N-Acetylcysteine suppress oxidative and nitrosative stress in EAE rat brains. Redox Rep. 16, 166-172.
135. Ljubisavljevic, S., Stojanovic, I., Pavlovic, D., Milojkovic, M., Vojinovic, S., Sokolovic, D., and Stevanovic, I. (2012a) Correlation of nitric oxide levels in the cerebellum and spinal cord of experimental autoimmune encephalomyelitis rats with clinical symptoms. Acta Neurobiol. Exp. 72, 33-39.
136. Ljubisavljevic, S., Stojanovic, I., Pavlovic, R., Stojnev, S., Stevanovic, I., Sokolovic, D., and Pavlovic, D. (2012b) The reduced glutathione and Sfinitrosothiols levels in acute phase of experimental demyelination-pathophysiological approach and possible clinical relevancy. Neuroscience 219, 175-182.
137. Ljubisavljevic, S., Stojanovic, I., Pavlovic, D., and Pavlovic, R. (2014). The importance of nitric oxide and arginase in the pathogenesis of acute neuroinflammation: are those contra players with the same direction? Neurotox. Res. 2014. doi: 10.1007/s12640-014-9470-3.
138. Macco, R., Pelizzoni, I., Consonni, A., Vitali, I., Giacalone, G., Martinelli Boneschi, F., Codazzi, F., Grohovaz, F., and Zacchetti, D. (2013). Astrocytes acquire resistance to iron-dependent oxidative stress upon proinflammatory activation. J. Neuroinflamm. 10, 130.
139. Mahad, D.J., Ziabreva, I., Campbell, G., Lax, N., White, K., Hanson, P.S., Lassmann, H., and Turnbull, D.M. (2009). Mitochondrial changes within axons in multiple sclerosis. Brain 132, 1161-1174.
140. Malabendu, J. and Kalipada, P. (2005). Redox regulation of cytokinemediated inhibition of myelin gene expression in human primary oligodendrocytes. Free Radic. Biol. Med. 39, 823-831.
141. Mancuso, C., Scapagini, G., Curro, D., Giuffrida Stella, A.M., De Marco, C., Butterfield, D.A., and Calabrese, V. (2007). Mitochondrial dysfunction, free radical generation and cellular stress response in neurodegenerative disorders. Front. Biosci. 12, 1107-1123.
142. Mandolesi, G., Musella, A., Gentile, A., Grasselli, G., Haji, N., Sepman, H., Fresegna, D., Bullitta, S., De Vito, F., Musumeci, G., et al. (2013). Interleukin-1?alters glutamate transmission at Purkinje cell synapses in a mouse model of multiple sclerosis. J. Neurosci. 33, 12105-12121.
143. Marchetti, B., Morale, M.C., Brouwer, J., Tirolo, C., Testa, N., Caniglia, S., Barden, N., Amor, S., Smith, P.A., and Dijkstra, C.D. (2002). Exposure to a dysfunctional glucocorticoid receptor from early embryonic life programs the resistance to experimental autoimmune encephalomyelitis via nitric oxide-induced immunosuppression. J. Immunol. 168, 5848-5859.
144. Marik, C., Felts, P., Bauer, J., Lassmann, H., and Smith, K.J. (2007). Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130, 2800-2815.
145. Marques, C., Cheeran, M., Palmquist, J., Hu, S., and Lokensgard, J. (2008). Microglia are the major cellular source of inducible nitric oxide synthase during experimental herpes encephalitis. J. Neurovirol. 14, 229-238.
146. Marrie, R.A. (2004). Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol. 3, 709-718.
147. Marshall, H.E. and Stamler, J.S. (2002). Nitrosative stress-induced apoptosis through inhibition of NF-kappaB. J. Biol. Chem. 277, 34223-34228.
148. Mart?nez, M.C. and Andriantsitohaina, R. (2009). Reactive nitrogen species: molecular mechanisms and potential significance in health and disease. Antioxid. Redox Signal. 11, 669-702.
149. Miljkovic, D. and Trajkovic, V. (2004). Inducible nitric oxide synthase activation by interleukin-17. Cytokine Growth Factor Rev. 15, 21-32.
150. Miljkovic, D., Timotijevic, G., and Mostarica Stojkovic, M. (2011). Astrocytes in the tempest of multiple sclerosis. FEBS Lett. 585, 3781-3788.
151. Miller, E., Mrowicka, M., Saluk-Juszczak, J., and Ireneusz, M. (2011). The level of isoprostanes as a non-invasive marker for in vivo lipid peroxidation in secondary progressive multiple sclerosis. Neurochem. Res. 36, 1012-1016.
152. Milo, R. and Kahana, E. (2010). Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun. Rev. 9, 387-394.
153. Moncada, S. and Bolanos, J.P. (2006). Nitric oxide, cell bioenergetics and neurodegeneration. J. Neurochem. 97, 1676-1689.
154. Morrison, B.M., Lee, Y. and Rothstein, J.D. (2013). Oligodendroglia: metabolic supporters of axons. Trends Cell Biol. 23, 644-651.
155. Motoyoshi-Yamashiro, A., Tamura, M., Moriyama, M., Takano, K., Kawabe, K., Nakajima, H., Katoh-Semba, R., Furuichi, T., and Nakamura, Y. (2013). Activation of cultured astrocytes by amphotericin B: stimulation of NO and cytokines production and changes in neurotrophic factors production. Neurochem. Int. 63, 93-100.
156. Murphy, P., Sharp, A., Shin, J., Gavrilyuk, V., Dello Russo, C., Weinberg, G., Sharp, F.R., Lu, A., Heneka, M.T., and Feinstein, D.L. (2002). Suppressive effects of ansamycins on inducible nitric oxide synthase expression and the development of experimental autoimmune encephalomyelitis. J. Neurosci. Res. 67, 461-470.
157. Muzhou, W.U. and Tsirka, S.E. (2009). Endothelial NOS-deficient mice reveal dual roles for nitric oxide during experimental autoimmune encephalomyelitis. Glia 57, 1204-1215.
158. Napoli, I. and Neumann, H. (2010). Protective effects of microglia in multiple sclerosis. Exp. Neurol. 225, 24-28.
159. Naughton, P., Hoque, M., Green, C.J., Foresti, R., and Motterlini, R. (2002). Interaction of heme with nitroxyl or nitric oxide amplifies heme oxygenase-1 induction: involvement of the transcription factor Nrf2. Cell Mol. Biol. 48, 885-894.
160. Nicot, A., Ratnakar, P.V., Ron, Y., Chen, C.C., and Elkabes, S. (2003). Regulation of gene expression in experimental autoimmune encephalomyelitis indicates early neuronal dysfunction. Brain 126, 398-412.
161. Nikolaeva, M.A., Mukherjee, B., and Stys, P.K. (2005). Na+ dependent sources of intraaxonal Ca2+ release in rat optic nerve during in vitro chemical ischemia. J. Neurosci. 25, 9960-9967.
162. Nozik-Grayck, E., Suliman, H.B., and Piantadosi, C.A. (2005). Extracellular superoxide dismutase. Int. J. Biochem. Cell Biol. 37, 2466-2471.
163. O'Brien, N.C., Charlton, B., Cowden, W.B., and Willenborg, D.O. (2001). 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. 167, 5904-5912.
164. Oksenberg, J.R. and Baranzini, S.E. (2010). Multiple sclerosis genetics: is the glass half full, or half empty? Nat. Rev. Neurol. 6, 429-437.
165. Okuda, Y., Sakoda, S., Fujimura, H., and Yanagihara, T. (1998). 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. 81, 201-210.
166. Oliveira, S.R., Kallaur, A.P., Simao, A.N.C., Morimoto, H.K., Lopes, J., Panis, C., Petenucci, D.L., da Silva, E., Cecchini, R., Kaimen-Maciel, D.R., et al. (2012). Oxidative stress in multiple sclerosis patients in clinical remission: association with the expanded disability status scale. J. Neurol. Sci. 321, 49-53.
167. Ortiz, G.G., Pacheco-Moisés, F.P., Bitzer-Quintero, O.K., Ramírez-Anguiano, A.C., Flores-Alvarado, L.J., Ramírez-Ramírez, V., Macias-Islas, M.A., and Torres-Sánchez, E.D. (2013). Immunology and oxidative stress in multiple sclerosis: clinical and basic approach. Clin. Dev. Immunol. 2013, 708659.
168. Pacher, P., Schulz, R., Liaudet, L., and Szabo, C. (2005). Nitrosative stress and pharmacological modulation of heart failure. Trends Pharmacol. Sci. 26, 302-310.
169. Pacher, P., Beckman, J.S., and Liaudet, L. (2007). Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87, 315-424.
170. Pachner, A.R. (2011). Experimental models of multiple sclerosis. Curr. Opin. Neurol. 24, 291-299.
171. Packer, M.A., Stasiv, Y., Benraiss, A., Chmielnicki, E., Grinberg, H., Westphal, H., Goldman, S.A., and Enikolopov, G. (2003). Nitric oxide negatively regulates mammalian adult neurogenesis. Proc. Natl. Acad. Sci. USA 100, 9566-9571.
172. Paget, M.S. and Buttner, M.J. (2003). Thiol-based regulatory switches. Annu. Rev. Genet. 37, 91-121.
173. Pahan, K. (2010). Neuroimmune pharmacological control of EAE. J. Neuroimmun. Pharm. 5, 165-167.
174. Pahan, K. and Mondal, S. (2012). Crosstalk between nitric oxide and T helper cells. J. Clin. Cell Immunol. 3, e109.
175. Pahan, K., Sheikh, F.G., Namboodiri, A.M., and Singh, I. (1998). N-Acetyl cysteine inhibits induction of NO production by endotoxin or cytokine stimulated rat peritoneal macrophages, C6 glial cells and astrocytes. Free Radic. Biol. Med. 24, 39-48.
176. Paintlia, M.K., Paintlia, A.S., Singh, A.K., and Singh, I. (2011). Synergistic activity of interleukin-17 and tumor necrosis factor-? enhances oxidative stress-mediated oligodendrocyte apoptosis. J. Neurochem. 116, 508-521.
177. Paintlia, M.K., Paintlia, A.S., Singh, A.K., and Singh, I. (2013). Sfinitrosoglutathione induces ciliary neurotrophic factor expression in astrocytes, which has implications to protect the central nervous system under pathological conditions. J. Biol. Chem. 288, 3831-3843.
178. Papadopoulos, D., Pham-Dinh, D., and Reynolds, R. (2006). Axon loss is responsible for chronic neurological deficit following inflammatory demyelination in the rat. Exp. Neurol. 197, 373-385.
179. Parratt, J.D. and Prineas, J.W. (2010). Neuromyelitis optica: a demyelinating disease characterized by acute destruction and regeneration of perivascular astrocytes. Mult. Scler. J. 16, 1156-1172.
180. Pautz, A., Art, J., Hahn, S., Nowag, S., Voss, C., and Kleinert, H. (2010). Regulation of the expression of inducible nitric oxide synthase. Nitric Oxide 23, 75-93.
181. Perkins, N.D. (2007). Integrating cell-signalling pathways with NFkappaB and IKK function. Nat. Rev. Mol. Cell Biol. 8, 49-62.
182. Petkovic, F., Blazevski, J., Momcilovic, M., Mostarica Stojkovic, M., and Miljkovic, D. (2013). Nitric oxide inhibits CXCL12 expression in neuroinflammation. Immunol. Cell Biol. 91, 427-434.
183. Petratos, S., Azari, M.F., Ozturk, E., Papadopoulos, R., and Bernard, C.C. (2010). Novel therapeutic targets for axonal degeneration in multiple sclerosis. J. Neuropathol. Exp. Neurol. 69, 323-334.
184. Petzold, A., Eikelenboom, M.J., Gveric, D., Keir, G., Chapman, M., Lazeron, R.H., Cuzner, M.L., Polman, C.H., Uitdehaag, B.M., Thompson, E.J., et al. (2002). Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations. Brain 125, 1462-1473.
185. Polman, C.H., Reingold, S.C., Banwell, B., Clanet, M., Cohen, J.A., Filippi, M., Fujihara, K., Havrdova, E., Hutchinson, M., Kappos, L., et al. (2011). Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann. Neurol. 69, 292-302.
186. Ponomarev, E.D., Shriver, L.P., Maresz, K., and Dittel, B.N. (2005). Microglial cell activation and proliferation precedes the onset of CNS autoimmunity. J. Neurosci. Res. 81, 374-389.
187. Prineas, J.W. and Parratt, J.D. (2012). Oligodendrocytes and the early multiple sclerosis lesion. Ann. Neurol. 72, 18-31.
188. Przedborski, S. and Ischiropoulos, H. (2005). Reactive oxygen and nitrogen species: weapons of neuronal destruction in models of Parkinson's disease. Antioxid. Redox Signal. 7, 685-693.
189. Puca, A.A., Carrizzo, A., Ferrario, A., Villa, F., and Vecchione, C. (2012). Endothelial nitric oxide synthase, vascular integrity and human exceptional longevity. Immun. Ageing 9, 26.
190. Puerta, C., Martínez, I., Baranda, P., Blasco, M.R., Castejón, R., Vargas, J.A., and García-Merino, A. (2000). Aminoguanidine reduces apoptosis of circulating V beta 8.2 T lymphocytes in Lewis rats with actively induced experimental autoimmune encephalomyelitis. Association with persistent inflammation of the central nervous system and lack of recovery. J. Neuroimmunol. 110, 140-150.
191. Qi, X., Lewin, A.S., Sun, L., Hauswirth, W.W., and Guy, J. (2006). Mitochondrial protein nitration primes neurodegeneration in experimental autoimmune encephalomyelitis. J. Biol. Chem. 281, 31950-31962.
192. Ransohoff, R.M., Kivisakk, P., and Kidd, G. (2003). Three or more routes for leukocyte migration into the central nervous system. Nat. Rev. Immunol. 3, 569-581.
193. Rao, P. and Segal, B.M. (2012). Experimental autoimmune encephalomyelitis. Methods Mol. Biol. 900, 363-380.
194. Reiter, T. (2006). NO chemistry: a diversity of targets in the cell. Redox Rep. 11, 194-206.
195. Rejdak, K., Eikelenboom, M.J., Petzold, A., Thompson, E.J., Stelmasiak, Z., Lazeron, R.H.C., Barkhof, F., Polman, C.H., Uitdehaag, B.M., and Giovannoni, G. (2004). CSF nitric oxide metabolites are associated with activity and progression of multiple sclerosis. Neurology 63, 1439-1445.
196. Rivers, T.M., Sprunt, D.H., and Berry, G.P. (1933). Observations on attempts to produce acute disseminated encephalomyelitis in monkeys. J. Exp. Med. 58, 39-53.
197. Rodríguez-Sáinz, M.C., Sánchez-Ramón, S., de Andrés, C., Rodríguez-Mahou, M., and Muñoz-Fernández, M.A. (2002). Th1/Th2 cytokine balance and nitric oxide in cerebrospinal fluid and serum from patients with multiple sclerosis. Eur. Cytokine Netw. 13, 110-114.
198. Rosado, E., Rodríguez-Vilarrupla, A., Gracia-Sancho, J., Monclus, M., Bosch, J., and García-Pagán, J.C. (2012). Interaction between NO and COX pathways modulating hepatic endothelial cells from control and cirrhotic rats. J. Cell. Mol. Med. 16, 2461-2470.
199. Ruck, T., Bittner, S., Gross, C.C., Breuer, J., Albrecht, S., Korr, S., Göbel, K., Pankratz, S., Henschel, C.M., Schwab, N., et al. (2013). CD4(+)NKG2D(+) T cells exhibit enhanced migratory and encephalitogenic properties in neuroinflammation. PLoS One 8, e81455.
200. Rumzan, R., Wang, J.J., Zeng, C., Chen, X., Li, Y., Luo, T., Lv, F., Wang, Z.P., Hou, H., and Huang, F. (2013). Iron deposition in the precentral grey matter in patients with multiple sclerosis: a quantitative study using susceptibility-weighted imaging. Eur. J. Radiol. 82, 95-99.
201. Saha, R.N. and Pahan, K. (2006). Regulation of inducible nitric oxide synthase gene in glial cells. Antioxid. Redox Signal. 8, 929-947.
202. Saito, S., Kidd, G.J., Trapp, B.D., Dawson, T.M., Bredt, D.S., Wilson, D.A., Traystman, R.J., Snyder, S.H., and Hanley, D.F. (1994). Rat spinal cord neurons contain nitric oxide synthase. Neuroscience 59, 447-456.
203. Sajad, M., Zargan, J., Chawla, R., Umar, S., Sadaqat, M., and Khan, H. (2009). Hippocampal neurodegeneration in experimental autoimmune encephalomyelitis (EAE): potential role of inflammation activated myeloperoxidase. Mol. Cell Biochem. 328, 183-188.
204. Satoh, T. and Lipton, S.A. (2007). Redox regulation of neuronal survival mediated by electrophilic compounds. Trends Neurosci. 1, 37-45.
205. Sattler, M.B. and Bahr, M. (2010). Future neuroprotective strategies. Exp. Neurol. 225, 40-47.
206. Schnell, L., Fearn, S., Klassen, H., Schwab, M.E., and Perry, V.H. (1999). Acute inflammatory responses to mechanical lesions in the CNS: differences between brain and spinal cord. Eur. J. Neurosci. 11, 3648-3658.
207. Sellebjerg, F., Giovannoni, G., Hand, A., Madsen, H.O., Jensen, C.V., and Garred, P. (2002). Cerebrospinal fluid levels of nitric oxide metabolites predict response to methylprednisolone treatment in multiple sclerosis and optic neuritis. J. Neuroimmunol. 125, 198-203.
208. Shah, D., Kiran, R., Wanchu, A., and Bhatnagar, A. (2010). Oxidative stress in systemic lupus erythematosus: relationship to Th1 cytokine and disease activity. Immunol. Lett. 129, 7-12.
209. Shin, T., Kim, S., Moon, C., Wie, M., and Kim, H. (2000). Aminoguanidine-induced amelioration of autoimmune encephalomyelitis is mediated by reduced expression of inducible nitric oxide synthase in the spinal cord. Immunol. Invest. 29, 233-241.
210. Sims, N.R. and Muyderman, H. (2010). Mitochondria, oxidative metabolism and cell death in stroke. Biochim. Biophys. Acta 1802, 80-91.
211. Singh, I., Paintlia, A.S., Khan, M., Stanislaus, R., Paintlia, M.K., Haq, E., Singh, A.K., and Contreras, M.A. (2004). Impaired peroxisomal function in the central nervous system with inflammatory disease of experimental autoimmune encephalomyelitis animals and protection by lovastatin treatment. Brain Res. 1022, 1-11.
212. Smith, K.J. and Lassmann, H. (2002). The role of nitric oxide in multiple sclerosis. Lancet Neurol. 1, 232-241.
213. Smith, K.J., Kapoor, R., Hall, S.M., and Davies, M. (2001). Electrically active axons degenerate when exposed to nitric oxide. Ann. Neurol. 49, 470-476.
214. Soellner, I.A., Rabe, J., Mauri, V., Kaufmann, J., Addicks, K., and Kuerten, S. (2013). Differential aspects of immune cell infiltration and neurodegeneration in acute and relapse experimental autoimmune encephalomyelitis. Clin. Immunol. 149, 519-529.
215. Speciale, L., Sarasella, M., Ruzzante, S., Caputo, D., Mancuso, R., Calvo, M.G., Guerini, F.R., and Ferrante, P. (2000). Endothelin and nitric oxide levels in cerebrospinal fluid of patients with multiple sclerosis. J. Neurovirol. 6, S62-S66.
216. Spiro, S. (2007). Regulators of bacterial responses to nitric oxide. FEMS Microbiol. Rev. 31, 193-211.
217. Stadelmann, C., Kerschensteiner, M., Misgeld, T., Brück, W., Hohlfeld, R., and Lassmann, H. (2002). BDNF and gp145trkB in multiple sclerosis brain lesions: neuroprotective interaction between immune and neuronal cells? Brain 125, 75-85.
218. Stadelmann, C., Kerschensteiner, M., Misgeld, T., Brück, W., Hohlfeld, R., Lassmann, H., Stadtman, E.R., Moskovitz, J., and Levine, R.L. (2003). Oxidation of methionine residues of proteins: biological consequences. Antioxid. Redox Sign. 5, 577-582.
219. Stanislaus, R., Gilg, A.G., Singh, A.K., and Singh, I. (2005). N-Acetyl-L-cysteine ameliorates the inflammatory disease process in experimental autoimmune encephalomyelitis in Lewis rats. J. Autoimmune Dis. 2, 4.
220. Staykova, M.A., Paridaen, J.T., Cowden, W.B., and Willenborg, D.O. (2005). Nitric oxide contributes to resistance of the brown Norway rat to experimental autoimmune encephalomyelitis. Am. J. Pathol. 166, 147-157.
221. Stevanovic, I., Ninkovic, M., Stojanovic, I., Ljubisavljevic, S., Stojnev, S., and Bokonjic, D. (2013). Beneficial effect of agmatine in the acute phase of experimental autoimmune encephalomyelitis in iNOS-/-knockout mice. Chem. Biol. Interact. 206, 309-318.
222. Stirling, D.P. and Stys, P.K. (2010). Mechanisms of axonal injury: internodal nanocomplexes and calcium deregulation. Trends Mol. Med. 16, 160-170.
223. Stojanovic, I., Ljubisavljevic, S., Stevanovic, I., Pavlovic, R., Cvetkovic, T., Djordjevic, V., Pavlovic, D., Vojinovic, S., and Basic, J. (2012). Nitric oxide-mediated signalization and nitrosative stress in neuropathology. J. Med. Biochem. 31, 295-300.
224. Stys, P.K. (2004). White matter injury mechanisms. Curr. Mol. Med. 4, 113-130.
225. Stys, P.K. (2005). General mechanisms of axonal damage and its prevention. J. Neurol. Sci. 233, 3-13.
226. Sullivan, G.M., Mierzwa, A.J., Kijpaisalratana, N., Tang, H., Wang, Y., Song, S.K., Selwyn, R., and Armstrong, R.C. (2013). Oligodendrocyte lineage and subventricular zone response to traumatic axonal injury in the corpus callosum. J. Neuropathol. Exp. Neurol. 72, 1106-1125.
227. Thiel, V.E. and Audus, K.L. (2001). Nitric oxide and blood-brain barrier integrity. Antioxid. Redox Sign. 3, 273-278.
228. Tian, D.H., Perera, C.J., Apostolopoulos, V., and Moalem-Taylor, G. (2013). Effects of vaccination with altered peptide ligand on chronic pain in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Front. Neurol. 4, 168.
229. Tiberio, M., Chard, D.T., Altmann, G.R., Davies, G., Griffin, C.M., McLean, M.A., Rashid, W., Sastre-Garriga, J., Thompson, A.J. and Miller, D.H. (2006). Metabolite changes in early relapsingremitting multiple sclerosis. A two year follow-up study. J. Neurol. 253, 224-230.
230. Tishkina, A., Rukhlenko, A., Stepanichev, M., Levshina, I., Pasikova, N., Onufriev, M., Moiseeva, Y., Piskunov, A., and Gulyaeva, N. (2012). Region-specific changes in activities of cell deathrelated proteases and nitric oxide metabolism in rat brain in a chronic unpredictable stress model. Metab. Brain Dis. 27, 431-441.
231. Trapp, B.D., and Nave, K.A. (2008). Multiple sclerosis: An immune or neurodegenerative disorder Ann. Rev. Neurosci. 31, 247-269.
232. Uccelli, A., Pedemonte, E., Narciso, E., and Mancardi, G. (2003). Biological markers of the inflammatory phase of multiple sclerosis. Neurol. Sci. 24, S271-S274.
233. van der Veen, R.C. and Roberts, L.J. (1999). Contrasting roles for nitric oxide and peroxynitrite in the peroxidation of myelin lipids. J. Neuroimmunol. 95, 1-7.
234. van der Veen, R.C., Dietlin, T.A., Hofman, F.M., Pen, L., Segal, B.H., and Holland, S.M. (2000). Superoxide prevents nitric oxidemediated suppression of helper T lymphocytes: decreased autoimmune encephalomyelitis in nicotinamide adenine dinucleotide phosphate oxidase knockout mice. J. Immunol. 164, 5177-5183.
235. van Horssen, J., Schreibelt, G., Drexhage, J., Hazes, T., Dijkstra, C.D., van der Valk, P., and de Vries, H.E. (2008). Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic. Biol. Med. 45, 1729-1737.
236. Vartanian, T.K. (2008). MS as a neurodegenerative disease (a thought experiment): the clinical evidence. Adv. Stud. Med. 8, 305-308.
237. Waldner, H., Collins, M., and Kuchroo, V.K. (2004). Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoimmune disease. J. Clin. Invest. 113, 990-997.
238. Waxsman, S.G. (2005). Multiple Sclerosis as a Neuronal Disease. Boston: Elsevier Academic Press.
239. Willard, S.S. and Koochekpour, S. (2013). Glutamate signaling in benign and malignant disorders: current status, future perspectives, and therapeutic implications. Int. J. Biol. Sci. 9, 728-742.
240. Willenborg, D.O., Staykova, M., Fordham, S., O'Brien, N., and Linares, D. (2007). The contribution of nitric oxide and interferon gamma to the regulation of the neuro-inflammation in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 191, 16-25.
241. Wilms, H., Sievers, J., Rickert, U., Rostami-Yazdi, M., Mrowietz, U., and Lucius, R. (2010). Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide, IL-1?, TNF-?and IL-6 in an in-vitro model of brain inflammation. J. Neuroinflamm. 7, 30.
242. Wolswijk, G. (2000). Oligodendrocyte survival, loss and birth in lesions of chronic-stage multiple sclerosis. Brain 123, 105-115.
243. Xiang, W., Weisbach, V., Sticht, H., Seebahn, A., Bussmann, J., Zimmermann, R., and Becker, C.M. (2013). Oxidative stressinduced posttranslational modifications of human hemoglobin in erythrocytes. Arch. Biochem. Biophys. 529, 34-44.
244. Xu, L.Y., Yang, J.S., Link, H., and Xiao, B.G. (2001). SIN-1, a nitric oxide donor, ameliorates the time window rats in the incipient phase: the importance of experimental allergic encephalomyelitis in Lewis. J. Immunol. 166, 5810-5816.
245. Yin, W., Signore, A.P., Iwai, M., Cao, G., Gao, Y., and Chen, J. (2008). Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury. Stroke 39, 3057-3063.
246. Yokoyama, H., Yano, R., Aoki, E., Kato, H., and Araki, T. (2008). Comparative pharmacological study of free radical scavenger, nitric oxide synthase inhibitor, nitric oxide synthase activator and cyclooxygenase inhibitor against MPTP neurotoxicity in mice. Metab. Brain Dis. 23, 335-349.
247. Zaffaroni, M. (2003). Biological indicators of the neurodegenerative phase of multiple sclerosis. Neurol. Sci. 24, 279-282.
248. Zang, L., He, H., Ye, Y., Liu, W., Fan, S., Tashiro, S., Onodera, S., and Ikejima T. (2012). Nitric oxide augments oridonin-induced efferocytosis by human histocytic lymphoma U937 cells via autophagy and the NF-?B-COX-2-IL-1pathway. Free Radic. Res. 46, 1207-1219.
249. Zeis, T., Graumann, U., Reynolds, R., and Schaeren-Wiemers, N. (2008). Normal-Appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection. Brain 131, 288-303.
250. Zheng, H., Zhang, H., Liu, F., Qi, Y., and Jiang, H. (2013). T celldepleted splenocytes from mice pre-immunized with neuroantigen in incomplete Freund's adjuvant involved in protection from experimental autoimmune encephalomyelitis. Immunol. Lett. 157, 38-44.
251. Zhou, P., Qian, L., and Iadecola, C. (2005). Nitric oxide inhibits caspase activation and apoptotic morphology but does not rescue neuronal death. J. Cereb. Blood Flow Metab. 25, 348-357.
252. Zhu, X., Su, B., Wang, X., Smith, M.A., and Perry, G. (2007). Causes of oxidative stress in Alzheimer disease. Cell. Mol. Life Sci. 64, 2202-2210.
253. Zorzella-Pezavento, S.F., Chiuso-Minicucci, F., França, T.G., Ishikawa, L.L., da Rosa, L.C., Marques, C., Ikoma, M.R., and Sartori, A. (2013). Persistent inflammation in the CNS during chronic EAE despite local absence of IL-17 production. Mediat. Inflamm. 2013, 519627.