1. Martin R,McFarland HF,McFarlin DE.Immunological aspects of demyelinating diseases.Annu Rev Immunol,1992,10:153-187.

2. Mirshafiey.A.Novel promising therapeutic agents in multiple sclerosis.Recent Patents on Inflammation & Allergy Drug Discovery,2007,1:218-228.

3. Frohman EM,Racke MK,Raine CS.Multiple sclerosis the plaque and its pathogenesis.N Engl J Med,2006,354:942-955.

4. Fressinaud C,Sarlieve LL,Vincendon G.Multiple sclerosis:review of main experimental data and pathogenic hypotheses.Rev Med Interne,1990,11:201-208.

5. Martin R,McFarland HF,McFarlin DE.Immunological aspects of demyelinating diseases.Annu Rev Immunol,1992,10:153-187.

6. Mirshafiey A,Matsuo H,Nakane S,Rehm BH,Koh CS,Mivoshi S.Novel immunosuppressive therapy by M2000 in experimental multiple sclerosis.Immunopharmacol Immunotoxicol,2005,27（2）:255-265.

7. Noseworthy JH.Progress in determining the causes and treatment of multiple sclerosis.Nature,1999,399:A40-47.

8. Baker D,Hankey DJ.Gene therapy in autoimmune,demyelinating disease of the central nervous system.Gene Ther,2003,10:844-853.

9. Owens T.The enigma of multiple sclerosis:inflammation and neurodegeneration cause heterogeneous dysfunction and damage.Curr Opin Neurol,2003,16:259-265.

10. Giuliani F,Yong VW.Immune-mediated neurodegeneration and neuroprotection in MS.Int MS J,2003,10:122-130.

11. Kornek B,Storch MK,Weissert R,Wallstroem E,Stefferl A,Olsson T,et al.Multiple sclerosis and chronic autoimmune encephalomyelitis:a comparative quantitative study of axonal injury in active,inactive,and remyelinated lesions.Am J Pathol,2000,157:267-276.

12. Petzold A,Rejdak K,Plant GT.Axonal degeneration and inflammation in acute optic neuritis.J Neurol Neurosurg Psychiatry,2004,75:1178-1180.

13. Bjartmar C,Wujek JR,Trapp BD.Axonal loss in the pathology of MS:consequences for understanding the progressive phase of the disease.J Neurol Sci,2003,206:165-171.

14. Qi X,Lewin AS,Sun L,Hauswirth WW,Guy J.Suppression of Mitochondrial Oxidative Stress Provides Long-term Neuroprotection in Experimental Optic Neuritis.Invest Ophthalmol Vis Sci,2007,48:681-691.

15. Ghafourifar P,Mousavizadeh K,Parihar MS,Nazarewicz RR,Parihar A,Zenebe WJ.Mitochondria in multiple sclerosis.Front Biosci,2008,13:3116-3126.

16. Knight JA.Reactive oxygen species and the neurodegenerative disorders.Ann Clin Lab Sci,1997,27:11-25.

17. Halliwell B,Gutteridge MC.Oxygen radicals and the nervous system.Trends Neurosci,1985,8:22-29.

18. Brück W,Sommermeier N,Bergmann M,Zettl U,Goebel HH,Kretzschmar HA,et al.Macrophages in multiple sclerosis.Immunobiology,1996,195:588-600.

19. Ruuls SR,Bauer J,Sontrop K,Huitinga I,t Hart BA,Dijkstra CD.Reactive oxygen species are involved in the pathogenesis of experimental allergic encephalomyelitis in Lewis rats.J.Neuroimmunol,1995,56:207-217.

20. Parkinson JF,Mitrovic B,Merrill JE.The role of nitric oxide in multiple sclerosis.J Mol Med,1997,75:174-186.

21. Benveniste EN.Cytokine actions in the central nervous system.Cytokine Growth Factor Rev,1998,9:259-275.

22. van Horssen J,Schreibelt G,B L,Montagne L,Drukarch B,van Muiswinkel FL,et al.NAD（P）H:quinone oxidoreductase 1 expression in multiple sclerosis lesions.Free Radic Biol Med,2006,41:311-317.

23. Hendriks JJ,Alblas J,Van Der Pol SM,van Tol EA,Dijkstra CD,de Vries HE.Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis.J Exp Med,2004,200:1667-1672.

24. Gilgun-Sherki Y,Melamed E,Offen D.The role of oxidative stress in the pathogenesis of multiple sclerosis:the need for effective antioxidant therapy.J Neurol,2004,251:261-268.

25. Lambeth JD.NOX enzymes and the biology of reactive oxygen.Nat Rev Immunol,2004,4:181-189.

26. Ilhan A,Akyol O,Gurel A,Armutcu F,Iraz M,Oztas E.Protective effects of caffeic acid phenethyl ester against experimental allergic encephalomyelitis-induced oxidative stress in rats.Free Radic Biol Med,2004,37:386-394.

27. Nicholls D.Mitochondrial bioenergetics,aging,and aging-related disease.Sci Aging Knowledge Environ,2002,2002:pe12.

28. Turrens JF,Alexandre A,Lehninger AL.Ubisemiquinone is the electron donor for superoxide formation by complex III of heart mitochondria.Arch.Biochem Biophys,1985,237:408-414.

29. Boveris A,Chance B.The mitochondrial generation of hydrogen peroxide.General properties and effect of hyperbaric oxygen.J Biochem,1973,134:707-716.

30. Beckman KB,Ames BN.The free radical theory of aging matures.Physiol Rev,1998,78:547-581.

31. Hitchon CA,El-Gabalawy HS.Oxidation in rheumatoid arthritis.Arthritis Res Ther,2004,6:265-278.

32. Henrotin YE,Bruckner P,Pujol JP.The role of reactive oxygen species in homeostasis and degradation of cartilage.OsteoArthritis Cartilage,2003,11:747-755.

33. Hiran TS,Moulton PJ,Hancock JT.In situ detection of superoxide anions within porcine articular cartilage.Br J Biomed Sci,1998,55:199-203.

34. Clancy RM,Leszczynska-Piziak J,Abramson SB.Nitric oxide an endothelial cell relaxation factor inhibits neutrophil superoxide anion production via a direct action on the NADPH oxidase.J Clin Invest,1992,90:1116-1121.

35. Afonso V,Champy R,Mitrovic D,Collin P,Lomri A.Reactive oxygen species and superoxide dismutases:Role in joint diseases.Joint Bone Spine,2007,74:324-329.

36. Haddad JJ.Antioxidant,prooxidant mechanisms in the regulation of redox（y）-sensitive transcription factors.Cell Signal,2002,14:879-897.

37. Schreibelt G,van Horssen J,van Rossum S,Dijkstra CD,Drukarch B,de Vries HE.Therapeutic potential and biological role of endogenous antioxidant enzymes in multiple sclerosis pathology.Brain Res Rev,2007,56:322-330.

38. Roos D,van Bruggen R,Meischl C.Oxidative killing of microbes by neutrophils.Microbes Infect,2003,5:1307-1315.

39. Segal BH,Leto LT,Gallin JI,Malech HL,Holland SM.Genetic biochemical and clinical features of chronic granulomatous disease.Medicine,2000,79:170-200.

40. Biemond P,Swaak AJ,Penders JM,Beindorff CM,Koster JF.Superoxide production by polymorphonuclear leucocytes in rheumatoid arthritis and osteoarthritis:In vivo inhibition by the antirheumatic drug piroxicam due to interference with the activation of the NADPH-oxidase.Ann Rheum Dis,1986,45:249-255.

41. Lee BW,Yap HK.Polyarthritis resembling juvenile rheumatoid arthritis in a girl with chronic granulomatous disease.Arthritis Rheum,1986,37:773-776.

42. Joan M.Cook-mills.VCAM-1 signals during lymphocyte migration:role of reactive oxygen species.Molecular Immunology,2002,39:499-508.

43. Tudor KS,Hess KL,Cook-Mills JM.Cytokines modulate endothelial cell intracellular signal transduction required for VCAM-1-dependent lymphocyte transendothelial migration.Cytokine,2001,15:196-211.

44. Deem TL,Cook-Mills JM.Vascular cell adhesion molecule 1 （VCAM-1） activation of endothelial cell matrix metalloproteinases:role of reactive oxygen species.Blood,2004,104:2385-2393.

45. Hamedani M,Vatanpour H,Saadat F,Reza Khorramizaheh M,Mirshafiey A.Bee venom,immunostimulant or immunosuppressor? Insight into the effect on matrix metalloproteinases and interferons.Immunopharmacol Immunotoxicol,2005,27:671-681.

46. Matheny HE,Deem TL,Cook-Mills JM.Lymphocyte migration through monolayers of endothelial cell lines involves VCAM-1 signaling via endothelial cell NADPH oxidase.J Immunol,2000,164:6550-6655.

47. Baron JL,Madri JA,Ruddle NH,Hashim G,Janeway CA Jr.Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma.J Exp Med,1993,177:57-68.

48. Abdala-Valencia H,Cook-Mills JM.VCAM-1 Signals Activate Endothelial Cell Protein Kinase Cα via Oxidation.J Immunol,2006,177:6379-6387.

49. Savina A,Jancic C,Hugues S,Guermonprez P,Vargas P,Moura IC,et al.NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells.Cell,2006,126:205-218.

50. Park B,Lee S,Kim E,Cho K,Riddell SR,Cho S,et al.Redox regulation facilitates optimal peptide selection by MHC class I during antigen processing.Cell,2006,127:369-382.

51. Mirshafiey A.Venom therapy in multiple sclerosis.Neuropharmacology,2007,53:353-361.

52. Raine CS.The Norton Lecture:a review of the oligodendrocyte in the multiple sclerosis lesion.J Immunol,1997,77:135-152.

53. Winrow VR,Winyard PG,Morris CJ,Blake DR.Free radicals in inflammation:second messengers and mediators of tissue destruction.Br Med Bull,1993,49:506-522.

54. Gilgun-SherkiY,Melamed E,Offen D.The role of oxidative stress in the pathogenesis of multiple sclerosis:the need for effective antioxidant therapy.J.Neurol,2004,251:261-268.

55. Lutskii MA,Esaulenko IE.Oxidant stress in the pathogenesis of multiple sclerosis.Neurosci.Behav.Physiol,2007,37:209-213.

56. Halliwell B,Gutteridge JM.The definition and measurement of antioxidants in biological systems.Free Radic Biol Med,1995,18:125-126.

57. Smith KJ,Kapoor R,Felts PA.Demyelination:the role of reactive oxygen and nitrogen species.Brain Pathol,1999,9:69-92.

58. van der Goes A,Brouwer J,Hoekstra K,Roos D,van den Berg TK,Dijkstra CD.Reactive oxygen species are required for the phagocytosis of myelin by macrophages.J Neuroimmunol,1998,92:67-75.

59. van Meeteren ME,Hendriks JJ,Dijkstra CD,van Tol EA.Dietary compounds prevent oxidative damage and nitric oxide production by cells involved in demyelinating disease.Biochem Pharmacol,2004,67:967-975.

60. Hendriks JJ,van Meeteren ME,Van Der Pol SM,Newman TA,Dijkstra CD,de Vries HE.Axonal damage and oxidative stress during chronic experimental allergic encephalomyelitis,Int J Neuroprotec Neuroregen,2005,1:171-176.

61. Vladimirova O,OConnor J,Cahill A,Alder H,Butunoi C,Kalman B.Oxidative damage to DNA in plaques of MS brains.Mult Scler.1998,4:413-418.

62. Gelinas S,Chapados C,Beauregard M,Gosselin I,Martinoli MG.Effect of oxidative stress on stability and structure of neurofilament proteins.Biochem Cell Biol,2000,78:667-674.

63. Liu Y,Hao W,Letiembre M,Walter S,Kulanga M,Neumann H,Fassbender K.Suppression of Microglial Inflammatory Activity by Myelin Phagocytosis:Role of p47-PHOX-Mediated Generation of Reactive Oxygen Species.J Neurosci,2006,26:12904-12913.

64. Beal MF,Hyman BT,Koroshetz W.Do defects in mitochondrial energy metabolism underlie the pathology of neurodegenerative diseases? Trends Neurosci,1993,16:125-131.

65. Calabrese V,Scapagnini G,Giuffrida Stella AM,Bates TE,Clark JB.Mitochondrial involvement in brain function and dysfunction:relevance to aging,neurodegenerative disorders and longevity.Neurochem Res,2001,26:739-764.

66. Chen Q,Vazquez EJ,Moghaddas S,Hoppel CL,Lesnefsky EJ.Production of reactive oxygen species by mitochondria:central role of complex III.J Biol Chem,2003,278:36027-36031.

67. Koch M,Ramsaransing GS,Arutjunyan AV,Stepanov M,Teelken A,Heersema DJ,De Keyser J.Oxidative stress in serum and peripheral blood leukocytes in patients with different disease courses of multiple sclerosis.J Neurol,2006,253:483-487.

68. Lieven CJ,Vrabec JP,Levin LA.The effects of oxidative stress on mitochondrial transmembrane potential in retinal ganglion cells.Antioxid Redox Signal,2003,5:641-646.

69. Green DR,Reed JC.Mitochondria and apoptosis.Science,1998,281:1309-1312.

70. Vrabec JP,Lieven CJ,Levin LA.Cell-type-specific opening of the retinal ganglion cell mitochondrial permeability transition pore.Invest Ophthalmol Vis Sci,2003,44:2774-2782.

71. Banisor I,Kalman B.Bcl-2 and its homologues in the brain of patients with multiple sclerosis.Mult Scler,2004,10:176-181.

72. Tajouri L,Mellick AS,Ashton KJ,Tannenberg AE,Nagra RM,Tourtellotte WW,Griffiths LR.Quantitative and qualitative changes in gene expression patterns characterize the activity of plaques in multiple sclerosis.Brain Res Mol Brain Res,2003,119:170-183.

73. Bongarzone ER,Pasquini JM,Soto EF.Oxidative damage to proteins and lipids of CNS myelin produced by in vitro generated reactive oxygen species.J Neurosci Res,1995,41:213-221.

74. J.F.Keaney JF Jr,Vita JA.Atherosclerosis,oxidative stress,and antioxidant protection in endothelium-derived relaxing factor action.Prog Cardiovasc Dis,1995,38:129-154.

75.Albers DS,Beal MF.Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease.J Neural Transm,2000,59:133-154.

76. Rubanyi GM.Vascular effects of oxygen-derived free radical.Free Radic Biol Med,1988,4:107-120.

77. Van der Goes A,Wouters D,Van Der Pol SM,Huizinga R,Ronken E,Adamson P,et al.Reactive oxygen species enhance the migration of monocytes across the blood-brain barrier in vitro.FASEB J,2001,15:1852-1854.

78. Imaizumi S,Kondo T,Deli MA,Gobbel G,Joó F,Epstein CJ,et al.The influence of oxygen free radicals on the permeability of the monolayer of cultured brain endothelial cells.Neurochem Int,1996,29:205-211.

79. Lagrange P,Romero IA,Minn A,Revest PA.Transendothelial permeability changes induced by free radicals in an in vitro model of the blood-brain barrier.Free Radical Biol Med,1999,27:667-672.

80. Olesen SP.Free oxygen radicals decrease electrical resistance of microvascular endothelium in brain.Acta Physiol Scand,1987,129:181-187.

81. Adamson P,Etienne S,Couraud PO,Calder V,Greenwood J.Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a Rho-dependent pathway.J Immunol,1999,162:2964-2973.

82. Jin L,Ying Z,Webb RC.Activation of Rho/Rho kinase signaling pathway by reactive oxygen species in rat aorta.Am J Physiol,2004,287:H1495-1500.

83. van der Veen RC,Hinton DR,Incardonna F,Hofman FM.Extensive peroxynitrite activity during progressive stages of central nervous system inflammation.J.Neuroimmunol,1997,77:1-7.

84. Hooper DC,Bagasra O,Marini JC,Zborek A,Ohnishi ST,Kean R,et al.Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite:implications for the treatment of multiple sclerosis.Proc Natl Acad Sci,1997,94:2528-2533.

85. Hendriks JJ,Alblas J,van der Pol SM,van Tol EA,Dijkstra CD,de Vries HE.Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis.J Exp Med,2004,200:1667-1672.

86. Ruuls SR,Bauer J,Sontrop K,Huitinga I,t Hart BA,Dijkstra CD.Reactive oxygen species are involved in the pathogenesis of experimental allergic encephalomyelitis in Lewis rats.J Neuroimmunol,1995,56:207-217.

87. Lehmann D,Karussis D,Misrachi-Koll R,Shezen E,Ovadia H,Abramsky O.Oral administration of the oxidant-scavenger N-acetyl-L-cysteine inhibits acute experimental autoimmune encephalomyelitis.J Neuroimmunol,1994,50:35-42.

88. Liu Y,Zhu B,Wang X,Luo L,Li P,Paty DW,et al.Bilirubin as a potent antioxidant suppresses experimental autoimmune encephalomyelitis:implications for the role of oxidative stress in the development of multiple sclerosis.J Neuroimmunol,2003,139:27-35.

89. Marracci GH,Jones RE,McKeon GP,Bourdette DN.Alpha lipoic acid inhibits T cell migration into the spinal cord and suppresses and treats experimental autoimmune encephalomyelitis.J Neuroimmunol,2002,131:104-114.

90. Morini M,Roccatagliata L,DellEva R,Pedemonte E,Furlan R,Minghelli S,et al.Alpha-lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis.J Neuroimmunol,2004,148:146-153.

91. Schreibelt G,Musters RJ,Reijerkerk A,de Groot LR,van der Pol SM,Hendrikx EM,et al.Lipoic Acid Affects Cellular Migration into the Central Nervous System and Stabilizes Blood-Brain Barrier Integrity.J Immunol,2006,177:2630-2637.

92. Gilgun-Sherki Y,Melamed E,Offen D.The role of oxidative stress in the pathogenesis of multiple sclerosis:the need for effective antioxidant therapy.J Neurol,2004,251:261-268.

93. van Meeteren ME,Teunissen CE,Dijkstra CD,van Tol EA.Antioxidants and polyunsaturated fatty acids in multiple sclerosis.Eur J Clin Nutr,2005,59:1347-1361.

94. Hultqvist M,Bcklund J,Bauer K,Gelderman KA,Holmdahl R.Lack of reactive oxygen species breaks T cell tolerance to collagen type II and allows development of arthritis in mice.J Immunol,2007,179:1431-1437.

95. Sahaf B,Heydari K,Herzenberg LA,Herzenberg LA.Lymphocyte surface thiol levels.Proc Natl Acad Sci USA,2003,100:4001-4005.

96. Gelderman KA,Hultqvist M,Jens Holmberg J,Peter Olofsson P,Holmdahl R.T cell surface redox levels determine T cell reactivity and arthritis susceptibility.Proc Natl Acad Sci U S A,2006,22:12831-12836.

97. Solomon S,Rajasekaran N,Jeisy-Walder E,Snapper SB,Illges H.A crucial role for macrophages in the pathology of K/B x N serum-induced arthritis.Eur J Immunol,2005,35:3064-3073.

98. Blom T,Franzen A,Heinegard,D.Holmdahl,R.Comment on The influence of the proinflammatory cytokine,osteopontin,on autoimmune demyelinating disease.Science,2003,299:1845.

99. Hultqvist M,Olofsson P,Holmberg J,Bckstrm BT,Tordsson J,Holmdahl R.Enhanced autoimmunity,arthritis,and encephalomyelitis in mice with a reduced oxidative burst due to a mutation in the Ncf1 gene.Proc Natl Acad Sci U S A,2004,101:12646-12651.