Antioxidative defense mechanisms controlled by Nrf2: state-of-the-art and clinical perspectives in neurodegenerative diseases

Archives of Toxicology

Volumn 88, Issue 10, 2014, Pages 1773-1786

  Lim, Jamie L ^a   Wilhelmus, Micha M M ^a   de Vries, Helga E ^a   Drukarch, Benjamin ^a   Hoozemans, Jeroen J M ^a   van Horssen, Jack ^a  

^a VU UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Antioxidant enzymes; Free radicals; Neurodegenerative disorders; Nrf2; Oxidative stress; Reactive oxygen species

Indexed keywords

REACTIVE OXYGEN METABOLITE; TRANSCRIPTION FACTOR NRF2; ANTIOXIDANT;

ALZHEIMER DISEASE; DEGENERATIVE DISEASE; HUMAN; HUNTINGTON CHOREA; MULTIPLE SCLEROSIS; NEUROPATHOLOGY; NONHUMAN; PARKINSON DISEASE; PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; ANIMAL; BRAIN; DISEASE MODEL; DRUG EFFECTS; METABOLISM; MICROGLIA; MITOCHONDRION; NEURODEGENERATIVE DISEASES; OXIDATIVE STRESS; PATHOLOGY;

ANIMALS; ANTIOXIDANTS; BRAIN; DISEASE MODELS, ANIMAL; HUMANS; MICROGLIA; MITOCHONDRIA; NEURODEGENERATIVE DISEASES; NF-E2-RELATED FACTOR 2; OXIDATIVE STRESS; REACTIVE OXYGEN SPECIES;

EID: 84919926861     PISSN: 03405761     EISSN: 14320738     Source Type: Journal    
DOI: 10.1007/s00204-014-1338-z     Document Type: Review

References (179)

1. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O’Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421
2. Alam ZI, Daniel SE, Lees AJ, Marsden DC, Jenner P, Halliwell B (1997a) A generalised increase in protein carbonyls in the brain in Parkinson’s but not incidental Lewy body disease. J Neurochem 69:1326–1329
3. Alam ZI, Jenner A, Daniel SE, Lees AJ, Cairns N, Marsden CD, Jenner P, Halliwell B (1997b) Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem 69:1196–1203
4. Beal MF (2001) Experimental models of Parkinson’s disease. Nat Rev Neurosci 2:325–334
5. Beal MF (2002) Oxidatively modified proteins in aging and disease. Free Radic Biol Med 32:797–803
6. Bedard K, Krause KH (2007) The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245–313
7. Beyer K, Ariza A (2007) Protein aggregation mechanisms in synucleinopathies: commonalities and differences. J Neuropathol Exp Neurol 66:965–974
8. Bo L, Dawson TM, Wesselingh S, Mork S, Choi S, Kong PA, Hanley D, Trapp BD (1994) Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann Neurol 36:778–786
9. Bogdanov MB, Andreassen OA, Dedeoglu A, Ferrante RJ, Beal MF (2001) Increased oxidative damage to DNA in a transgenic mouse model of Huntington’s disease. J Neurochem 79:1246–1249
10. Bolanos JP, Almeida A, Stewart V, Peuchen S, Land JM, Clark JB, Heales SJ (1997) Nitric oxide-mediated mitochondrial damage in the brain: mechanisms and implications for neurodegenerative diseases. J Neurochem 68:2227–2240
11. Bove J, Prou D, Perier C, Przedborski S (2005) Toxin-induced models of Parkinson’s disease. NeuroRx 2:484–494
12. Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259
13. Brigelius-Flohe R, Maiorino M (2013) Glutathione peroxidases. Biochim Biophys Acta 1830:3289–3303
14. Browne SE, Beal MF (2006) Oxidative damage in Huntington’s disease pathogenesis. Antioxid Redox Signal 8:2061–2073
15. Browne SE, Bowling AC, MacGarvey U, Baik MJ, Berger SC, Muqit MM, Bird ED, Beal MF (1997) Oxidative damage and metabolic dysfunction in Huntington’s disease: selective vulnerability of the basal ganglia. Ann Neurol 41:646–653
16. Browne SE, Ferrante RJ, Beal MF (1999) Oxidative stress in Huntington’s disease. Brain Pathol 9:147–163
17. Bryan HK, Olayanju A, Goldring CE, Park BK (2013) The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem Pharmacol 85:705–717
18. Bush AI (2003) The metallobiology of Alzheimer’s disease. Trends Neurosci 26:207–214
19. Calabrese V, Raffaele R, Cosentino E, Rizza V (1994) Changes in cerebrospinal fluid levels of malondialdehyde and glutathione reductase activity in multiple sclerosis. Int J Clin Pharmacol Res 14:119–123
20. Calkins MJ, Jakel RJ, Johnson DA, Chan K, Kan YW, Johnson JA (2005) Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proc Natl Acad Sci USA 102:244–249
21. Campbell GR, Ziabreva I, Reeve AK, Krishnan KJ, Reynolds R, Howell O, Lassmann H, Turnbull DM, Mahad DJ (2011) Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann Neurol 69:481–492
22. Carlson NG, Rose JW (2006) Antioxidants in multiple sclerosis: do they have a role in therapy? CNS Drugs 20:433–441
23. Chen CM, Wu YR, Cheng ML, Liu JL, Lee YM, Lee PW, Soong BW, Chiu DT (2007) Increased oxidative damage and mitochondrial abnormalities in the peripheral blood of Huntington’s disease patients. Biochem Biophys Res Commun 359:335–340
24. Chen JW, Breckwoldt MO, Aikawa E, Chiang G, Weissleder R (2008) Myeloperoxidase-targeted imaging of active inflammatory lesions in murine experimental autoimmune encephalomyelitis. Brain 131:1123–1133
25. Chen PC, Vargas MR, Pani AK, Smeyne RJ, Johnson DA, Kan YW, Johnson JA (2009) Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: critical role for the astrocyte. Proc Natl Acad Sci USA 106:2933–2938
26. Chinta SJ, Andersen JK (2008) Redox imbalance in Parkinson’s disease. Biochim Biophys Acta 1780:1362–1367
27. Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP (2006) DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci USA 103:15091–15096
28. Colton CA, Gilbert DL (1987) Production of superoxide anions by a CNS macrophage, the microglia. FEBS Lett 223:284–288
29. Colton CA, Chernyshev ON, Gilbert DL, Vitek MP (2000) Microglial contribution to oxidative stress in Alzheimer’s disease. Ann N Y Acad Sci 899:292–307
30. Cook AL, Vitale AM, Ravishankar S, Matigian N, Sutherland GT, Shan J, Sutharsan R, Perry C, Silburn PA, Mellick GD, Whitelaw ML, Wells CA, kay-Sim A, Wood SA (2011) NRF2 activation restores disease related metabolic deficiencies in olfactory neurosphere-derived cells from patients with sporadic Parkinson’s disease. PLoS one 6:e21907
31. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (2003) Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23:7198–7209
32. Cummings JL (2004) Alzheimer’s disease. N Engl J Med 351:56–67
33. Dawson TM, Dawson VL (2003) Molecular pathways of neurodegeneration in Parkinson’s disease. Science 302:819–822
34. De Groot CJ, Ruuls SR, Theeuwes JW, Dijkstra CD, 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
35. Dexter DT, Carter CJ, Wells FR, Javoy-Agid F, Agid Y, Lees A, Jenner P, Marsden CD (1989) Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem 52:381–389
36. Ding Q, Markesbery WR, Cecarini V, Keller JN (2006) Decreased RNA, and increased RNA oxidation, in ribosomes from early Alzheimer’s disease. Neurochem Res 31:705–710
37. Doraiswamy PM, Finefrock AE (2004) Metals in our minds: therapeutic implications for neurodegenerative disorders. Lancet Neurol 3:431–434
38. Drechsel DA, Patel M (2008) Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson’s disease. Free Radic Biol Med 44:1873–1886
39. Dringen R, Pawlowski PG, Hirrlinger J (2005) Peroxide detoxification by brain cells. J Neurosci Res 79:157–165
40. Eckert A, Keil U, Marques CA, Bonert A, Frey C, Schussel K, Muller WE (2003) Mitochondrial dysfunction, apoptotic cell death, and Alzheimer’s disease. Biochem Pharmacol 66:1627–1634
41. Ellrichmann G, Petrasch-Parwez E, Lee DH, Reick C, Arning L, Saft C, Gold R, Linker RA (2011) Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Huntington’s disease. PLoS one 6:e16172
42. Esterbauer H, Schaur RJ, Zollner H (1991) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med 11:81–128
43. Evans MD, Dizdaroglu M, Cooke MS (2004) Oxidative DNA damage and disease: induction, repair and significance. Mutat Res 567:1–61
44. Farr SA, Ripley JL, Sultana R, Zhang Z, Niehoff ML, Platt TL, Murphy MP, Morley JE, Kumar V, Butterfield DA (2014) Antisense oligonucleotide against GSK-3beta in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: involvement of transcription factor Nrf2 and implications for Alzheimer disease. Free Radic Biol Med 67:387–395
45. Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, Beal MF (2002) Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci 22:1592–1599
46. Ferretti G, Bacchetti T, Principi F, Di Ludovico F, Viti B, Angeleri VA, Danni M, Provinciali L (2005) Increased levels of lipid hydroperoxides in plasma of patients with multiple sclerosis: a relationship with paraoxonase activity. Mult Scler 11:677–682
47. Fiebiger SM, Bros H, Grobosch T, Janssen A, Chanvillard C, Paul F, Dorr J, Millward JM, Infante-Duarte C (2013) The antioxidant idebenone fails to prevent or attenuate chronic experimental autoimmune encephalomyelitis in the mouse. J Neuroimmunol 262:66–71
48. Fischer MT, Sharma R, Lim JL, Haider L, Frischer JM, Drexhage J, Mahad D, Bradl M, van Horssen J, Lassmann H (2012) NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury. Brain 135:886–899
49. Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, Viglietta V, Dawson KT (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367:1087–1097
50. French HM, Reid M, Mamontov P, Simmons RA, Grinspan JB (2009) Oxidative stress disrupts oligodendrocyte maturation. J Neurosci Res 87:3076–3087
51. Gilgun-Sherki Y, Melamed E, Offen D (2001) Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 40:959–975
52. Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367:1098–1107
53. Goswami A, Dikshit P, Mishra A, Mulherkar S, Nukina N, Jana NR (2006) Oxidative stress promotes mutant huntingtin aggregation and mutant huntingtin-dependent cell death by mimicking proteasomal malfunction. Biochem Biophys Res Commun 342:184–190
54. Gray E, Thomas TL, Betmouni S, Scolding N, Love S (2008a) Elevated activity and microglial expression of myeloperoxidase in demyelinated cerebral cortex in multiple sclerosis. Brain Pathol 18:86–95
55. Gray E, Thomas TL, Betmouni S, Scolding N, Love S (2008b) Elevated myeloperoxidase activity in white matter in multiple sclerosis. Neurosci Lett 444:195–198
56. Greco A, Minghetti L, Sette G, Fieschi C, Levi G (1999) Cerebrospinal fluid isoprostane shows oxidative stress in patients with multiple sclerosis. Neurology 53:1876–1879
57. Haider L, Fischer MT, Frischer JM, Bauer J, Hoftberger R, Botond G, Esterbauer H, Binder CJ, Witztum JL, Lassmann H (2011) Oxidative damage in multiple sclerosis lesions. Brain 134:1914–1924
58. Healy DG, bou-Sleiman PM, Valente EM, Gilks WP, Bhatia K, Quinn N, Lees AJ, Wood NW (2004a) DJ-1 mutations in Parkinson’s disease. J Neurol Neurosurg Psychiatry 75:144–145
59. Healy DG, bou-Sleiman PM, Wood NW (2004b) PINK, PANK, or PARK? A clinicians’ guide to familial parkinsonism. Lancet Neurol 3:652–662
60. Hendriks JJ, Alblas J, Van Der Pol SM, van Tol EA, Dijkstra CD, De Vries HE (2004) Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis. J Exp Med 200:1667–1672
61. Hersch SM, Gevorkian S, Marder K, Moskowitz C, Feigin A, Cox M, Como P, Zimmerman C, Lin M, Zhang L, Ulug AM, Beal MF, Matson W, Bogdanov M, Ebbel E, Zaleta A, Kaneko Y, Jenkins B, Hevelone N, Zhang H, Yu H, Schoenfeld D, Ferrante R, Rosas HD (2006) Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2′dG. Neurology 66:250–252
62. Higgins GC, Beart PM, Shin YS, Chen MJ, Cheung NS, Nagley P (2010) Oxidative stress: emerging mitochondrial and cellular themes and variations in neuronal injury. J Alzheimers Dis 20(Suppl 2):S453–S473
63. Hofmann B, Hecht HJ, Flohe L (2002) Peroxiredoxins. Biol Chem 383:347–364
64. Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W (2009) The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am J Pathol 174:1241–1251
65. Huang X, Moir RD, Tanzi RE, Bush AI, Rogers JT (2004) Redox-active metals, oxidative stress, and Alzheimer’s disease pathology. Ann N Y Acad Sci 1012:153–163
66. Husain J, Juurlink BH (1995) Oligodendroglial precursor cell susceptibility to hypoxia is related to poor ability to cope with reactive oxygen species. Brain Res 698:86–94
67. Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M (2000) Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 275:16023–16029
68. Iskander K, Li J, Han S, Zheng B, Jaiswal AK (2006) NQO1 and NQO2 regulation of humoral immunity and autoimmunity. J Biol Chem 281:30917–30924
69. Isobe C, Abe T, Terayama Y (2010) Levels of reduced and oxidized coenzyme Q-10 and 8-hydroxy-2′-deoxyguanosine in the cerebrospinal fluid of patients with living Parkinson’s disease demonstrate that mitochondrial oxidative damage and/or oxidative DNA damage contributes to the neurodegenerative process. Neurosci Lett 469:159–163
70. Itoh K, Wakabayashi N, Katoh Y, Ishii T, O’Connor T, Yamamoto M (2003) Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells 8:379–391
71. Jaiswal AK (2000) Regulation of genes encoding NAD(P)H:quinone oxidoreductases. Free Radic Biol Med 29:254–262
72. Jakel RJ, Kern JT, Johnson DA, Johnson JA (2005) Induction of the protective antioxidant response element pathway by 6-hydroxydopamine in vivo and in vitro. Toxicol Sci 87:176–186
73. Jakel RJ, Townsend JA, Kraft AD, Johnson JA (2007) Nrf2-mediated protection against 6-hydroxydopamine. Brain Res 1144:192–201
74. Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79:368–376
75. Jellinger KA (2008) Neuropathological aspects of Alzheimer disease, Parkinson disease and frontotemporal dementia. Neurodegener Dis 5:118–121
76. Jo C, Gundemir S, Pritchard S, Jin YN, Rahman I, Johnson GV (2014) Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nat Commun 5:3496
77. Johnson F, Giulivi C (2005) Superoxide dismutases and their impact upon human health. Mol Asp Med 26:340–352
78. Johnson DA, Amirahmadi S, Ward C, Fabry Z, Johnson JA (2010) The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis. Toxicol Sci 114:237–246
79. Juurlink BH, Thorburne SK, Hertz L (1998) Peroxide-scavenging deficit underlies oligodendrocyte susceptibility to oxidative stress. Glia 22:371–378
80. Kanninen K, Malm TM, Jyrkkanen HK, Goldsteins G, Keksa-Goldsteine V, Tanila H, Yamamoto M, Yla-Herttuala S, Levonen AL, Koistinaho J (2008) Nuclear factor erythroid 2-related factor 2 protects against beta amyloid. Mol Cell Neurosci 39:302–313
81. Kanninen K, Heikkinen R, Malm T, Rolova T, Kuhmonen S, Leinonen H, Yla-Herttuala S, Tanila H, Levonen AL, Koistinaho M, Koistinaho J (2009) Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 106:16505–16510
82. Karg E, Klivenyi P, Nemeth I, Bencsik K, Pinter S, Vecsei L (1999) Nonenzymatic antioxidants of blood in multiple sclerosis. J Neurol 246:533–539
83. Karkkainen V, Pomeshchik Y, Savchenko E, Dhungana H, Kurronen A, Lehtonen S, Naumenko N, Tavi P, Levonen AL, Yamamoto M, Malm T, Magga J, Kanninen KM, Koistinaho J (2014) Nrf2 regulates neurogenesis and protects neural progenitor cells against Abeta toxicity. Stem Cells 32:1904–1916
84. Kasai H (2002) Chemistry-based studies on oxidative DNA damage: formation, repair, and mutagenesis. Free Radic Biol Med 33:450–456
85. Kim YJ, Ahn JY, Liang P, Ip C, Zhang Y, Park YM (2007) Human prx1 gene is a target of Nrf2 and is up-regulated by hypoxia/reoxygenation: implication to tumor biology. Cancer Res 67:546–554
86. Klivenyi P, Ferrante RJ, Gardian G, Browne S, Chabrier PE, Beal MF (2003) Increased survival and neuroprotective effects of BN82451 in a transgenic mouse model of Huntington’s disease. J Neurochem 86:267–272
87. Koch M, Ramsaransing GS, Arutjunyan AV, Stepanov M, Teelken A, Heersema DJ, 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
88. Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189
89. Lee SC, Dickson DW, Liu W, Brosnan CF (1993) Induction of nitric oxide synthase activity in human astrocytes by interleukin-1 beta and interferon-gamma. J Neuroimmunol 46:19–24
90. Li Y, Jaiswal AK (1992) Regulation of human NAD(P)H:quinone oxidoreductase gene. Role of AP1 binding site contained within human antioxidant response element. J Biol Chem 267:15097–15104
91. Li HY, Zhong YF, Wu SY, Shi N (2007) NF-E2 related factor 2 activation and heme oxygenase-1 induction by tert-butylhydroquinone protect against deltamethrin-mediated oxidative stress in PC12 cells. Chem Res Toxicol 20:1242–1251
92. Li B, Cui W, Liu J, Li R, Liu Q, Xie XH, Ge XL, Zhang J, Song XJ, Wang Y, Guo L (2013) Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice. Exp Neurol 250:239–249
93. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795
94. Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G, Bruck W, Dawson K, Goelz S, Wiese S, Scannevin RH, Lukashev M, Gold R (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134:678–692
95. Liu JS, Zhao ML, Brosnan CF, Lee SC (2001) Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. Am J Pathol 158:2057–2066
96. Long DJ, Jaiswal AK (2000) NRH:quinone oxidoreductase2 (NQO2). Chem Biol Interact 129:99–112
97. Long JD, Matson WR, Juhl AR, Leavitt BR, Paulsen JS (2012) 8OHdG as a marker for Huntington disease progression. Neurobiol Dis 46:625–634
98. Lovell MA, Ehmann WD, Mattson MP, Markesbery WR (1997) Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer’s disease. Neurobiol Aging 18:457–461
99. Lu F, Selak M, O’Connor J, Croul S, Lorenzana C, Butunoi C, Kalman B (2000) Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. J Neurol Sci 177:95–103
100. Mahad DJ, Ziabreva I, Campbell G, Lax N, White K, Hanson PS, Lassmann H, Turnbull DM (2009) Mitochondrial changes within axons in multiple sclerosis. Brain 132:1161–1174
101. Maldonado PD, Molina-Jijon E, Villeda-Hernandez J, Galvan-Arzate S, Santamaria A, Pedraza-Chaverri J (2010) NAD(P)H oxidase contributes to neurotoxicity in an excitotoxic/prooxidant model of Huntington’s disease in rats: protective role of apocynin. J Neurosci Res 88:620–629
102. Mao P, Manczak M, Shirendeb UP, Reddy PH (2013) MitoQ, a mitochondria-targeted antioxidant, delays disease progression and alleviates pathogenesis in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Biochim Biophys Acta 1832:2322–2331
103. Mariani E, Polidori MC, Cherubini A, Mecocci P (2005) Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview. J Chromatogr B Analyt Technol Biomed Life Sci 827:65–75
104. Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ (2007) Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130:2800–2815
105. Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23:134–147
106. Marklund SL (1982) Human copper-containing superoxide dismutase of high molecular weight. Proc Natl Acad Sci USA 79:7634–7638
107. Mason RP, Casu M, Butler N, Breda C, Campesan S, Clapp J, Green EW, Dhulkhed D, Kyriacou CP, Giorgini F (2013) Glutathione peroxidase activity is neuroprotective in models of Huntington’s disease. Nat Genet 45:1249–1254
108. McCord JM (1976) Iron- and manganese-containing superoxide dismutases: structure, distribution, and evolutionary relationships. Adv Exp Med Biol 74:540–550
109. McCord JM, Edeas MA (2005) SOD, oxidative stress and human pathologies: a brief history and a future vision. Biomed Pharmacother 59:139–142
110. McCord JM, Fridovich I (1969) Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem 244:6049–6055
111. Mecocci P, MacGarvey U, Beal MF (1994) Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease. Ann Neurol 36:747–751
112. Mitrovic B, Ignarro LJ, Montestruque S, Smoll A, Merrill JE (1994) Nitric oxide as a potential pathological mechanism in demyelination: its differential effects on primary glial cells in vitro. Neuroscience 61:575–585
113. Moosmann B, Behl C (2002) Antioxidants as treatment for neurodegenerative disorders. Expert Opin Investig Drugs 11:1407–1435
114. Morrow JD, Chen Y, Brame CJ, Yang J, Sanchez SC, Xu J, Zackert WE, Awad JA, Roberts LJ (1999) The isoprostanes: unique prostaglandin-like products of free-radical-initiated lipid peroxidation. Drug Metab Rev 31:117–139
115. Mosley RL, Benner EJ, Kadiu I, Thomas M, Boska MD, Hasan K, Laurie C, Gendelman HE (2006) Neuroinflammation, Oxidative Stress and the pathogenesis of Parkinson’s disease. Clin Neurosci Res 6:261–281
116. Nakaso K, Nakamura C, Sato H, Imamura K, Takeshima T, Nakashima K (2006) Novel cytoprotective mechanism of anti-parkinsonian drug deprenyl: PI3K and Nrf2-derived induction of antioxidative proteins. Biochem Biophys Res Commun 339:915–922
117. Nguyen T, Sherratt PJ, Pickett CB (2003) Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 43:233–260
118. Nguyen T, Yang CS, Pickett CB (2004) The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. Free Radic Biol Med 37:433–441
119. Nikic I, Merkler D, Sorbara C, Brinkoetter M, Kreutzfeldt M, Bareyre FM, Bruck W, Bishop D, Misgeld T, Kerschensteiner M (2011) A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat Med 17:495–499
120. Nunomura A, Honda K, Takeda A, Hirai K, Zhu X, Smith MA, Perry G (2006) Oxidative damage to RNA in neurodegenerative diseases. J Biomed Biotechnol 2006:82323
121. Pareek TK, Belkadi A, Kesavapany S, Zaremba A, Loh SL, Bai L, Cohen ML, Meyer C, Liby KT, Miller RH, Sporn MB, Letterio JJ (2011) Triterpenoid modulation of IL-17 and Nrf-2 expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis. Sci Rep 1:201
122. Parker WD Jr, Parks JK, Swerdlow RH (2008) Complex I deficiency in Parkinson’s disease frontal cortex. Brain Res 1189:215–218
123. Perez-Severiano F, Santamaria A, Pedraza-Chaverri J, Medina-Campos ON, Rios C, Segovia J (2004) Increased formation of reactive oxygen species, but no changes in glutathione peroxidase activity, in striata of mice transgenic for the Huntington’s disease mutation. Neurochem Res 29:729–733
124. Perez-Severiano F, Montes S, Geronimo-Olvera C, Segovia J (2013) Study of oxidative damage and antioxidant systems in two Huntington’s disease rodent models. Methods Mol Biol 1010:177–200
125. Przedborski S, Ischiropoulos H (2005) Reactive oxygen and nitrogen species: weapons of neuronal destruction in models of Parkinson’s disease. Antioxid Redox Signal 7:685–693
126. Qi X, Lewin AS, Sun L, Hauswirth WW, Guy J (2006) Mitochondrial protein nitration primes neurodegeneration in experimental autoimmune encephalomyelitis. J Biol Chem 281:31950–31962
127. Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, Hamilton RL, Chu CT, Jordan-Sciutto KL (2007) Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 66:75–85
128. Rhee SG, Chae HZ, Kim K (2005) Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. Free Radic Biol Med 38:1543–1552
129. Riedl AG, Watts PM, Brown CT, Jenner P (1999) P450 and heme oxygenase enzymes in the basal ganglia and their roles in Parkinson’s disease. Adv Neurol 80:271–286
130. Ryter SW, Alam J, Choi AM (2006) Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 86:583–650
131. Salazar M, Rojo AI, Velasco D, de Sagarra RM, Cuadrado A (2006) Glycogen synthase kinase-3beta inhibits the xenobiotic and antioxidant cell response by direct phosphorylation and nuclear exclusion of the transcription factor Nrf2. J Biol Chem 281:14841–14851
132. Santamaria A, Perez-Severiano F, Rodriguez-Martinez E, Maldonado PD, Pedraza-Chaverri J, Rios C, Segovia J (2001) Comparative analysis of superoxide dismutase activity between acute pharmacological models and a transgenic mouse model of Huntington’s disease. Neurochem Res 26:419–424
133. Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, Bista P, Zeng W, Ryan S, Yamamoto M, Lukashev M, Rhodes KJ (2012) Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther 341:274–284
134. Scherzinger E, Lurz R, Turmaine M, Mangiarini L, Hollenbach B, Hasenbank R, Bates GP, Davies SW, Lehrach H, Wanker EE (1997) Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 90:549–558
135. Schimrigk S, Brune N, Hellwig K, Lukas C, Bellenberg B, Rieks M, Hoffmann V, Pohlau D, Przuntek H (2006) Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol 13:604–610
136. Schipper HM (2004) Heme oxygenase expression in human central nervous system disorders. Free Radic Biol Med 37:1995–2011
137. Schreibelt G, Musters RJ, Reijerkerk A, de Groot LR, Van Der Pol SM, Hendrikx EM, Dopp ED, Dijkstra CD, Drukarch B, De Vries HE (2006) Lipoic acid affects cellular migration into the central nervous system and stabilizes blood-brain barrier integrity. J Immunol 177:2630–2637
138. Shcherbatykh I, Carpenter DO (2007) The role of metals in the etiology of Alzheimer’s disease. J Alzheimers Dis 11:191–205
139. Shih AY, Imbeault S, Barakauskas V, Erb H, Jiang L, Li P, Murphy TH (2005a) Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J Biol Chem 280:22925–22936
140. Shih AY, Li P, Murphy TH (2005b) A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. J Neurosci 25:10321–10335
141. Shimohama S, Tanino H, Kawakami N, Okamura N, Kodama H, Yamaguchi T, Hayakawa T, Nunomura A, Chiba S, Perry G, Smith MA, Fujimoto S (2000) Activation of NADPH oxidase in Alzheimer’s disease brains. Biochem Biophys Res Commun 273:5–9
142. Siddiqui A, Rivera-Sanchez S, Castro MR, cevedo-Torres K, Rane A, Torres-Ramos CA, Nicholls DG, Andersen JK, yala-Torres S (2012) Mitochondrial DNA damage is associated with reduced mitochondrial bioenergetics in Huntington’s disease. Free Radic Biol Med 53:1478–1488
143. Smith MA, Harris PLR, Sayre LM, Beckman JS, Perry G (1997) Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci 17:2653–2657
144. Sofic E, Lange KW, Jellinger K, Riederer P (1992) Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson’s disease. Neurosci Lett 142:128–130
145. Sofic E, Sapcanin A, Tahirovic I, Gavrankapetanovic I, Jellinger K, Reynolds GP, Tatschner T, Riederer P (2006) Antioxidant capacity in postmortem brain tissues of Parkinson’s and Alzheimer’s diseases. J Neural Transm Suppl 71:39-43
146. Spitsin SV, Scott GS, Mikheeva T, Zborek A, Kean RB, Brimer CM, Koprowski H, Hooper DC (2002) Comparison of uric acid and ascorbic acid in protection against EAE. Free Radic Biol Med 33:1363–1371
147. Springer W, Kahle PJ (2006) Mechanisms and models of alpha-synuclein-related neurodegeneration. Curr Neurol Neurosci Rep 6:432–436
148. Stack C, Ho D, Wille E, Calingasan NY, Williams C, Liby K, Sporn M, Dumont M, Beal MF (2010) Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington’s disease. Free Radic Biol Med 49:147–158
149. Stoy N, Mackay GM, Forrest CM, Christofides J, Egerton M, Stone TW, Darlington LG (2005) Tryptophan metabolism and oxidative stress in patients with Huntington’s disease. J Neurochem 93:611–623
150. Sultana R, Perluigi M, Butterfield DA (2006) Protein oxidation and lipid peroxidation in brain of subjects with Alzheimer’s disease: insights into mechanism of neurodegeneration from redox proteomics. Antioxid Redox Signal 8:2021–2037
151. Thorburne SK, Juurlink BH (1996) Low glutathione and high iron govern the susceptibility of oligodendroglial precursors to oxidative stress. J Neurochem 67:1014–1022
152. Uversky VN (2007) Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem 103:17–37
153. Valencia A, Sapp E, Kimm JS, McClory H, Reeves PB, Alexander J, Ansong KA, Masso N, Frosch MP, Kegel KB, Li X, DiFiglia M (2013) Elevated NADPH oxidase activity contributes to oxidative stress and cell death in Huntington’s disease. Hum Mol Genet 22:1112–1131
154. Valente EM, bou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del TD, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160
155. Van der Goes A, Wouters D, Van Der Pol SM, Huizinga R, Ronken E, Adamson P, Greenwood J, Dijkstra CD, De Vries HE (2001) Reactive oxygen species enhance the migration of monocytes across the blood-brain barrier in vitro. FASEB J 15:1852–1854
156. van Horssen J, Schreibelt G, Drexhage J, Hazes T, Dijkstra CD, Van der Valk P, De Vries HE (2008) Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radic Biol Med 45:1729–1737
157. van Horssen J, Drexhage JA, Flor T, Gerritsen W, Van der Valk P, De Vries HE (2010) Nrf2 and DJ1 are consistently upregulated in inflammatory multiple sclerosis lesions. Free Radic Biol Med 49:1283–1289
158. van Horssen J, Witte ME, Schreibelt G, De Vries HE (2011) Radical changes in multiple sclerosis pathogenesis. Biochim Biophys Acta 1812:141–150
159. Van Muiswinkel FL, Veerhuis R, Eikelenboom P (1996) Amyloid beta protein primes cultured rat microglial cells for an enhanced phorbol 12-myristate 13-acetate-induced respiratory burst activity. J Neurochem 66:2468–2476
160. Van Muiswinkel FL, Raupp SF, de Vos NM, Smits HA, Verhoef J, Eikelenboom P, Nottet HS (1999) The amino-terminus of the amyloid-beta protein is critical for the cellular binding and consequent activation of the respiratory burst of human macrophages. J Neuroimmunol 96:121–130
161. Van Muiswinkel FL, de Vos RA, Bol JG, Andringa G, Jansen Steur EN, Ross D, Siegel D, Drukarch B (2004) Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra. Neurobiol Aging 25:1253–1262
162. Volkel W, Sicilia T, Pahler A, Gsell W, Tatschner T, Jellinger K, Leblhuber F, Riederer P, Lutz WK, Gotz ME (2006) Increased brain levels of 4-hydroxy-2-nonenal glutathione conjugates in severe Alzheimer’s disease. Neurochem Int 48:679–686
163. von Otter M, Landgren S, Nilsson S, Celojevic D, Bergstrom P, Hakansson A, Nissbrandt H, Drozdzik M, Bialecka M, Kurzawski M, Blennow K, Nilsson M, Hammarsten O, Zetterberg H (2010a) Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson’s disease. BMC Med Genet 11:36
164. von Otter M, Landgren S, Nilsson S, Zetterberg M, Celojevic D, Bergstrom P, Minthon L, Bogdanovic N, Andreasen N, Gustafson DR, Skoog I, Wallin A, Tasa G, Blennow K, Nilsson M, Hammarsten O, Zetterberg H (2010b) Nrf2-encoding NFE2L2 haplotypes influence disease progression but not risk in Alzheimer’s disease and age-related cataract. Mech Ageing Dev 131:105–110
165. Wagener FA, Volk HD, Willis D, Abraham NG, Soares MP, Adema GJ, Figdor CG (2003) Different faces of the heme–heme oxygenase system in inflammation. Pharmacol Rev 55:551–571
166. Walker FO (2007) Huntington’s Disease. Semin Neurol 27:143–150
167. Wallace MN, Geddes JG, Farquhar DA, Masson MR (1997) Nitric oxide synthase in reactive astrocytes adjacent to beta-amyloid plaques. Exp Neurol 144:266–272
168. Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–1086
169. Wang CX, Shuaib A (2007) Neuroprotective effects of free radical scavengers in stroke. Drugs Aging 24:537–546
170. Wang J, Xiong S, Xie C, Markesbery WR, Lovell MA (2005) Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer’s disease. J Neurochem 93:953–962
171. Williamson TP, Amirahmadi S, Joshi G, Kaludov NK, Martinov MN, Johnson DA, Johnson JA (2012) Discovery of potent, novel Nrf2 inducers via quantum modeling, virtual screening, and in vitro experimental validation. Chem Biol Drug Des 80:810–820
172. Witte ME, Bo L, Rodenburg RJ, Belien JA, Musters R, Hazes T, Wintjes LT, Smeitink JA, Geurts JJ, De Vries HE, Van der Valk J, van Horssen J (2009) Enhanced number and activity of mitochondria in multiple sclerosis lesions. J Pathol 219:193–204
173. Witte ME, Geurts JJ, De Vries HE, Van der Valk J, van Horssen J (2010) Mitochondrial dysfunction: a potential link between neuroinflammation and neurodegeneration? Mitochondrion 10:411–418
174. Wruck CJ, Claussen M, Fuhrmann G, Romer L, Schulz A, Pufe T, Waetzig V, Peipp M, Herdegen T, Gotz ME (2007) Luteolin protects rat PC12 and C6 cells against MPP + induced toxicity via an ERK dependent Keap1-Nrf2-ARE pathway. J Neural Transm Suppl 72:57-67
175. yala-Pena S (2013) Role of oxidative DNA damage in mitochondrial dysfunction and Huntington’s disease pathogenesis. Free Radic Biol Med 62:102–110
176. Yasuhara T, Hara K, Sethi KD, Morgan JC, Borlongan CV (2007) Increased 8-OHdG levels in the urine, serum, and substantia nigra of hemiparkinsonian rats. Brain Res 1133:49–52
177. Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman ER, Mizuno Y (1996) Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci USA 93:2696–2701
178. Zhao J, Kobori N, Aronowski J, Dash PK (2006) Sulforaphane reduces infarct volume following focal cerebral ischemia in rodents. Neurosci Lett 393:108–112
179. Zhao J, Moore AN, Redell JB, Dash PK (2007) Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. J Neurosci 27:10240–10248