Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter October 24, 2014

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

  • Srdjan Ljubisavljevic

    Srdjan Ljubisavljevic is a specialist in Neurology. He works at the Faculty of Medicine and Clinic for Neurology in University Clinical centre of Niš, Serbia. His scientific activities are based on investigations of biomarkers of neuroinflammation and the possibilities of its modulation in the preclinical and clinical conditions, as well as, demyelination, headaches and other pain-associated neurological disorders. Dr Ljubisavljevic published and reviewed many articles in prominent neurological journals. He has received an award from the European Federation of Neurological Societies for the best annual investigation in neuroinflammation.

    EMAIL logo
    and Ivana Stojanovic

    Ivana Stojanovic is an Associate Professor of Biochemistry at the Faculty of Medicine, University of Niš. She is the leader of the scientific subproject titled: “Biomarkers and modulators of inflammatory response and late changes in CNS diseases”. The topics of her scientific interest are L-arginine metabolites and inflammatory mediators interplay in neurotoxicity and neuroinflammation, as well as the involvement of oxidative and nitrosative stress in those processes, encompassing both in vivo and in vitro experimental models, as well as clinical investigations. She authored 263 scientific articles, published in journals or presented at meetings.

Abstract

The role of nitrosative stress in the early pathogenesis of neuroinflammation and demyelination is undoubtedly wide. This review summarizes and integrates the results, found in previously performed studies, which have evaluated nitrosative stress participation in neuroinflammation. The largest number of studies indicates that the supply of nitrosative stress inhibitors has led to the opposite clinical effects in experimental studies. Some results claim that attributing the protective role to nitric oxide, outside the total changes of redox oxidative processes and without following the clinical and paraclinical correlates of neuroinflammation, is an overrated role of this mediator. The fact is that the use of nitrosative stress inhibitors would be justified in the earlier phases of neuroinflammation. The ideal choice would be a specific inducible nitric oxide synthase (iNOS) inhibitor, because its use would preserve the physiological features of nitric oxide produced by the effects of constitutive NOS. This review discusses the antinitrosative therapy as a potential mode of therapy that aims to control neuroinflammation in early phases, delaying its later phases, which are accompanied with irreversible neurological disabilities. Some parameters of nitrosative stress might serve as surrogate biomarkers for neuroinflammation intensity and its radiological and clinical correlates.


Corresponding author: Srdjan Ljubisavljevic, Clinic of Neurology, Clinical Center Nis, Bul. Dr Zorana Djindjica 48, 18000 Nis, Serbia; and Faculty of Medicine, University of Nis, Bul. Dr Zorana Djindjica 81, 18000 Nis, Serbia, e-mail:

About the authors

Srdjan Ljubisavljevic

Srdjan Ljubisavljevic is a specialist in Neurology. He works at the Faculty of Medicine and Clinic for Neurology in University Clinical centre of Niš, Serbia. His scientific activities are based on investigations of biomarkers of neuroinflammation and the possibilities of its modulation in the preclinical and clinical conditions, as well as, demyelination, headaches and other pain-associated neurological disorders. Dr Ljubisavljevic published and reviewed many articles in prominent neurological journals. He has received an award from the European Federation of Neurological Societies for the best annual investigation in neuroinflammation.

Ivana Stojanovic

Ivana Stojanovic is an Associate Professor of Biochemistry at the Faculty of Medicine, University of Niš. She is the leader of the scientific subproject titled: “Biomarkers and modulators of inflammatory response and late changes in CNS diseases”. The topics of her scientific interest are L-arginine metabolites and inflammatory mediators interplay in neurotoxicity and neuroinflammation, as well as the involvement of oxidative and nitrosative stress in those processes, encompassing both in vivo and in vitro experimental models, as well as clinical investigations. She authored 263 scientific articles, published in journals or presented at meetings.

Acknowledgments

This work was supported by the grant from the Ministry of Education and Science, Republic of Serbia (scientific project number 41018).

Conflict of interest statement: None.

References

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, 602–608.10.1177/1352458507085550Search in Google Scholar

Abraham, M., Gola, J., Cometto-Muniz, E., and Cain, W. (2000). The solvation properties of nitric oxide. J. Chem. Soc. Perkin. Trans 2, 2067–2070.10.1039/b004419iSearch in Google Scholar

Acar, G. (2003). Nitric oxide as an activity marker in multiple sclerosis. J. Neurol. 250, 588–592.10.1007/s00415-003-1041-0Search in Google Scholar

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, 1760–1777.10.1093/brain/awt093Search in Google Scholar

Alvarez, B. and Radi, R. (2003). Peroxynitrite reactivity with amino acids and proteins. Amino Acids 25, 295–311.10.1007/s00726-003-0018-8Search in Google Scholar

Ames, A.I. (2000). CNS energy metabolism as related to function. Brain Res. Rev. 34, 42–68.10.1016/S0165-0173(00)00038-2Search in Google Scholar

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, 465–476.10.1002/ana.22054Search in Google Scholar PubMed

Arend, C., Brandmann, M., and Dringen, R. (2013). The antiretroviral protease inhibitor ritonavir accelerates glutathione export from cultured primary astrocytes. Neurochem. Res. 38, 732–741.10.1007/s11064-013-0971-xSearch in Google Scholar PubMed

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, 2454–2468.10.1172/JCI60842Search in Google Scholar PubMed PubMed Central

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, 427–433.10.4049/jimmunol.168.1.427Search in Google Scholar PubMed

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, 65–72.10.1159/000272940Search in Google Scholar PubMed

Ascherio, A. and Munger, K.L. (2007). Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann. Neurol. 61, 288–299.10.1002/ana.21117Search in Google Scholar PubMed

Ascherio, A. and Munger, K. (2008). Epidemiology of multiple sclerosis: from risk factors to prevention. Semin. Neurol. 28, 17–28.10.1055/s-2007-1019126Search in Google Scholar PubMed

Bachmann, M.F., Kopf, M., and Marsland, B.J. (2006). Chemokines: more than just road signs. Nat. Rev. Immunol. 6, 159–164.10.1038/nri1776Search in Google Scholar PubMed

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, 149–188.10.1615/CritRevImmunol.v26.i2.40Search in Google Scholar PubMed

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, 121–132.10.1191/135248506ms1304rrSearch in Google Scholar PubMed

Baxter, A.G. (2007). The origin and application of experimental autoimmune encephalomyelitis. Nat. Rev. Immunol. 7, 904–912.10.1038/nri2190Search in Google Scholar PubMed

Beal, M.F. (2003). Mitochondria, oxidative damage, and inflammation in Parkinson’s disease. Ann. N. Y. Acad. Sci. 991, 120–131.10.1111/j.1749-6632.2003.tb07470.xSearch in Google Scholar PubMed

Bennett, M. and Heard, R. (2010). Hyperbaric oxygen therapy for multiple sclerosis. CNS Neurosci. Ther. 16, 115–124.10.1111/j.1755-5949.2009.00129.xSearch in Google Scholar PubMed PubMed Central

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, 93–104.10.1111/j.1471-4159.2009.05891.xSearch in Google Scholar PubMed PubMed Central

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, 1174–1183.10.1093/brain/123.6.1174Search in Google Scholar

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, 656–667.10.1002/jnr.20771Search in Google Scholar

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, 78.10.1186/1471-2202-11-78Search in Google Scholar

Bo, L., Esiri, M., Evangelou, N., and Kuhlmann, T. (2013). Demyelination and Remyelination in Multiple Sclerosis. Myelin Repair and Neuroprotection in Multiple Sclerosis, pp. 23–45.10.1007/978-1-4614-2218-1_2Search in Google Scholar

Boullerne, A.I., Rodrıguez, 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, 123–132.10.1523/JNEUROSCI.22-01-00123.2002Search in Google Scholar

Brea, D., Sobrino, T., Ramos-Cabrer, P., and Castillo, J. (2009). Inflammatory and neuroimmunomodulatory changes in acute cerebral ischemia. Cerebrovasc. Dis. 27, 48–64.10.1159/000200441Search in Google Scholar

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, 390–393.10.1136/jnnp.70.3.390Search in Google Scholar

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, 261–269.10.1111/j.1600-0404.2004.00207.xSearch in Google Scholar

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, 4364–4372.10.1021/bi400342tSearch in Google Scholar

Brown, G.C. and Bal-Price, A. (2003). Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol. Neurobiol. 27, 325–355.10.1385/MN:27:3:325Search in Google Scholar

Butterfield, D.A. and Sultana, R. (2008). Identification of 3-nitrotyrosine-modified brain proteins by redox proteomics. Methods Enzymol. 440, 295–308.10.1016/S0076-6879(07)00819-1Search in Google Scholar

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 S-nitrosothiols and with changes in glutathione levels. J. Neurosci. Res. 70, 580–587.10.1002/jnr.10408Search in Google Scholar PubMed

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, 797–807.10.1007/s11064-005-6874-8Search in Google Scholar PubMed

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, 1975–1986.10.1089/ars.2006.8.1975Search in Google Scholar PubMed

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, 766–775.10.1038/nrn2214Search in Google Scholar PubMed

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, 376–397.10.2741/3250Search in Google Scholar PubMed

Carreras, M.C. and Poderoso, J.J. (2007). Mitochondrial nitric oxide in the signaling of cell integrated responses. Am. J. Physiol. Cell Physiol. 292, 1569–1580.10.1152/ajpcell.00248.2006Search in Google Scholar PubMed

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, 125.10.1186/1742-2094-10-125Search in Google Scholar PubMed PubMed Central

Charil, A. and Filippi, M. (2007). Inflammatory demyelination and neurodegeneration in early multiple sclerosis. J. Neurol. Sci. 259, 7–15.10.1016/j.jns.2006.08.017Search in Google Scholar PubMed

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, 174–181.10.1016/j.tips.2009.01.002Search in Google Scholar PubMed PubMed Central

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, 81–90.10.1016/S1388-1981(02)00286-XSearch in Google Scholar

Confavreux, C. and Vukusic, S. (2006). Natural history of multiple sclerosis: a unifying concept. Brain 129, 606–616.10.1093/brain/awl007Search in Google Scholar

Contestabile, A. and Ciani, E. (2004). Role of nitric oxide in the regulation of neuronal proliferation, survival and differentiation. Neurochem. Int. 45, 903–914.10.1016/j.neuint.2004.03.021Search in Google Scholar

Contestabile, A., Monti, B., and Polazzi, E. (2012). Neuronal-glial interactions define the role of nitric oxide in neural functional processes. Curr. Neuropharmacol. 10, 303–310.10.2174/157015912804499465Search in Google Scholar

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, 616–621.10.1016/j.apmr.2012.10.020Search in Google Scholar

Corthals, A.P. (2011). Multiple sclerosis is not a disease of the immune system. Q. Rev. Biol. 86, 287–321.10.1086/662453Search in Google Scholar

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, 1043–1054.10.4049/jimmunol.1200485Search in Google Scholar

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, 112–118.10.1016/S0165-5728(02)00464-2Search in Google Scholar

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, 39327–39333.10.1074/jbc.M111841200Search in Google Scholar PubMed PubMed Central

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, 10–20.10.1097/00005072-199701000-00002Search in Google Scholar PubMed

Dedon, P.C. and Tannenbaum, S.R. (2004). Reactive nitrogen species in the chemical biology of inflammation. Arch. Biochem. Biophys. 423, 12–22.10.1016/j.abb.2003.12.017Search in Google Scholar PubMed

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, 146–150.10.1016/j.jneuroim.2006.05.005Search in Google Scholar PubMed

Dinkova-Kostova, A.T. and Talalay, P. (2008). Direct and indirect antioxidant properties of inducers of cytoprotective proteins. Mol. Nutr. Food Res. 52, 128–138.10.1002/mnfr.200700195Search in Google Scholar PubMed

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, 82–93.10.1016/j.nbd.2013.02.007Search in Google Scholar PubMed

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.Search in Google Scholar

Elfering, S.L., Sarkela, T.M., and Giulivi, C. (2002). Biochemistry of mitochondrial nitric-oxide synthase. J. Biol. Chem. 277, 38079–38086.10.1074/jbc.M205256200Search in Google Scholar PubMed

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, 18–23.10.1016/j.expneurol.2009.12.020Search in Google Scholar PubMed

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, 32–38.10.1159/000107286Search in Google Scholar PubMed

Fernandez-Fernandez, S., Almeida, A., and Bolaños, J.P. (2012). Antioxidant and bioenergetic coupling between neurons and astrocytes. Biochem. J. 443, 3–11.10.1042/BJ20111943Search in Google Scholar PubMed

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, 677–682.10.1191/1352458505ms1240oaSearch in Google Scholar PubMed

Flynn, R.W., MacWalter, R.S., and Doney, A.S. (2008). The cost of cerebral ischaemia. Neuropharmacology 55, 250–256.10.1016/j.neuropharm.2008.05.031Search in Google Scholar PubMed

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, 246–256.10.1152/ajpcell.00516.2003Search in Google Scholar

Foster, M.W., McMahon, T.J., and Stamler, J.S. (2003). S-nitrosylation in health and disease. Trends Mol. Med. 9, 160–168.10.1016/S1471-4914(03)00028-5Search in Google Scholar

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, 1175–1189.10.1093/brain/awp070Search in Google Scholar

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, 535–540.10.1038/nrneurol.2013.98Search in Google Scholar

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, 227–233.10.2220/biomedres.30.227Search in Google Scholar

Garden, G.A. and Moller, T. (2006). Microglia biology in health and disease. J. Neuroimmun. Pharmacol. 1, 127–137.10.1007/s11481-006-9015-5Search in Google Scholar

Gaston, B.M., Carver, J., Doctor, A., and Palmer, L.A. (2003). S-nitrosylation signaling in cell biology. Mol. Interv. 3, 253–263.10.1124/mi.3.5.253Search in Google Scholar

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, 261–268.10.1007/s00415-004-0348-9Search in Google Scholar

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, 125–135.10.1385/JMN:27:1:125Search in Google Scholar

Glass, C., Saijo, K., Winner, B., Marchetto, M., and Gage, F. (2010). Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934.10.1016/j.cell.2010.02.016Search in Google Scholar PubMed PubMed Central

Gold, R. and Wolinsky, J.S. (2011). Pathophysiology of multiple sclerosis and the place of teriflunomide. Acta Neurol. Scand. 124, 75–84.10.1111/j.1600-0404.2010.01444.xSearch in Google Scholar

Gold, R., Hartung, H.P., and Toyka, K.V. (2000). Animal models for autoimmune demyelinating disorders of the nervous system. Mol. Med. Today 6, 88–91.10.1016/S1357-4310(99)01639-1Search in Google Scholar

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, 1953–1971.10.1093/brain/awl075Search in Google Scholar PubMed

Gonsette, R.E. (2008). Neurodegeneration in multiple sclerosis: the role of oxidative stress and excitotoxicity. J. Neurol. Sci. 274, 48–53.10.1016/j.jns.2008.06.029Search in Google Scholar PubMed

Gonsette, R.E. (2010). Endogenous neuroprotection in multiple sclerosis. Acta Neurol. Belg. 110, 26–35.Search in Google Scholar

Graber, J.J. and Dhib-Jalbut, S. (2011). Biomarkers of disease activity in multiple sclerosis. J. Neurol. Sci. 305, 1–10.10.1016/j.jns.2011.03.026Search in Google Scholar PubMed

Graeber, M.B. and Christie, M.J. (2012). Multiple mechanisms of microglia: a gatekeeper’s contribution to pain states. Exp. Neurol. 234, 255–261.10.1016/j.expneurol.2012.01.007Search in Google Scholar PubMed

Griffin, W.S. (2006). Inflammation and neurodegenerative diseases. Am. J. Clin. Nutr. 83, 470S–474S.10.1093/ajcn/83.2.470SSearch in Google Scholar PubMed

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, 126–152.10.1016/j.pneurobio.2005.06.001Search in Google Scholar PubMed

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, 94–96.10.1097/00001756-199412300-00025Search in Google Scholar PubMed

Hafler, D.A. (2004). Multiple sclerosis. J. Clin. Invest. 113, 788–794.10.1172/JCI21357Search in Google Scholar PubMed PubMed Central

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, 1914–1924.10.1093/brain/awr128Search in Google Scholar PubMed PubMed Central

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, 1076–1081.10.1038/nature06559Search in Google Scholar PubMed

Henderson, A., Barnett, M., Parratt, J., and Prineas, J. (2009). Multiple sclerosis: distribution of inflammatory cells in newly forming lesions. Ann. Neurol. 66, 739–753.10.1002/ana.21800Search in Google Scholar PubMed

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, 106–118.10.1097/NEN.0b013e31827fd9e8Search in Google Scholar PubMed

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, 171–179.10.1016/j.jneuroim.2004.02.005Search in Google Scholar PubMed

Hohlfeld, R. (2009). ECTRIMS lecture: future challenges in MS. Mult. Scler. J. 15, S8–S9.Search in Google Scholar

Hohlfeld, R. and Wekerle, H. (2001). Immunological update on multiple sclerosis. Curr. Opin. Neurol. 14, 299–304.10.1097/00019052-200106000-00006Search in Google Scholar PubMed

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, 691–698.10.1096/fasebj.14.5.691Search in Google Scholar PubMed

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, 1017–1033.10.1097/NEN.0b013e3181f3a5b1Search in Google Scholar PubMed PubMed Central

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-α/δ and NF-κB. Inflamm. Res. 61, 1107–1116.10.1007/s00011-012-0503-1Search in Google Scholar PubMed

Jack, C., Ruffini, F., Bar-Or, A., and Antel, J.P. (2005). Microglia and multiple sclerosis. J. Neurosci. Res. 81, 363–373.10.1002/jnr.20482Search in Google Scholar PubMed

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, 926–934.10.1002/glia.20514Search in Google Scholar

Jaffrey, S.R., Erdjument-Bromage, H., Ferris, C.D., Tempst, P., and Snyder, S.H. (2001). Protein S-nitrosylation: a physiological signal for neuronal nitric oxide. Nat. Cell. Biol. 3, 193–197.10.1038/35055104Search in Google Scholar

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, 5–15.10.1016/j.jns.2008.12.010Search in Google Scholar

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, 1–17.10.1016/j.freeradbiomed.2008.03.011Search in Google Scholar

Jha, M.K., Jeon, S., and Suk, K. (2012). Glia as a link between neuroinflammation and neuropathic pain. Immune Netw. 12, 41–47.10.4110/in.2012.12.2.41Search in Google Scholar

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, 20–30.10.1016/j.jneuroim.2010.03.011Search in Google Scholar

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, 56–64.10.1016/S0165-5728(03)00097-3Search in Google Scholar

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, 410–417.10.1016/j.fct.2008.11.041Search in Google Scholar PubMed

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, 198–205.10.1002/jnr.10649Search in Google Scholar PubMed

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, 214–222.10.1016/j.mito.2010.09.014Search in Google Scholar PubMed

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.Search in Google Scholar

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, 174–180.10.1002/ana.10443Search in Google Scholar PubMed

Khan, H.A. (2012). N-nitro-L-arginine, a nitric oxide synthase inhibitor, aggravates iminodipropionitrile-induced neurobehavioral and vestibular toxicities in rats. Exp. Toxicol. Pathol. 64, 791–796.10.1016/j.etp.2011.01.017Search in Google Scholar PubMed

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, 823–834.10.1093/brain/awf070Search in Google Scholar PubMed

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, 11–17.10.4142/jvs.2000.1.1.11Search in Google Scholar

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, 626–632.10.1016/j.nbd.2005.09.009Search in Google Scholar PubMed

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-κB-mediated iNOS induction and microglial activation. J. Neuroimmunol. 259, 26–36.10.1016/j.jneuroim.2013.03.006Search in Google Scholar PubMed

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, 6064–6069.10.1073/pnas.0909794107Search in Google Scholar PubMed PubMed Central

Knott, A.B. and Bossy-Wetzel, E. (2009). Nitric oxide in health and disease of the nervous system. Antioxid. Redox Signal. 11, 541–553.10.1089/ars.2008.2234Search in Google Scholar PubMed PubMed Central

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, 483–487.10.1007/s00415-005-0037-3Search in Google Scholar PubMed

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, 178–190.10.1152/ajprenal.00048.2003Search in Google Scholar PubMed

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.Search in Google Scholar

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, 267–276.10.1016/S0002-9440(10)64537-3Search in Google Scholar

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, 385–391.10.1177/1352458512463769Search in Google Scholar PubMed

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, 553–562.10.1007/s007020070078Search in Google Scholar PubMed

Kurtzke, J.F. (2005). Epidemiology and etiology of multiple sclerosis. Phys. Med. Rehabil. Clin. N. Am. 16, 327–349.10.1016/j.pmr.2005.01.013Search in Google Scholar PubMed

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, 196–206.10.1016/j.brainresrev.2004.12.009Search in Google Scholar PubMed

Lambeth, J.D. (2004). NOX enzymes and the biology of reactive oxygen. Nat. Rev. Immunol. 4, 181–189.10.1038/nri1312Search in Google Scholar PubMed

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, 29690–29701.10.1074/jbc.M111.338095Search in Google Scholar PubMed PubMed Central

Lassmann, H. (2003). Axonal injury in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 74, 695–697.10.1136/jnnp.74.6.695Search in Google Scholar PubMed PubMed Central

Lassmann, H. and van Horssen, J. (2011). The molecular basis of neurodegeneration in multiple sclerosis. FEBS Lett. 585, 3715–3723.10.1016/j.febslet.2011.08.004Search in Google Scholar PubMed

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, e5786.10.1371/journal.pone.0005786Search in Google Scholar PubMed PubMed Central

Leiper, J. and Nandi, M. (2011). The therapeutic potential of targeting endogenous inhibitor of nitric oxide synthesis. Nat. Rev. Drug Discov. 10, 277–291.10.1038/nrd3358Search in Google Scholar

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, 150–155.10.1016/j.neuroscience.2010.11.018Search in Google Scholar

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, 678–689.10.1038/nri2156Search in Google Scholar

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, 9936–9941.10.1073/pnas.0502552102Search in Google Scholar

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, 474–80.10.1016/S0166-2236(02)02245-2Search in Google Scholar

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, 2057–2066.10.1016/S0002-9440(10)64677-9Search in Google Scholar

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, 318–331.10.1111/j.1749-6632.2002.tb04077.xSearch in Google Scholar

Liversidge, J., Dick, A., and Gordon, S. (2002). Nitric oxide mediates apoptosis through formation of peroxynitrite and Fas/Fas-ligand interactions in experimental autoimmune uveitis. Am. J. Pathol. 160, 905–916.10.1016/S0002-9440(10)64913-9Search in Google Scholar

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, 166–172.10.1179/1351000211Y.0000000007Search in Google Scholar PubMed PubMed Central

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.Search in Google Scholar

Ljubisavljevic, S., Stojanovic, I., Pavlovic, R., Stojnev, S., Stevanovic, I., Sokolovic, D., and Pavlovic, D. (2012b) The reduced glutathione and S-nitrosothiols levels in acute phase of experimental demyelination – pathophysiological approach and possible clinical relevancy. Neuroscience 219, 175–182.10.1016/j.neuroscience.2012.05.062Search in Google Scholar PubMed

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/s12640-014-9470-3.10.1007/s12640-014-9470-3Search in Google Scholar

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, 130.10.1186/1742-2094-10-130Search in Google Scholar

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, 1161–1174.10.1093/brain/awp046Search in Google Scholar

Malabendu, J. and Kalipada, P. (2005). Redox regulation of cytokine-mediated inhibition of myelin gene expression in human primary oligodendrocytes. Free Radic. Biol. Med. 39, 823–831.10.1016/j.freeradbiomed.2005.05.014Search in Google Scholar

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, 1107–1123.10.2741/2130Search in Google Scholar

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-1β alters glutamate transmission at Purkinje cell synapses in a mouse model of multiple sclerosis. J. Neurosci. 33, 12105–12121.10.1523/JNEUROSCI.5369-12.2013Search in Google Scholar

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, 5848–5859.10.4049/jimmunol.168.11.5848Search in Google Scholar

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, 2800–2815.10.1093/brain/awm236Search in Google Scholar

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, 229–238.10.1080/13550280802093927Search in Google Scholar

Marrie, R.A. (2004). Environmental risk factors in multiple sclerosis aetiology. Lancet Neurol. 3, 709–718.10.1016/S1474-4422(04)00933-0Search in Google Scholar

Marshall, H.E. and Stamler, J.S. (2002). Nitrosative stress-induced apoptosis through inhibition of NF-kappaB. J. Biol. Chem. 277, 34223–34228.10.1074/jbc.M201638200Search in Google Scholar PubMed

Martınez, M.C. and Andriantsitohaina, R. (2009). Reactive nitrogen species: molecular mechanisms and potential significance in health and disease. Antioxid. Redox Signal. 11, 669–702.10.1089/ars.2007.1993Search in Google Scholar PubMed

Miljkovic, D. and Trajkovic, V. (2004). Inducible nitric oxide synthase activation by interleukin-17. Cytokine Growth Factor Rev. 15, 21–32.10.1016/j.cytogfr.2003.10.003Search in Google Scholar PubMed

Miljkovic, D., Timotijevic, G., and Mostarica Stojkovic, M. (2011). Astrocytes in the tempest of multiple sclerosis. FEBS Lett. 585, 3781–3788.10.1016/j.febslet.2011.03.047Search in Google Scholar PubMed

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, 1012–1016.10.1007/s11064-011-0442-1Search in Google Scholar PubMed PubMed Central

Milo, R. and Kahana, E. (2010). Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmun. Rev. 9, 387–394.10.1016/j.autrev.2009.11.010Search in Google Scholar PubMed

Moncada, S. and Bolanos, J.P. (2006). Nitric oxide, cell bioenergetics and neurodegeneration. J. Neurochem. 97, 1676–1689.10.1111/j.1471-4159.2006.03988.xSearch in Google Scholar PubMed

Morrison, B.M., Lee, Y. and Rothstein, J.D. (2013). Oligodendroglia: metabolic supporters of axons. Trends Cell Biol. 23, 644–651.10.1016/j.tcb.2013.07.007Search in Google Scholar PubMed PubMed Central

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, 93–100.10.1016/j.neuint.2013.05.007Search in Google Scholar PubMed

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, 461–470.10.1002/jnr.10139Search in Google Scholar PubMed

Muzhou, W.U. and Tsirka, S.E. (2009). Endothelial NOS-deficient mice reveal dual roles for nitric oxide during experimental autoimmune encephalomyelitis. Glia 57, 1204–1215.10.1002/glia.20842Search in Google Scholar

Napoli, I. and Neumann, H. (2010). Protective effects of microglia in multiple sclerosis. Exp. Neurol. 225, 24–28.10.1016/j.expneurol.2009.04.024Search in Google Scholar

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.Search in Google Scholar

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, 398–412.10.1093/brain/awg041Search in Google Scholar

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, 9960–9967.10.1523/JNEUROSCI.2003-05.2005Search in Google Scholar

Nozik-Grayck, E., Suliman, H.B., and Piantadosi, C.A. (2005). Extracellular superoxide dismutase. Int. J. Biochem. Cell Biol. 37, 2466–2471.10.1016/j.biocel.2005.06.012Search in Google Scholar

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, 5904–5912.10.4049/jimmunol.167.10.5904Search in Google Scholar

Oksenberg, J.R. and Baranzini, S.E. (2010). Multiple sclerosis genetics: is the glass half full, or half empty? Nat. Rev. Neurol. 6, 429–437.10.1038/nrneurol.2010.91Search in Google Scholar

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, 201–210.10.1016/S0165-5728(97)00180-XSearch in Google Scholar

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, 49–53.10.1016/j.jns.2012.07.045Search in Google Scholar PubMed

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, 708659.10.1155/2013/708659Search in Google Scholar PubMed PubMed Central

Pacher, P., Schulz, R., Liaudet, L., and Szabo, C. (2005). Nitrosative stress and pharmacological modulation of heart failure. Trends Pharmacol. Sci. 26, 302–310.10.1016/j.tips.2005.04.003Search in Google Scholar

Pacher, P., Beckman, J.S., and Liaudet, L. (2007). Nitric oxide and peroxynitrite in health and disease. Physiol. Rev. 87, 315–424.10.1152/physrev.00029.2006Search in Google Scholar

Pachner, A.R. (2011). Experimental models of multiple sclerosis. Curr. Opin. Neurol. 24, 291–299.10.1097/WCO.0b013e328346c226Search in Google Scholar

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, 9566–9571.10.1073/pnas.1633579100Search in Google Scholar

Paget, M.S. and Buttner, M.J. (2003). Thiol-based regulatory switches. Annu. Rev. Genet. 37, 91–121.10.1146/annurev.genet.37.110801.142538Search in Google Scholar

Pahan, K. (2010). Neuroimmune pharmacological control of EAE. J. Neuroimmun. Pharm. 5, 165–167.10.1007/s11481-010-9219-6Search in Google Scholar

Pahan, K. and Mondal, S. (2012). Crosstalk between nitric oxide and T helper cells. J. Clin. Cell Immunol. 3, e109.10.4172/2155-9899.1000e109Search in Google Scholar

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, 39–48.10.1016/S0891-5849(97)00137-8Search in Google Scholar

Paintlia, M.K., Paintlia, A.S., Singh, A.K., and Singh, I. (2011). Synergistic activity of interleukin-17 and tumor necrosis factor-α enhances oxidative stress-mediated oligodendrocyte apoptosis. J. Neurochem. 116, 508–521.10.1111/j.1471-4159.2010.07136.xSearch in Google Scholar PubMed PubMed Central

Paintlia, M.K., Paintlia, A.S., Singh, A.K., and Singh, I. (2013). S-nitrosoglutathione induces ciliary neurotrophic factor expression in astrocytes, which has implications to protect the central nervous system under pathological conditions. J. Biol. Chem. 288, 3831–3843.10.1074/jbc.M112.405654Search in Google Scholar PubMed PubMed Central

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, 373–385.10.1016/j.expneurol.2005.10.033Search in Google Scholar PubMed

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, 1156–1172.10.1177/1352458510382324Search in Google Scholar PubMed

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, 75–93.10.1016/j.niox.2010.04.007Search in Google Scholar PubMed

Perkins, N.D. (2007). Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat. Rev. Mol. Cell Biol. 8, 49–62.10.1038/nrm2083Search in Google Scholar PubMed

Petkovic, F., Blazevski, J., Momcilovic, M., Mostarica Stojkovic, M., and Miljkovic, D. (2013). Nitric oxide inhibits CXCL12 expression in neuroinflammation. Immunol. Cell Biol. 91, 427–434.10.1038/icb.2013.23Search in Google Scholar PubMed

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, 323–334.10.1097/NEN.0b013e3181d60ddbSearch in Google Scholar PubMed

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, 1462–1473.10.1093/brain/awf165Search in Google Scholar PubMed

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, 292–302.10.1002/ana.22366Search in Google Scholar PubMed PubMed Central

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, 374–389.10.1002/jnr.20488Search in Google Scholar PubMed

Prineas, J.W. and Parratt, J.D. (2012). Oligodendrocytes and the early multiple sclerosis lesion. Ann. Neurol. 72, 18–31.10.1002/ana.23634Search in Google Scholar PubMed

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, 685–693.10.1089/ars.2005.7.685Search in Google Scholar

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, 26.10.1186/1742-4933-9-26Search in Google Scholar

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, 140–150.10.1016/S0165-5728(00)00347-7Search in Google Scholar

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, 31950–31962.10.1016/S0021-9258(19)84109-1Search in Google Scholar

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, 569–581.10.1038/nri1130Search in Google Scholar PubMed

Rao, P. and Segal, B.M. (2012). Experimental autoimmune encephalomyelitis. Methods Mol. Biol. 900, 363–380.10.1007/978-1-60761-720-4_18Search in Google Scholar PubMed

Reiter, T. (2006). NO chemistry: a diversity of targets in the cell. Redox Rep. 11, 194–206.10.1179/135100006X116718Search in Google Scholar PubMed

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, 1439–1445.10.1212/01.WNL.0000142043.32578.5DSearch in Google Scholar

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, 39–53.10.1084/jem.58.1.39Search in Google Scholar PubMed PubMed Central

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.Search in Google Scholar

Rosado, E., Rodríguez-Vilarrupla, A., Gracia-Sancho, J., Monclús, 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, 2461–2470.10.1111/j.1582-4934.2012.01563.xSearch in Google Scholar PubMed PubMed Central

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, e81455.10.1371/annotation/e93fa4e6-ee8f-468a-8552-0e0aa505beaaSearch in Google Scholar

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, 95–99.10.1016/j.ejrad.2012.09.006Search in Google Scholar

Saha, R.N. and Pahan, K. (2006). Regulation of inducible nitric oxide synthase gene in glial cells. Antioxid. Redox Signal. 8, 929–947.10.1089/ars.2006.8.929Search in Google Scholar

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, 447–456.10.1016/0306-4522(94)90608-4Search in Google Scholar

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, 183–188.10.1007/s11010-009-0088-3Search in Google Scholar

Satoh, T. and Lipton, S.A. (2007). Redox regulation of neuronal survival mediated by electrophilic compounds. Trends Neurosci. 1, 37–45.10.1016/j.tins.2006.11.004Search in Google Scholar

Sattler, M.B. and Bahr, M. (2010). Future neuroprotective strategies. Exp. Neurol. 225, 40–47.10.1016/j.expneurol.2009.08.016Search in Google Scholar

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, 3648–3658.10.1046/j.1460-9568.1999.00792.xSearch in Google Scholar

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, 198–203.10.1016/S0165-5728(02)00037-1Search in Google Scholar

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, 7–12.10.1016/j.imlet.2010.01.005Search in Google Scholar PubMed

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, 233–241.10.3109/08820130009060864Search in Google Scholar

Sims, N.R. and Muyderman, H. (2010). Mitochondria, oxidative metabolism and cell death in stroke. Biochim. Biophys. Acta 1802, 80–91.10.1016/j.bbadis.2009.09.003Search in Google Scholar

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, 1–11.10.1016/j.brainres.2004.06.059Search in Google Scholar

Smith, K.J. and Lassmann, H. (2002). The role of nitric oxide in multiple sclerosis. Lancet Neurol. 1, 232–241.10.1016/S1474-4422(02)00102-3Search in Google Scholar

Smith, K.J., Kapoor, R., Hall, S.M., and Davies, M. (2001). Electrically active axons degenerate when exposed to nitric oxide. Ann. Neurol. 49, 470–476.10.1002/ana.96Search in Google Scholar

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, 519–529.10.1016/j.clim.2013.10.011Search in Google Scholar PubMed

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.Search in Google Scholar

Spiro, S. (2007). Regulators of bacterial responses to nitric oxide. FEMS Microbiol. Rev. 31, 193–211.10.1111/j.1574-6976.2006.00061.xSearch in Google Scholar PubMed

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, 75–85.10.1093/brain/awf015Search in Google Scholar PubMed

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, 577–582.10.1089/152308603770310239Search in Google Scholar PubMed

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, 4.10.1186/1740-2557-2-4Search in Google Scholar PubMed PubMed Central

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, 147–157.10.1016/S0002-9440(10)62240-7Search in Google Scholar

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, 309–318.10.1016/j.cbi.2013.09.006Search in Google Scholar PubMed

Stirling, D.P. and Stys, P.K. (2010). Mechanisms of axonal injury: internodal nanocomplexes and calcium deregulation. Trends Mol. Med. 16, 160–170.10.1016/j.molmed.2010.02.002Search in Google Scholar PubMed PubMed Central

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, 295–300.10.2478/v10011-012-0030-1Search in Google Scholar

Stys, P.K. (2004). White matter injury mechanisms. Curr. Mol. Med. 4, 113–130.10.2174/1566524043479220Search in Google Scholar PubMed

Stys, P.K. (2005). General mechanisms of axonal damage and its prevention. J. Neurol. Sci. 233, 3–13.10.1016/j.jns.2005.03.031Search in Google Scholar PubMed

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, 1106–1125.10.1097/NEN.0000000000000009Search in Google Scholar PubMed PubMed Central

Thiel, V.E. and Audus, K.L. (2001). Nitric oxide and blood-brain barrier integrity. Antioxid. Redox Sign. 3, 273–278.10.1089/152308601300185223Search in Google Scholar PubMed

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, 168.10.3389/fneur.2013.00168Search in Google Scholar PubMed PubMed Central

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 relapsing-remitting multiple sclerosis. A two year follow-up study. J. Neurol. 253, 224–230.10.1007/s00415-005-0964-zSearch in Google Scholar PubMed

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 death-related proteases and nitric oxide metabolism in rat brain in a chronic unpredictable stress model. Metab. Brain Dis. 27, 431–441.10.1007/s11011-012-9328-4Search in Google Scholar

Trapp, B.D., and Nave, K.A. (2008). Multiple sclerosis: An immune or neurodegenerative disorder? Ann. Rev. Neurosci. 31, 247–269.10.1146/annurev.neuro.30.051606.094313Search in Google Scholar

Uccelli, A., Pedemonte, E., Narciso, E., and Mancardi, G. (2003). Biological markers of the inflammatory phase of multiple sclerosis. Neurol. Sci. 24, S271–S274.10.1007/s10072-003-0172-5Search in Google Scholar

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, 1–7.10.1016/S0165-5728(98)00239-2Search in Google Scholar

van der Veen, R.C., Dietlin, T.A., Hofman, F.M., Pen, L., Segal, B.H., and Holland, S.M. (2000). Superoxide prevents nitric oxide-mediated suppression of helper T lymphocytes: decreased autoimmune encephalomyelitis in nicotinamide adenine dinucleotide phosphate oxidase knockout mice. J. Immunol. 164, 5177–5183.10.4049/jimmunol.164.10.5177Search in Google Scholar PubMed

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, 1729–1737.10.1016/j.freeradbiomed.2008.09.023Search in Google Scholar PubMed

Vartanian, T.K. (2008). MS as a neurodegenerative disease (a thought experiment): the clinical evidence. Adv. Stud. Med. 8, 305–308.Search in Google Scholar

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, 990–997.10.1172/JCI19388Search in Google Scholar PubMed PubMed Central

Waxsman, S.G. (2005). Multiple Sclerosis as a Neuronal Disease. Boston: Elsevier Academic Press.Search in Google Scholar

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, 728–742.10.7150/ijbs.6475Search in Google Scholar PubMed PubMed Central

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, 16–25.10.1016/j.jneuroim.2007.09.007Search in Google Scholar PubMed

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-1β, TNF-α and IL-6 in an in-vitro model of brain inflammation. J. Neuroinflamm. 7, 30.10.1186/1742-2094-7-30Search in Google Scholar PubMed PubMed Central

Wolswijk, G. (2000). Oligodendrocyte survival, loss and birth in lesions of chronic-stage multiple sclerosis. Brain 123, 105–115.10.1093/brain/123.1.105Search in Google Scholar PubMed

Xiang, W., Weisbach, V., Sticht, H., Seebahn, A., Bussmann, J., Zimmermann, R., and Becker, C.M. (2013). Oxidative stress-induced posttranslational modifications of human hemoglobin in erythrocytes. Arch. Biochem. Biophys. 529, 34–44.10.1016/j.abb.2012.11.002Search in Google Scholar PubMed

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, 5810–5816.10.4049/jimmunol.166.9.5810Search in Google Scholar PubMed

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, 3057–3063.10.1161/STROKEAHA.108.520114Search in Google Scholar PubMed PubMed Central

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, 335–349.10.1007/s11011-008-9096-3Search in Google Scholar PubMed

Zaffaroni, M. (2003). Biological indicators of the neurodegenerative phase of multiple sclerosis. Neurol. Sci. 24, 279–282.10.1007/s10072-003-0174-3Search in Google Scholar PubMed

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-κB-COX-2-IL-1β pathway. Free Radic. Res. 46, 1207–1219.10.3109/10715762.2012.700515Search in Google Scholar PubMed

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, 288–303.10.1093/brain/awm291Search in Google Scholar PubMed

Zheng, H., Zhang, H., Liu, F., Qi, Y., and Jiang, H. (2013). T cell-depleted splenocytes from mice pre-immunized with neuroantigen in incomplete Freund’s adjuvant involved in protection from experimental autoimmune encephalomyelitis. Immunol. Lett. 157, 38–44.10.1016/j.imlet.2013.11.001Search in Google Scholar PubMed

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, 348–357.10.1038/sj.jcbfm.9600036Search in Google Scholar PubMed

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, 2202–2210.10.1007/s00018-007-7218-4Search in Google Scholar PubMed

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, 519627.10.1155/2013/519627Search in Google Scholar PubMed PubMed Central

Received: 2014-8-19
Accepted: 2014-9-30
Published Online: 2014-10-24
Published in Print: 2015-2-1

©2015 by De Gruyter

Downloaded on 19.3.2024 from https://www.degruyter.com/document/doi/10.1515/revneuro-2014-0060/html
Scroll to top button