Stres oksydacyjny w patogenezie stwardnienia rozsianego. Nowe możliwości terapeutyczne

• Authors: Agata Karpińska , Dagmara Mirowska-Guzel

Title variants

EN

Oxidative stress in the pathogenesis of multiple sclerosis. New possibilities of treatment

• Languages of publication: PL

Abstracts

PL

Stwardnienie rozsiane to choroba zapalno-demielinizacyjna ośrodkowego układu nerwowego o dotychczas nieznanej przyczynie. W przebiegu stwardnienia rozsianego następuje uszkodzenie osłonki mielinowej komórek nerwowych oraz śmierć neuronów i  oligodendrocytów. W  ostatnich latach zwrócono uwagę, że ogniwem łączącym proces zapalny z neurodegeneracją może być stres oksydacyjny, czyli przewaga tworzenia wolnych rodników nad ich eliminacją przez systemy antyoksydacyjne komórki. Udowodniono, iż stres oksydacyjny ma związek z  patogenezą wielu chorób neurodegeneracyjnych, w tym choroby Parkinsona czy choroby Alzheimera. Wykazano także jego udział w patogenezie stwardnienia rozsianego. W związku z tym zwalczanie stresu oksydacyjnego stało się jednym z nowych celów terapeutycznych. W badaniach przedklinicznych i klinicznych oceniano skuteczność różnych substancji o właściwościach antyoksydacyjnych, m.in. polifenoli, witamin, kwasu α-liponowego czy ekstraktów z Ginkgo biloba, jako potencjalnych leków na stwardnienie rozsiane. Ich skuteczność w modelach zwierzęcych rzadko znajduje odzwierciedlenie w wynikach badań klinicznych, ale wybrane związki są obecnie w trakcie oceny klinicznej. W badaniach zarówno przedklinicznych, jak i klinicznych skuteczny okazał się fumaran dimetylu, zarejestrowany w 2013 roku do leczenia stwardnienia rozsianego. Mechanizm działania tego związku nie został jeszcze w pełni poznany. Wiadomo jednak, że pobudza on naturalny szlak antyoksydacyjny związany z czynnikiem transkrypcyjnym Nrf2, co prowadzi do redukcji nasilenia stresu oksydacyjnego.

EN

Multiple sclerosis is a progressive inflammatory and demyelinating disease of the central nervous system. Although the primary cause of this disease has not been established yet, it is known that destruction of myelin sheaths and loss of neurons and oligodendrocytes can be observed as disease progresses. It has been suggested that a  possible link between neuroinflammation and neurodegeneration could be the phenomenon of oxidative stress. Oxidative stress develops when there are too many free radicals produced within the cell, and the natural antioxidative mechanisms are not effective enough to dispose of them. It has been proven to contribute to the pathomechanism of such neurodegenerative disorders as Parkinson’s disease or Alzheimer’s disease. The role of oxidative stress in the pathogenesis of multiple sclerosis has also been recently confirmed, establishing it as a new target in the disease’s management. Even though the efficacy of such antioxidants as polyphenols, vitamins (A, C, E) and alpha-lipoic acid has been confirmed in many preclinical experiments, no significant effect has been shown in clinical trials. However, some clinical trials related to the use of antioxidants in multiple sclerosis treatment are still in progress. One compound with antioxidant potential that has been proven effective and safe in both preclinical and clinical trials is dimethyl fumarate. It was licensed for the treatment of multiple sclerosis in 2013. Even though its mechanism of action has not been fully established, one of its known effects is the induction of antioxidant pathway related to Nrf2 transcription factor and synthesis of antioxidant enzymes, leading to decrease in oxidative stress.

Keywords

EN

antyoksydanty; fumaran dimetylu; stres oksydacyjny; stwardnienie rozsiane; wolne rodniki

Discipline

• MEDICINE: MEDICINE

• Publisher: Medical Communications
• Journal: Aktualności Neurologiczne
• Year: 2016
• Volume: 16
• Issue: 3
• Pages: 136–145

Contributors

author

Agata Karpińska

• Katedra i Zakład Farmakologii Doświadczalnej iKlinicznej, Warszawski Uniwersytet Medyczny

author

Dagmara Mirowska-Guzel

• Katedra i Zakład Farmakologii Doświadczalnej iKlinicznej, Warszawski Uniwersytet Medyczny

References

• Acar A, Ugur Cevik M, Evliyaoglu O et al.: 2012. Evaluation of serum oxidant/antioxidant balance in multiple sclerosis. Acta Neurol Belg 2012; 112: 275–280.
• Aktas O, Prozorovski T, Smorodchenko A et al.: Green tea epigallocatechin-3-gallate mediates T cellular NF-κB inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol 2004; 173: 5794–5800.
• Altmeyer PJ, Matthes U, Pawlak F et al.: Antipsoriatic effect of fumaric acid derivatives. Results of a multicenter double-blind study in 100 patients. J Am Acad Dermatol 1994; 30: 977–981.
• Asahi M, Fujii J, Takao T et al.: The oxidation of selenocysteine is involved in the inactivation of glutathione peroxidase by nitric oxide donor. J Biol Chem 1997; 272: 19152–19157.
• Barnett MH, Prineas JW: Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 2004; 55: 458–468.
• Bizzozero OA, DeJesus G, Bixler HA et al.: Evidence of nitrosative damage in the brain white matter of patients with multiple sclerosis. Neurochem Res 2005; 30: 139–149.
• Blum J, Fridovich I: Inactivation of glutathione peroxidase by superoxide radical. Arch Biochem Biophys 1985; 240: 500–508.
• Bö L, Dawson TM, Wesselingh S et al.: Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann Neurol 1994; 36: 778–786.
• Bray PF, Bloomer LC, Salmon VC et al.: Epstein-Barr virus infection and antibody synthesis in patients with multiple sclerosis. Arch Neurol 1983; 40: 406–408.
• Breuer K, Gutzmer R, Völker B et al.: Therapy of noninfectious granulomatous skin diseases with fumaric acid esters. Br J Dermatol 2005; 152: 1290–1295.
• Brown GC, Cooper CE: Nanomolar concentrations of nitric oxide reversibly inhibit synaptosomal respiration by competing with oxygen at cytochrome oxidase. FEBS Lett 1994; 356: 295–298.
• Calabrese V, Bates TE, Stella AM: NO synthase and NO-dependent signal pathways in brain aging and neurodegenerative disorders: the role of oxidant/antioxidant balance. Neurochem Res 2000; 25: 1315–1341.
• Campbell GR, Ziabreva I, Reeve AK et al.: Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol 2011; 69: 481–492.
• Chandra J, Samali A, Orrenius S: Triggering and modulation of apoptosis by oxidative stress. Free Radic Biol Med 2000; 29: 323–333.
• Chaudhary P, Marracci GH, Bourdette DN: Lipoic acid inhibits expression of ICAM-1 and VCAM-1 by CNS endothelial cells and T cell migration into the spinal cord in experimental autoimmune encephalomyelitis. J Neuroimmunol 2006; 175: 87–96.
• Chaudhary P, Marracci G, Yu X et al.: Lipoic acid decreases inflammation and confers neuroprotection in experimental autoimmune optic neuritis. J Neuroimmunol 2011; 233: 90–96.
• Chiurchiù V, Orlacchio A, Maccarrone M: Is modulation of oxidative stress an answer? The state of the art of redox therapeutic actions in neurodegenerative diseases. Oxid Med Cell Longev 2016; 2016: 7909380.
• Colton CA, Gilbert DL: Production of superoxide anions by a CNS macrophage, the microglia. FEBS Lett 1987; 223: 284–288.
• Dehmel T, Döbert M, Pankratz S et al.: Monomethylfumarate reduces in vitro migration of mononuclear cells. Neurol Sci 2014; 35: 1121–1125.
• Diamond BJ, Johnson SK, Kaufman M et al.: A randomized controlled pilot trial: the effects of EGb 761 on information processing and executive function in multiple sclerosis. Explore (NY) 2013; 9: 106–107.
• Dröge W: Free radicals in the physiological control of cell function. Physiol Rev 2002; 82: 47–95.
• Eberlein-König B, Mempel M, Stahlecker J et al.: Disseminated granuloma annulare – treatment with fumaric acid esters. Dermatology 2005; 210: 223–226.
• Ercal N, Gurer-Orhan H, Aykin-Burns N: Toxic metals and oxidative stress part I: mechanisms involved in metal-induced oxidative damage. Curr Top Med Chem 2001; 1: 529–539.
• Fiorini A, Koudriavtseva T, Bucaj E et al.: Involvement of oxidative stress in occurrence of relapses in multiple sclerosis: the spectrum of oxidatively modified serum proteins detected by proteomics and redox proteomics analysis. PLoS One 2013; 8: e65184. doi:10.1371/journal.pone.0065184
• Fischer MT, Sharma R, Lim JL et al.: NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain 2012; 135: 886–899.
• Fischer MT, Wimmer I, Höftberger R et al.: Disease-specific molecular events in cortical multiple sclerosis lesions. Brain 2013; 136: 1799–1815.
• Fonseca-Kelly Z, Nassrallah M, Uribe J et al.: Resveratrol neuroprotection in a chronic mouse model of multiple sclerosis. Front Neurol 2012; 3: 84.
• Forte M, Gold BG, Marracci G et al.: Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Proc Natl Acad Sci U S A 2007; 104: 7558–7563.
• Fox RJ, Miller DH, Phillips JT et al.; CONFIRM Study Investigators: Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012; 367: 1087–1097.
• French HM, Reid M, Mamontov P et al.: Oxidative stress disrupts oligodendrocyte maturation. J Neurosci Res 2009; 87: 3076–3087.
• Ghoreschi K, Brück J, Kellerer C et al.: Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med 2011; 208: 2291–2303.
• Gold R, Kappos L, Arnold DL et al.; DEFINE Study Investigators: Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012; 367: 1098–1107.
• Goodin DS: The epidemiology of multiple sclerosis: insights to disease pathogenesis. In: Goodin DS (ed.): Handbook of Clinical Neurology: Multiple Sclerosis and Related Disorders. Elsevier, Amsterdam 2014: 231–266.
• Goudarzvand M, Javan M, Mirnajafi-Zadeh J et al.: Vitamins E and D3 attenuate demyelination and potentiate remyelination processes of hippocampal formation of rats following local injection of ethidium bromide. Cell Mol Neurobiol 2010; 30: 289–299.
• Gray E, Thomas TL, Betmouni S et al.: Elevated activity and microglial expression of myeloperoxidase in demyelinated cerebral cortex in multiple sclerosis. Brain Pathol 2008; 18: 86–95.
• Guan JZ, Guan WP, Maeda T et al.: Patients with multiple sclerosis show increased oxidative stress markers and somatic telomere length shortening. Mol Cell Biochem 2015; 400: 183–187.
• Gutzmer R, Kapp A, Werfel T: [Successful treatment of skin and lung sarcoidosis with fumaric acid ester]. Hautarzt 2004; 55: 553–557.
• Haider L, Fischer MT, Frischer JM et al.: Oxidative damage in multiple sclerosis lesions. Brain 2011; 134: 1914–1924.
• Halliwell B: Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs Aging 2001; 18: 685–716.
• Halliwell B, Gutteridge JMC: Free Radicals in Biology and Medicine. 5th ed., Oxford University Press, Oxford 2015.
• Haorah J, Ramirez SH, Schall K et al.: Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood– brain barrier dysfunction. J Neurochem 2007; 101: 566–576.
• Hendriks JJ, Alblas J, van der Pol SM et al.: Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis. J Exp Med 2004; 200: 1667–1672.
• Herges K, Millward JM, Hentschel N et al.: Neuroprotective effect of combination therapy of glatiramer acetate and epigallocatechin3-gallate in neuroinflammation. PLoS One 2011; 6: e25456.
• van Horssen J, Drexhage JA, Flor T et al.: Nrf2 and DJ1 are consistently upregulated in inflammatory multiple sclerosis lesions. Free Radic Biol Med 2010; 49: 1283–1289.
• van Horssen J, Schreibelt G, Drexhage J et al.: Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic Biol Med 2008; 45: 1729–1737.
• Imler TJ Jr, Petro TM: Decreased severity of experimental autoimmune encephalomyelitis during resveratrol administration is associated with increased IL-17+IL-10+ T cells, CD4− IFN-γ+ cells, and decreased macrophage IL-6 expression. Int Immunopharmacol 2009; 9: 134–143.
• Itoh K, Tong KI, Yamamoto M: Molecular mechanism activating Nrf2–Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic Biol Med 2004; 36: 1208–1213.
• Jana M, Pahan K: Down-regulation of myelin gene expression in human oligodendrocytes by nitric oxide: implications for demyelination in multiple sclerosis. J Clin Cell Immunol 2013; 4.
• Johnson SK, Diamond BJ, Rausch S et al.: The effect of Ginkgo biloba on functional measures in multiple sclerosis: a pilot randomized controlled trial. Explore (NY) 2006; 2: 19–24.
• Jones RE, Moes N, Zwickey H et al.: Treatment of experimental autoimmune encephalomyelitis with alpha lipoic acid and associative conditioning. Brain Behav Immun 2008; 22: 538–543.
• de Jong R, Bezemer AC, Zomerdijk TP et al.: Selective stimulation of T helper 2 cytokine responses by the anti-psoriasis agent monomethylfumarate. Eur J Immunol 1996; 26: 2067–2074.
• Kalita J, Kumar V, Misra UK et al.: A study of oxidative stress, cytokines and glutamate in Wilson disease and their asymptomatic siblings. J Neuroimmunol 2014; 274: 141–148.
• Kang MI, Kobayashi A, Wakabayashi N et al.: Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes. Proc Natl Acad Sci U S A 2004; 101: 2046–2051.
• Karlík M, Valkovič P, Hančinová V et al.: Markers of oxidative stress in plasma and saliva in patients with multiple sclerosis. Clin Biochem 2015; 48: 24–28.
• Khalili M, Azimi A, Izadi V et al.: Does lipoic acid consumption affect the cytokine profile in multiple sclerosis patients: a double-blind, placebo-controlled, randomized clinical trial. Neuroimmunomodulation 2014a; 21: 291–296.
• Khalili M, Eghtesadi S, Mirshafiey A et al.: Effect of lipoic acid consumption on oxidative stress among multiple sclerosis patients: a randomized controlled clinical trial. Nutr Neurosci 2014b; 17: 16–20.
• Kingwell E, Marriott JJ, Jetté N et al.: Incidence and prevalence of multiple sclerosis in Europe: a systematic review. BMC Neurol 2013; 13: 128.
• Koch-Henriksen N, Sørensen PS: The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 2010; 9: 520–532.
• Kreuter A, Gambichler T, Altmeyer P et al.: Treatment of disseminated granuloma annulare with fumaric acid esters. BMC Dermatol 2002; 2: 5.
• Limón-Pacheco J, Gonsebatt ME: The role of antioxidants and antioxidant-related enzymes in protective responses to environmentally induced oxidative stress. Mutat Res 2009; 674: 137–147.
• Lin SX, Lisi L, Dello Russo C et al.: The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1. ASN Neuro 2011; 3: pii: e00055.
• Linker RA, Lee DH, Ryan S et al.: Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 2011; 134: 678–692.
• Litjens NH, Rademaker M, Ravensbergen B et al.: Monomethylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th1 lymphocyte responses. Eur J Immunol 2004; 34: 565–575.
• Liu JSH, Zhao ML, Brosnan CF et al.: Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Am J Pathol 2001; 158: 2057–2066.
• Lovera J, Bagert B, Smoot K et al.: Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis: a randomized, placebo-controlled trial. Mult Scler 2007; 13: 376–385.
• Lovera JF, Kim E, Heriza E et al.: Ginkgo biloba does not improve cognitive function in MS: a randomized placebo-controlled trial. Neurology 2012; 79: 1278–1284.v
• Lu F, Selak M, O’Connor J et al.: Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. J Neurol Sci 2000; 177: 95–103.
• Lublin FD, Reingold SC: Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology 1996; 46: 907–911.
• Lublin FD, Reingold SC, Cohen JA et al.: Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 2014; 83: 278–286.
• Lucchinetti C, Brück W, Parisi J et al.: Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000; 47: 707–717.
• Mahad DJ, Ziabreva I, Campbell G et al.: Mitochondrial changes within axons in multiple sclerosis. Brain 2009; 132: 1161–1174.
• Mander P, Borutaite V, Moncada S et al.: Nitric oxide from inflammatory-activated glia synergizes with hypoxia to induce neuronal death. J Neurosci Res 2005; 79: 208–215.
• Marracci GH, Jones RE, McKeon GP et al.: Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis. J Neuroimmunol 2002; 131: 104–114.
• Merrill JE, Ignarro LJ, Sherman MP et al.: Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. J Immunol 1993; 151: 2132–2141.
• Miller E, Mrowicka M, Saluk-Juszczak J et al.: The level of isoprostanes as a non-invasive marker for in vivo lipid peroxidation in secondary progressive multiple sclerosis. Neurochem Res 2011; 36: 1012–1016.
• Mitrovic B, Ignarro LJ, Montestruque S et al.: Nitric oxide as a potential pathological mechanism in demyelination: Its differential effects on primary glial cells in vitro. Neuroscience 1994; 61: 575–585.
• Morini M, Roccatagliata L, Dell’Eva R et al.: α-Lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis. J Neuroimmunol 2004; 148: 146–153.
• Mrowietz U, Christophers E, Altmeyer P: Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study. German Multicentre Study. Br J Dermatol 1998; 138: 456–460.
• Muthian G, Bright JJ: Quercetin, a flavonoid phytoestrogen, ameliorates experimental allergic encephalomyelitis by blocking IL-12 signaling through JAK-STAT pathway in T lymphocyte. J Clin Immunol 2004; 24: 542–552.
• Natarajan C, Bright JJ: Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes. J Immunol 2002; 168: 6506–6513.
• Nowack U, Gambichler T, Hanefeld C et al.: Successful treatment of recalcitrant cutaneous sarcoidosis with fumaric acid esters. BMC Dermatol 2002; 2: 15.
• Ohl K, Tenbrock K, Kipp M: Oxidative stress in multiple sclerosis: central and peripheral mode of action. Exp Neurol 2016; 277: 58–67.
• Pawate S, Shen Q, Fan F et al.: Redox regulation of glial inflammatory response to lipopolysaccharide and interferonγ. J Neurosci Res 2004; 77: 540–551.
• Peng H, Guerau-de-Arellano M, Mehta VB et al.: Dimethyl fumarate inhibits dendritic cell maturation via nuclear factor κB (NF-κB) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) and mitogen stress-activated kinase 1 (MSK1) signaling. J Biol Chem 2012; 287: 28017–28026.
• Pigeolet E, Corbisier P, Houbion A et al.: Glutathione peroxidase, superoxide dismutase, and catalase inactivation by peroxides and oxygen derived free radicals. Mech Ageing Dev 1990; 51: 283–297.
• Plemel JR, Juzwik CA, Benson CA et al.: Over-the-counter anti-oxidant therapies for use in multiple sclerosis: a systematic review. Mult Scler 2015; 21: 1485–1495.
• Pulsinelli WA, Duffy TE: Regional energy balance in rat brain after transient forebrain ischemia. J Neurochem 1983; 40: 1500–1503.
• Qi X, Lewin AS, Sun L et al.: Mitochondrial protein nitration primes neurodegeneration in experimental autoimmune encephalomyelitis. J Biol Chem 2006; 281: 31950–31962.
• Qi X, Lewin AS, Sun L et al.: Suppression of mitochondrial oxidative stress provides long-term neuroprotection in experimental optic neuritis. Invest Ophthalmol Vis Sci 2007; 48: 681–691.
• Qin L, Li G, Qian X et al.: Interactive role of the toll-like receptor 4 and reactive oxygen species in LPS-induced microglia activation. Glia 2005; 52: 78–84.
• Ray SK, Fidan M, Nowak MW et al.: Oxidative stress and Ca2+ influx upregulate calpain and induce apoptosis in PC12 cells. Brain Res 2000; 852: 326–334.
• Riise T, Nortvedt MW, Ascherio A: Smoking is a risk factor for multiple sclerosis. Neurology 2003; 61: 1122–1124.
• Ruuls SR, Bauer J, Sontrop K et al.: Reactive oxygen species are involved in the pathogenesis of experimental allergic encephalomyelitis in Lewis rats. J Neuroimmunol 1995; 56: 207–217.
• Schreibelt G, Musters RJ, Reijerkerk A et al.: Lipoic acid affects cellular migration into the central nervous system and stabilizes blood– brain barrier integrity. J Immunol 2006; 177: 2630–2637.
• Shindler KS, Ventura E, Dutt M et al.: Oral resveratrol reduces neuronal damage in a model of multiple sclerosis. J Neuroophthalmol 2010; 30: 328–339.
• Singh NP, Hegde VL, Hofseth LJ et al.: Resveratrol (trans-3,5,4’-trihydroxystilbene) ameliorates experimental allergic encephalomyelitis, primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor. Mol Pharmacol 2007; 72: 1508–1521.
• Smith KJ, Lassmann H: The role of nitric oxide in multiple sclerosis. Lancet Neurol 2002; 1: 232–241.
• Spanevello R, Mazzanti CM, Schmatz R et al.: Effect of vitamin E on ectonucleotidase activities in synaptosomes and platelets and parameters of oxidative stress in rats experimentally demyelinated. Brain Res Bull 2009; 80: 45–51.
• Ständer H, Stadelmann A, Luger T et al.: Efficacy of fumaric acid ester monotherapy in psoriasis pustulosa palmoplantaris. Br J Dermatol 2003; 149: 220–222
• Sumaya CV, Myers LW, Ellison GW: Epstein-Barr virus antibodies in multiple sclerosis. Arch Neurol 1980; 37: 94–96.
• Sun Q, Zheng Y, Zhang X et al.: Novel immunoregulatory properties of EGCG on reducing inflammation in EAE. Front Biosci (Landmark Ed) 2013; 18: 332–342.
• Trapp BD, Nave KA: Multiple sclerosis: an immune or neurodegenerative disorder? Annu Rev Neurosci 2008; 31: 247–269.
• Treumer F, Zhu K, Gläser R et al.: Dimethylfumarate is a potent inducer of apoptosis in human T cells. J Invest Dermatol 2003; 121: 1383–1388.
• Tullman MJ: Overview of the epidemiology, diagnosis, and disease progression associated with multiple sclerosis. Am J Manag Care 2013; 19 (Suppl): S15–S20.
• Verbeek R, van Tol EA, van Noort JM: Oral flavonoids delay recovery from experimental autoimmune encephalomyelitis in SJL mice. Biochem Pharmacol 2005; 70: 220–228.
• Vladutiu A, Cringulescu N: Suppression of experimental allergic encephalomyelitis by vitamin A. Experientia 1968; 24: 718–719.
• Wang J, Ren Z, Xu Y et al.: Epigallocatechin-3-gallate ameliorates experimental autoimmune encephalomyelitis by altering balance among CD4+ T-cell subsets. Am J Pathol 2012; 180: 221–234.
• Wang KC, Tsai CP, Lee CL et al.: α-Lipoic acid enhances endogenous peroxisome-proliferator-activated receptor-γ to ameliorate experimental autoimmune encephalomyelitis in mice. Clin Sci (Lond) 2013; 125: 329–340.
• Wang P, Xie K, Wang C et al.: Oxidative stress induced by lipid peroxidation is related with inflammation of demyelination and neurodegeneration in multiple sclerosis. Eur Neurol 2014; 72: 249–254.
• Weber HO, Borelli C, Röcken M et al.: Treatment of disseminated granuloma annulare with low-dose fumaric acid. Acta Derm Venereol 2009; 89: 295–298.
• Willer CJ, Dyment DA, Risch NJ et al.; Canadian Collaborative Study Group: Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci U S A 2003; 100: 12877–12882.
• Xie L, Li XK, Funeshima-Fuji N et al.: Amelioration of experimental autoimmune encephalomyelitis by curcumin treatment through inhibition of IL-17 production. Int Immunopharmacol 2009; 9: 575–581.
• Zhou JF, Yan XF, Guo FZ et al.: Effects of cigarette smoking and smoking cessation on plasma constituents and enzyme activities related to oxidative stress. Biomed Environ Sci 2000; 13: 44–55.

• Document Type: article