The Nrf2-ARE cytoprotective pathway in astrocytes

Expert Reviews in Molecular Medicine

Volumn 11, Issue , 2009, Pages

  Vargas, Marcelo R ^a   Johnson, Jeffrey A ^a,b  

^a UNIVERSITY OF WISCONSIN MADISON   (United States)

^b UNIVERSITY OF WISCONSIN MADISON   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HYDROGEN PEROXIDE; PROTEIN; SMALL INTERFERING RNA; TRANSCRIPTION FACTOR NRF2; VPS52 PROTEIN, MOUSE;

ANIMAL; ASTROCYTE; CELL CULTURE; CELL PROTECTION; GENE SILENCING; MAJOR HISTOCOMPATIBILITY COMPLEX; METABOLISM; MOUSE; MOUSE MUTANT; NERVE CELL; OXIDATIVE STRESS; PHYSIOLOGY; REVIEW; SIGNAL TRANSDUCTION; TRANSGENIC MOUSE;

ANIMALS; ASTROCYTES; CELLS, CULTURED; CYTOPROTECTION; GENE KNOCKDOWN TECHNIQUES; HYDROGEN PEROXIDE; MAJOR HISTOCOMPATIBILITY COMPLEX; MICE; MICE, KNOCKOUT; MICE, TRANSGENIC; NEURONS; NF-E2-RELATED FACTOR 2; OXIDATIVE STRESS; PROTEINS; RNA, SMALL INTERFERING; SIGNAL TRANSDUCTION;

EID: 70349333698     PISSN: 14623994     EISSN: None     Source Type: Journal    
DOI: 10.1017/S1462399409001094     Document Type: Review

References (184)

1. Chance, B., Sies, H. and Boveris, A. (1979) Hydroperoxide metabolism in mammalian organs. Physiological Reviews 59, 527-605 (Pubitemid 9236599)
2. Palmer, R.M.J., Rees, D.D., Ashton, D.S. and Moncada, S. (1988) L-Arginine is the physiological precursor for the formation of nitric oxide in endothelium dependent relaxation. Biochemical and Biophysical Research Communications 153, 1251-1256
3. Pacher, P., Beckman, J.S. and Liaudet, L. (2007) Nitric oxide and peroxynitrite in health and disease. Physiological Reviews 87, 315-424 (Pubitemid 46217686)
4. Gutteridge, J.M. and Halliwell, B. (2000) Free radicals and antioxidants in the year 2000. A historical look to the future. Annals of the New York Academy of Science 899, 136-147 (Pubitemid 30352782)
5. Goodall, E.F. and Morrison, K.E. (2006) Amyotrophic lateral sclerosis (motor neuron disease): proposed mechanisms and pathways to treatment. Expert Reviews in Molecular Medicine 8, 1-22 (Pubitemid 43904876)
6. Halliwell, B. (2006) Oxidative stress and neurodegeneration: where are we now? Journal of Neurochemistry 97, 1634-1658
7. Lin, M.T. and Beal, M.F. (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787-795 (Pubitemid 44622683)
8. Browne, S.E. and Beal, M.F. (2006) Oxidative damage in Huntington's disease pathogenesis. Antioxidants and Redox Signalling 8, 2061-2073 (Pubitemid 46489631)
9. Moi, P., Chan, K., Asunis, I. et al. (1994) Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proceedings of the National Academy of Sciences of the United States of America 91, 9926-9930 (Pubitemid 24311921)
10. Itoh, K., Igarashi, K., Hayashi, N. et al. (1995) Cloning and characterization of a novel erythroid cell-derived CNC familytranscription factor heterodimerizing with the small Maf family proteins. Molecular and Cellular Biology 15, 4184-4193
11. Rushmore, T.H. and Pickett, C.B. (1990) Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. Journal of Biological Chemistry 265, 14648-14653
12. Andrews, N.C., Erdjument-Bromage, H., Davidson, M.B. et al. (1993) Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein Nature. 362, 722-728 (Pubitemid 23125974)
13. Ney, P.A., Sorrentino, B.P., Lowrey, C.H. and Nienhuis, A.W. (1990) Inducibility of the HS II enhancer depends on binding of an erythroid specific nuclear protein. Nucleic Acids Research 18, 6011-6017
14. Strauss, E.C. and Orkin, S.H. (1992) In vivo protein- DNA interactions at hypersensitive site 3 of the human beta-globin locus control region. Proceedings of the National Academy of Sciences of the United States of America 89, 5809-5813
15. Itoh, K., Chiba, T., Takahashi, S. et al. (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochemical and Biophysical Research Communications 236, 313-322 (Pubitemid 27373291)
16. Motohashi, H., O'Connor, T., Katsuoka, F. et al. (2002) Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors. Gene 294, 1-12 (Pubitemid 35291008)
17. Itoh, K., Wakabayashi, N., Katoh, Y. et al. (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes and Development 13, 76-86 (Pubitemid 29045117)
18. Wakabayashi, N., Itoh, K., Wakabayashi, J. et al. (2003) Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nature Genetics 35, 238-245 (Pubitemid 37363177)
19. Stewart, D., Killeen, E., Naquin, R. et al. (2003) Degradation of transcription factor Nrf2 via the ubiquitin-proteasome pathway and stabilization by cadmium. Journal of Biological Chemistry 278, 2396-2402 (Pubitemid 36801313)
20. Alam, J., Killeen, E., Gong, P. et al. (2003) Heme activates the heme oxygenase-1 gene in renal epithelial cells by stabilizing Nrf2. American Journal of Physiology Renal Physiology 284, F743-F752 (Pubitemid 36336981)
21. McMahon, M., Thomas, N., Itoh, K. et al. (2004) Redox-regulated turnover of Nrf2 is determined by at least two separate protein domains, the redox-sensitive Neh2 degron and the redox-insensitive Neh6 degron. Journal of Biological Chemistry 279, 31556-31567 (Pubitemid 39037824)
22. Cullinan, S.B., Gordan, J.D., Jin, J. et al. (2004) The Keap1-BTB protein is an adaptor that bridges Nrf2 to a Cul3-based E3 ligase: oxidative stress sensing by a Cul3-Keap1 ligase. Molecular and Cellular Biology 24, 8477-8486 (Pubitemid 39245070)
23. Kobayashi, A., Kang, M.I., Okawa, H. et al. (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Molecular and Cellular Biology 24, 7130-7139 (Pubitemid 39014439)
24. McMahon, M., Thomas, N., Itoh, K. et al. (2006) Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a "tethering" mechanism: a two-site interaction model for the Nrf2-Keap1 complex. Journal of Biological Chemistry 281, 24756-24768 (Pubitemid 44274250)
25. Dinkova-Kostova, A.T., Holtzclaw, W.D., Cole, R.N. et al. (2002) Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proceedings of the National Academy of Sciences of the United States of America 99, 11908-11913 (Pubitemid 34994497)
26. Zhang, D.D. and Hannink, M. (2003) Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Molecular and Cellular Biology 23, 8137-8151 (Pubitemid 37377505)
27. Levonen, A.L., Landar, A., Ramachandran, A. et al. (2004) Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products. The Biochemical Journal 378, 373-382 (Pubitemid 38367228)
28. Wakabayashi, N., Dinkova-Kostova, A.T., Holtzclaw, W.D. et al. (2004) Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Proceedings of the National Academy of Sciences of the United States of America 101, 2040-2045 (Pubitemid 38229011)
29. Yamamoto, T., Suzuki,T., Kobayashi, A. et al. (2008) Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Molecular and Cellular Biology 28, 2758-2770 (Pubitemid 351542373)
30. Kobayashi, M. and Yamamoto, M. (2006) Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Advances in Enzyme Regulation 46, 113-140 (Pubitemid 44301353)
31. Sun, Z., Zhang, S., Chan, J.Y. and Zhang, D.D. (2007) Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2. Molecular and Cellular Biology 27, 6334-6349 (Pubitemid 47435741)
32. Nguyen, T., Sherratt, P.J., Nioi, P. et al. (2005) Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. Journal of Biological Chemistry 280, 32485-32492 (Pubitemid 41361861)
33. Velichkova, M. and Hasson, T. (2005) Keap1 regulates the oxidation-sensitive shuttling of Nrf2 into and out of the nucleus via a Crm1-dependent nuclear export mechanism. Molecular and Cellular Biology 25, 4501-4513 (Pubitemid 40705756)
34. Watai, Y., Kobayashi, A., Nagase, H. et al. (2007) Subcellular localization and cytoplasmic complex status of endogenous Keap1. Genes to Cells 12, 1163-1178 (Pubitemid 47500530)
35. Braun, S., Hanselmann, C., Gassmann, M.G. et al. (2002) Nrf2 transcription factor, a novel target of keratinocyte growth factor action which regulates gene expression and inflammation in the healing skin wound. Molecular and Cellular Biology 22, 5492-5505
36. Vargas, M.R., Pehar, M., Cassina, P. et al. (2005) Fibroblast growth factor-1 induces heme oxygenase-1 via nuclear factor erythroid 2-related factor 2 (Nrf2) in spinal cord astrocytes: consequences for motor neuron survival. Journal of Biological Chemistry 280, 25571-25579 (Pubitemid 40962264)
37. Lee, J.M., Li, J., Johnson, D.A. et al. (2005) Nrf2, a multi-organ protector? The FASEB Journal 19, 1061-1066 (Pubitemid 40946431)
38. Tenhunen, R., Marver, H.S. and Schmid, R. (1968) The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proceedings of the National Academy of Sciences of the United States of America 61, 748-755
39. Maines, M.D. (1988) Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. The FASEB Journal 2, 2557-2568
40. Shibahara, S., Müller, R., Taguchi, H. and Yoshida, T. (1985) Cloning and expression of cDNA for rat heme oxygenase. Proceedings of the National Academy of Sciences of the United States of America 82, 7865-7869 (Pubitemid 16169457)
41. Maines, M.D., Trakshel, G.M. and Kutty, R.K. (1986) Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible. Journal of Biological Chemistry 261, 411-419 (Pubitemid 16103962)
42. Barañano, D.E. and Snyder, S.H. (2001) Neural roles for heme oxygenase: contrasts to nitric oxide synthase. Proceedings of the National Academy of Sciences of the United States of America 98, 10996-11002 (Pubitemid 32928673)
43. Poss, K.D. and Tonegawa, S. (1997) Reduced stress defense in heme oxygenase 1-deficient cells. Proceedings of the National Academy of Sciences of the United States of America 94, 10925-10930 (Pubitemid 27430837)
44. Yachie, A., Niida,Y.,Wada, T. et al. (1999) Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. Journal of Clinical Investigation 103, 129-135 (Pubitemid 29031171)
45. Chen, K., Gunter, K. and Maines, M.D. (2000) Neurons overexpressing heme oxygenase-1 resist oxidative stress-mediated cell death. Journal of Neurochemistry 75, 304-313 (Pubitemid 30418197)
46. Dwyer, B.E., Nishimura, R.N., De Vellis, J. and Yoshida, T. (1992) Heme oxygenase is a heat shock protein and PEST protein in rat astroglial cells. Glia 5, 300-305
47. Dwyer, B.E., Nishimura, R.N. and Lu, S.Y. (1995) Differential expression of heme oxygenase-1 in cultured cortical neurons and astrocytes determined by the aid of a new heme oxygenase antibody. Response to oxidative stress. Brain Research Molecular Brain Research 30, 37-47
48. Kitamura, Y., Furukawa, M., Matsuoka, Y. et al. (1998) In vitro and in vivo induction of heme oxygenase-1 in rat glial cells: possible involvement of nitric oxide production from inducible nitric oxide synthase. Glia 22, 138-148 (Pubitemid 28084386)
49. Schipper, H.M., Bernier, L., Mehindate, K. and Frankel, D. (1999) Mitochondrial iron sequestration in dopamine-challenged astroglia: role of heme oxygenase-1 and the permeability transition pore. Journal of Neurochemistry 72, 1802-1811 (Pubitemid 29185982)
50. Regan, R.F., Guo, Y. and Kumar, N. (2000) Heme oxygenase-1 induction protects murine cortical astrocytes from hemoglobin toxicity. Neuroscience Letters 282, 1-4 (Pubitemid 30129154)
51. Mehindate, K., Sahlas, D.J., Frankel, D. et al. (2001) Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis. Journal of Neurochemistry 77, 1386-1395 (Pubitemid 32523691)
52. Fauconneau, B., Petegnief, V., Sanfeliu, C. et al. (2002) Induction of heat shock proteins (HSPs) by sodium arsenite in cultured astrocytes and reduction of hydrogen peroxide-induced cell death. Journal of Neurochemistry 83, 1338-1348 (Pubitemid 35477473)
53. Stocker, R., Yamamoto, Y., McDonagh, A.F. et al. (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235, 1043-1046 (Pubitemid 17049750)
54. Doré, S. and Snyder, S.H. (1999) Neuroprotective action of bilirubin against oxidative stress in primary hippocampal cultures. Annals of the New York Academy of Science 890, 167-172 (Pubitemid 30040374)
55. Ferris, C.D., Jaffrey, S.R., Sawa, A. et al. (1999) Haem oxygenase-1 prevents cell death by regulating cellular iron. Nature Cell Biology 1, 152-157 (Pubitemid 129656019)
56. Song, W., Su, H., Song, S., Paudel, H.K. and Schipper, H.M. (2006) Over-expression of heme oxygenase-1 promotes oxidative mitochondrial damage in rat astroglia. Journal of Cellular Physiology 206, 655-663 (Pubitemid 43191040)
57. Schipper, H.M. (2004) Brain iron deposition and the free radical-mitochondrial theory of ageing. Ageing Research Reviews 3, 265-301
58. Takeda, A., Itoyama, Y., Kimpara, T. et al. (2004) Heme catabolism and heme oxygenase in neurodegenerative disease. Antioxidants and Redox Signalling 6, 888-894 (Pubitemid 39237942)
59. Schipper, H.M. (2004) Heme oxygenase expression in human central nervous system disorders. Free Radical Biology and Medicine 37, 1995-2011
60. van Horssen, J., Schreibelt, G., Drexhage, J. et al. (2008) Severe oxidative damage in multiple sclerosis lesions coincides with enhanced antioxidant enzyme expression. Free Radical Biology and Medicine 45, 1729-1737
61. Ferrante, R.J., Shinobu, L.A., Schulz, J.B. et al. (1997) Increased 3-nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation. Annals of Neurology 42, 326-334 (Pubitemid 27391116)
62. Cuadrado, A. and Rojo, A.I. (2008) Heme oxygenase-1 as a therapeutic target in neurodegenerative diseases and brain infections. Current Pharmaceutical Design 14, 429-442 (Pubitemid 351516848)
63. Ho, Y.S., Magnenat, J.L., Bronson, R.T. et al. (1997) Mice deficient in cellular glutathione peroxidase develop normally and show no increased sensitivity to hyperoxia. Journal of Biological Chemistry 272, 16644-16651 (Pubitemid 27276497)
64. Ho, Y.S., Xiong, Y., Ma, W., Spector, A. and Ho, D.S. (2004) Mice lacking catalase develop normally but show differential sensitivity to oxidant tissue injury. Journal of Biological Chemistry 279, 32804-32812 (Pubitemid 39014740)
65. Lash, L.H. (2006) Mitochondrial glutathione transport: physiological, pathological and toxicological implications. Chemico-Biological Interactions 163, 54-67
66. Dringen, R., Pawlowski, P.G. and Hirrlinger, J. (2005) Peroxide detoxification by brain cells. Journal of Neuroscience Research 79, 157-165 (Pubitemid 40116430)
67. Hayes, J.D., Flanagan, J.U. and Jowsey, I.R. (2005) Glutathione transferases. Annual Review of Pharmacology and Toxicology 45, 51-88 (Pubitemid 40261798)
68. Cole, S.P. and Deeley, R.G. (2006) Transport of glutathione and glutathione conjugates by MRP1. Trends in Pharmacological Sciences 27, 438-446 (Pubitemid 44051570)
69. Meister, A. (1988) Glutathione metabolism and its selective modification. Journal of Biological Chemistry 263, 17205-17208
70. Moinova, H.R. and Mulcahy, R.T. (1999) Up-regulation of the human gamma-glutamylcysteine synthetase regulatory subunit gene involves binding of Nrf-2 to an electrophile responsive element. Biochemical and Biophysical Research Communications 261, 661-668 (Pubitemid 29408115)
71. Wild, A.C., Moinova, H.R. and Mulcahy, R.T. (1999) Regulation of gamma-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2. Journal of Biological Chemistry 274, 33627-33636 (Pubitemid 129511675)
72. Chan, J.Y. and Kwong, M. (2000) Impaired expression of glutathione synthetic enzyme genes in mice with targeted deletion of the Nrf2 basic-leucine zipper protein. Biochimica et Biophysica Acta 1517, 19-26
73. Harvey, C.J., Thimmulappa, R.K., Singh, A. et al. (2009) Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress. Free Radical Biology and Medicine 46, 443-453
74. Chanas, S.A., Jiang, Q., McMahon, M. et al. (2002) Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice. The Biochemical Journal 365, 405-416 (Pubitemid 36135312)
75. Hayashi, A., Suzuki, H., Itoh, K., Yamamoto, M. and Sugiyama, Y. (2003) Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts. Biochemical and Biophysical Research Communications 310, 824-829 (Pubitemid 37188696)
76. Sasaki, H., Sato, H., Kuriyama-Matsumura, K. et al. (2002) Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression. Journal of Biological Chemistry 277, 44765-44771 (Pubitemid 36159069)
77. Shih, A.Y., Erb, H., Sun, X. et al. (2006) Cystine/ glutamate exchange modulates glutathione supply for neuroprotection from oxidative stress and cell proliferation. Journal of Neuroscience 26, 10514-10523 (Pubitemid 44564602)
78. Yoh, K., Itoh, K., Enomoto, A. et al. (2001) Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney International 60, 1343-1353 (Pubitemid 32960028)
79. Li, J., Stein, T.D. and Johnson, J.A. (2004) Genetic dissection of systemic autoimmune disease in Nrf2-deficient mice. Physiological Genomics 18, 261-272 (Pubitemid 39319509)
80. Thimmulappa, R.K., Lee, H., Rangasamy, T. et al. (2006) Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. Journal of Clinical Investigation 116, 984-995
81. Hirayama, A., Yoh, K., Nagase, S. et al. (2003) EPR imaging of reducing activity in Nrf2 transcriptional factor-deficient mice. Free Radical Biology and Medicine 34, 1236-1242 (Pubitemid 36513966)
82. Kensler, T.W., Wakabayashi, N. and Biswal, S. (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annual Review of Pharmacology and Toxicology 47, 89-116
83. Suh, J.H., Shenvi, S.V., Dixon, B.M. et al. (2004) Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proceedings of the National Academy of Sciences of the United States of America 101, 3381-3386 (Pubitemid 38338203)
84. Kotlo, K.U.,Yehiely, F.,Efimova, E. et al. (2003) Nrf2 is an inhibitor of the Fas pathway as identified by Achilles' Heel Method, a new function-based approach to gene identification in human cells. Oncogene 22, 797-806 (Pubitemid 36255814)
85. Morito, N., Yoh, K., Itoh, K. et al. (2003) Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels. Oncogene 22, 9275-9281 (Pubitemid 38122039)
86. Raoul, C., Estévez, A.G., Nishimune, H. et al. (2002) Motoneuron death triggered by a specific pathway downstream of Fas. potentiation by ALS-linked SOD1 mutations. Neuron 35, 1067-1083 (Pubitemid 35279535)
87. Pehar, M., Cassina, P., Vargas, M.R. et al. (2004) Astrocytic production of nerve growth factor in motor neuron apoptosis: implications for amyotrophic lateral sclerosis. Journal of Neurochemistry 89, 464-473 (Pubitemid 38495994)
88. Pehar, M., Vargas, M.R., Robinson, K.M. et al. (2007) Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis. Journal of Neuroscience 27, 7777-7785 (Pubitemid 47093805)
89. Bronstein, D.M., Perez-Otano, I., Sun,V. et al. (1995) Glia-dependent neurotoxicity and neuroprotection in mesencephalic cultures. Brain Research 704, 112-116
90. Desagher, S., Glowinski, J. and Premont, J. (1996) Astrocytes protect neurons from hydrogen peroxide toxicity. Journal of Neuroscience 16, 2553-2562 (Pubitemid 26122677)
91. Tanaka, J., Toku, K., Zhang, B. et al. (1999) Astrocytes prevent neuronal death induced by reactive oxygen and nitrogen species. Glia 28, 85-96 (Pubitemid 29530608)
92. Drukarch, B., Schepens, E., Jongenelen, C.A. et al. (1997) Astrocyte-mediated enhancement of neuronal survival is abolished by glutathione deficiency. Brain Research 770, 123-130 (Pubitemid 27468059)
93. Gegg, M.E., Clark, J.B. and Heales, S.J. (2005) Co-culture of neurones with glutathione deficient astrocytes leads to increased neuronal susceptibility to nitric oxide and increased glutamate-cysteine ligase activity. Brain Research 1036, 1-6 (Pubitemid 40255838)
94. Sagara, J., Miura, K. and Bannai, S. (1993) Cystine uptake and glutathione level in fetal brain cells in primary culture and in suspension. Journal of Neurochemistry 61, 1667-1671 (Pubitemid 23317187)
95. Sagara, J., Makino, N. and Bannai, S. (1996) Glutathione efflux from cultured astrocytes. Journal of Neurochemistry 66, 1876-1881 (Pubitemid 26118775)
96. Dringen, R. (2000) Metabolism and functions of glutathione in brain. Progress in Neurobiology 62, 649-671
97. Sun, X., Shih, A.Y., Johannssen, H.C. et al. (2006) Two-photon imaging of glutathione levels in intact brain indicates enhanced redox buffering in developing neurons and cells at the cerebrospinal fluid and blood-brain interface. Journal of Biological Chemistry 281, 17420-17431
98. Lee, J.M., Calkins, M.J., Chan, K. et al. (2003) Identification of the NF-E2-related factor-2- dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. Journal of Biological Chemistry 278, 12029-12038 (Pubitemid 36800179)
99. Shih, A.Y., Johnson, D.A., Wong, G., Kraft, A.D., Jiang, L., Erb, H., Johnson, J.A. and Murphy, T.H. (2003) Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. Journal of Neuroscience 23, 3394-3406 (Pubitemid 36531981)
100. Kraft, A.D., Johnson, D.A., Johnson, J.A. (2004) Nuclear factor E2-related factor 2-dependent antioxidant response element activation by tert-butylhydroquinone and sulforaphane occurring preferentially in astrocytes conditions neurons against oxidative insult. Journal of Neuroscience 24, 1101-1112 (Pubitemid 38177017)
101. Vargas, M.R., Pehar, M., Cassina, P. et al. (2006) Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75NTR-dependent motor neuron apoptosis. Journal of Neurochemistry 97, 687-696
102. Drukarch, B., Schepens, E., Stoof, J.C. et al. (1998) Astrocyte-enhanced neuronal survival is mediated by scavenging of extracellular reactive oxygen species. Free Radical Biology and Medicine 25, 217-220 (Pubitemid 28293157)
103. Guo, N. and Shaw, C. (1992) Characterization and localization of glutathione binding sites on cultured astrocytes. Brain Research Molecular Brain Research 15, 207-215
104. Janáky, R., Ogita, K., Pasqualotto, B.A. et al. (1999) Glutathione and signal transduction in the mammalian CNS. Journal of Neurochemistry 73, 889-902 (Pubitemid 29395445)
105. Hermann, A., Varga, V., Oja, S.S. et al. (2002) Involvement of amino-acid side chains of membrane proteins in the binding of glutathione to pig cerebral cortical membranes. Neurochemical Research 27, 389-394 (Pubitemid 34579345)
106. Bolaños, J.P., Heales, S.J., Peuchen, S. et al. (1996) Nitric oxide-mediated mitochondrial damage: a potential neuroprotective role for glutathione. Free Radical Biology and Medicine 21, 995-1001 (Pubitemid 26365953)
107. Dringen, R., Pfeiffer, B. and Hamprecht, B. (1999) Synthesis of the antioxidant glutathione in neurons: supply by astrocytes of CysGly as precursor for neuronal glutathione. Journal of Neuroscience 19, 562-569 (Pubitemid 29036007)
108. Meister, A. (1995) Glutathione metabolism. Methods in Enzymology 251, 3-7
109. Hirrlinger, J., Konig, J., Keppler, D. et al. (2001) The multidrug resistance protein MRP1 mediates the release of glutathione disulfide from rat astrocytes during oxidative stress. Journal of Neurochemistry 76, 627-636 (Pubitemid 32097039)
110. Hirrlinger, J. and Dringen, R. (2005) Multidrug resistance protein 1-mediated export of glutathione and glutathione disulfide from brain astrocytes. Methods in Enzymology 400, 395-409 (Pubitemid 43052433)
111. Minich, T., Riemer, J., Schulz, J.B. et al. (2006) The multidrug resistance protein 1 (Mrp1), but not Mrp5, mediates export of glutathione and glutathione disulfide frombrain astrocytes. Journal of Neurochemistry 97, 373-384
112. Dringen, R., Kranich, O. and Hamprecht, B. (1997) The gamma-glutamyl transpeptidase inhibitor acivicin preserves glutathione released by astroglial cells in culture. Neurochemical Research 22, 727-733 (Pubitemid 27242249)
113. Dringen, R., Gutterer, J.M., Gros, C. and Hirrlinger, J. (2001) Aminopeptidase N mediates the utilization of the GSH precursor CysGly by cultured neurons. Journal of Neuroscience Research 66, 1003-1008
114. Vargas, M.R., Johnson, D.A., Sirkis, D.W. et al. (2008) Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. Journal of Neuroscience 28, 13574-13581
115. Ischiropoulos, H. and Beckman, J.S. (2003) Oxidative stress and nitration in neurodegeneration: cause, effect, or association? Journal of Clinical Investigation 111, 163-169 (Pubitemid 36105911)
116. Nunomura, A., Moreira, P.I., Lee, H.G. et al. (2007) Neuronal death and survival under oxidative stress in Alzheimer and Parkinson diseases. CNS and Neurological Disorders Drug Targets 6, 411-423 (Pubitemid 351486255)
117. van Muiswinkel, F.L. and Kuiperij, H.B. (2005) The Nrf2-ARE Signalling pathway: promising drug target to combat oxidative stress in neurodegenerative disorders. Current Drug TargetsCNSand Neurological Disorders 4, 267-281 (Pubitemid 40754162)
118. Calkins, M.J., Johnson, D.A., Townsend, J.A. et al. (2009) The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxidants and Redox Signalling 11, 497-508
119. de Vries, H.E., Witte, M., Hondius, D. et al. (2008) Nrf2-induced antioxidant protection: a promising target to counteract ROS-mediated damage in neurodegenerative disease? Free Radical Biology and Medicine 45, 1375-1383
120. Johnson, J.A., Johnson, D.A., Kraft, A.D. et al. (2008) The Nrf2-ARE pathway: an indicator and modulator of oxidative stress in neurodegeneration. Annals of the New York Academy of Science 1147, 61-69
121. Rowland, L.P. and Shneider, N.A. (2001) Amyotrophic lateral sclerosis. New England Journal of Medicine 344, 1688-1700 (Pubitemid 32479968)
122. Rosen, D.R., Siddique, T., Patterson, D. et al. (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59-62 (Pubitemid 23087289)
123. Gurney, M.E., Pu, H., Chiu, A.Y. et al. (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772-1775 (Pubitemid 24227760)
124. Howland, D.S., Liu, J., She, Y. et al. (2002) Focal loss of the glutamate transporterEAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proceedings of the National Academy of Sciences of the United States of America 99, 1604-1609 (Pubitemid 34136539)
125. Beckman, J.S., Estévez, A.G., Crow, J.P. and Barbeito, L. (2001) Superoxide dismutase and the death of motoneurons in ALS. Trends in Neurosciences 24, S15-S20
126. Cleveland, D.W. and Rothstein, J.D. (2001) From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nature Reviews Neuroscience 2, 806-819 (Pubitemid 33674062)
127. Bruijn, L.I., Miller, T.M. and Cleveland, D.W. (2004) Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annual Review of Neuroscience 27, 723-479
128. Manfredi, G. and Xu, Z. (2005) Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion 5, 77-87 (Pubitemid 40485768)
129. Boillée, S., Yamanaka, K., Lobsiger, C.S. et al. (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389-1392 (Pubitemid 43839552)
130. Beers, D.R., Henkel, J.S., Xiao, Q. et al. (2003) Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proceedings of the National Academy of Sciences of the United States of America 103, 16021-16026
131. Yamanaka, K., Chun, S.J., Boillee, S. et al. (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nature Neuroscience 11, 251-253 (Pubitemid 351311795)
132. Estévez, A.G., Spear, N., Manuel, S.M. et al. (1998) Nitric oxide and superoxide contribute to motor neuron apoptosis induced by trophic factor deprivation. Journal of Neuroscience 18, 923-931 (Pubitemid 28112915)
133. Barbeito, L.H., Pehar, M., Cassina, P. et al. (2004) A role for astrocytes in motor neuron loss in amyotrophic lateral sclerosis. Brain Research Brain Research Reviews 47, 263-274 (Pubitemid 39574324)
134. Sarlette, A., Krampfl, K., Grothe, C. et al. (2008) Nuclear erythroid 2-related factor 2-antioxidative response element signaling pathway in motor cortex and spinal cord in amyotrophic lateral sclerosis. Journal of Neuropathology and Experimental Neurology 67, 1055-1062
135. Ferraiuolo, L., Heath, P.R., Holden, H. et al. (2007) Microarray analysis of the cellular pathways involved in the adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of familial ALS. Journal of Neuroscience 27, 9201-9219 (Pubitemid 47312070)
136. Kraft, A.D., Resch, J.M., Johnson, D.A. and Johnson, J.A. (2007) Activation of the Nrf2-ARE pathway in muscle and spinal cord during ALS-like pathology in mice expressing mutant SOD1. Experimental Neurology 207, 107-117 (Pubitemid 47332487)
137. Gong, Y.H., Parsadanian, A.S., Andreeva, A. et al. (2000) Restricted expression of G86R Cu/Zn superoxide dismutase in astrocytes results in astrocytosis but does not cause motoneuron degeneration. Journal of Neuroscience 20, 660-665 (Pubitemid 30225568)
138. Nagai, M., Re, D.B., Nagata, T. et al. (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nature Neuroscience 10, 615-622 (Pubitemid 46652435)
139. Thomas, B. and Beal, M.F. (2007) Parkinson's disease. Human Molecular Genetics 16, R183-R194
140. Alam, Z.I., Daniel, S.E., Lees, A.J. et al. (1997) A generalised increase in protein carbonyls in the brain in Parkinson's but not incidental Lewy body disease. Journal of Neurochemistry 69, 1326-1329 (Pubitemid 27364859)
141. Alam, Z.I., Jenner, A., Daniel, S.E. et al. (1997) Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. Journal of Neurochemistry 69, 1196-1203 (Pubitemid 27364841)
142. Dexter, D.T., Holley, A.E., Flitter, W.D. et al. (1994) Increased levels of lipid hydroperoxides in the parkinsonian substantia nigra: an HPLC and ESR study. Movement Disorders 9, 92-97 (Pubitemid 24022621)
143. Valente, E.M., Abou-Sleiman, P.M., Caputo,V. et al. (2004) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158-1160 (Pubitemid 38661852)
144. Clements, C.M., McNally, R.S., Conti, B.J. et al. (2006) DJ-1, a cancer- and Parkinson's disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proceedings of the National Academy of Sciences of the United States of America 103, 15091-15096 (Pubitemid 44583169)
145. van Muiswinkel, F.L., de Vos, RA., Bol, J.G. et al. (2004) Expression of NAD(P)H:quinone oxidoreductase in the normal and Parkinsonian substantia nigra. Neurobiology of Aging 25, 1253-1262 (Pubitemid 39094028)
146. Schipper, H.M. (2004) Heme oxygenase expression in human central nervous system disorders. Free Radical Biology and Medicine 37, 1995-2011
147. Ramsey, C.P., Glass, C.A., Montgomery, M.B. et al. (2007) Expression of Nrf2 in neurodegenerative diseases. Journal of Neuropathology and Experimental Neurology 66, 75-85 (Pubitemid 46066791)
148. Yamamoto, N., Sawada, H., Izumi, Y. et al. (2007) Proteasome inhibition induces glutathione synthesis and protects cells from oxidative stress: relevance to Parkinson disease. Journal of Biological Chemistry 282, 4364-4372 (Pubitemid 47101000)
149. Jakel, R.J., Townsend, J.A., Kraft, A.D. and Johnson, J.A. (2007) Nrf2-mediated protection against 6-hydroxydopamine. Brain Research 1144, 192-201 (Pubitemid 46440842)
150. Wruck, C.J, Claussen, M., Fuhrmann, G. et al. (2007) Luteolin protects rat PC12 and C6 cells against MPP+ induced toxicity via an ERK dependent Keap1-Nrf2-ARE pathway. Journal of Neural Transmission Suppl 72, 57-67
151. Burton, N.C., Kensler, T.W. and Guilarte, T.R. (2006) In vivo modulation of the Parkinsonian phenotype by Nrf2. Neurotoxicology 27, 1094-1100 (Pubitemid 44838961)
152. Chen, P.C., Vargas, M.R., Pani, A.K. et al. (2009) Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson's disease: a critical role for the astrocyte. Proceedings of the National Academy of Sciences of the United States of America 106, 2933-2938
153. Bertram, L. and Tanzi, R.E. (2008) Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nature Reviews Neuroscience 9, 768-778
154. Marshak, D.R., Pesce, S.A., Stanley, L.C. and Griffin, W.S. (1992) Increased S100 beta neurotrophic activity in Alzheimer's disease temporal lobe. Neurobiology of Aging 13, 1-7
155. Smith, M.A., Harris, P.L., Sayre, L.M. and Perry, G. (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proceedings of the National Academy of Sciences of the United States of America 94, 9866-9868 (Pubitemid 27408156)
156. Schipper, H.M., Bennett, D.A., Liberman, A. et al. (2006) Glial heme oxygenase-1 expression in Alzheimer disease and mild cognitive impairment. Neurobiology of Aging 27, 252-261 (Pubitemid 43038549)
157. Wang, X., Su, B., Perry, G. et al. (2007) Insights into amyloid-beta-induced mitochondrial dysfunction in Alzheimer disease. Free Radical Biology and Medicine 43, 1569-1573 (Pubitemid 350122990)
158. Shaftel, S.S., Griffin, W.S. and O'Banion, M.K. (2008) The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. Journal of Neuroinflammation 5, 7
159. Raina, A.K., Templeton, D.J., Deak, J.C. et al. (1999) Quinone reductase (NQO1), a sensitive redox indicator, is increased in Alzheimer's disease. Redox Reports 4, 23-27 (Pubitemid 29296777)
160. Wang, Y., Santa-Cruz, K., DeCarli, C. and Johnson, J.A. (2000) NAD(P)H:quinone oxidoreductase activity is increased in hippocampal pyramidal neurons of patients with Alzheimer's disease. Neurobiology of Aging 21, 525-531 (Pubitemid 30621490)
161. SantaCruz, K.S., Yazlovitskaya, E., Collins, J. et al. (2004) Regional NAD(P)H:quinone oxidoreductase activity in Alzheimer's disease. Neurobiology of Aging 25, 63-69 (Pubitemid 37522194)
162. Kanninen, K., Malm, T.M., Jyrkkänen, H.K. et al. (2008) Nuclear factor erythroid 2-related factor 2 protects against beta amyloid. Molecular and Cellular Neurosciences 39, 302-313
163. Resende, R., Moreira, P.I., Proença, T. et al. (2008) Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease. Free Radical Biology and Medicine 44, 2051-2057
164. Wruck, C.J., Götz, M.E., Herdegen, T. et al. (2008) Kavalactones protect neural cells against amyloid beta peptide-induced neurotoxicity via extracellular signal-regulated kinase 1/2-dependent nuclear factor erythroid 2-related factor 2 activation. Molecular Pharmacology 73, 1785-1795 (Pubitemid 351724366)
165. Brennan,W.A. Jr., Bird, E.D. and Aprille, J.R. (1985) Regional mitochondrial respiratory activity in Huntington's disease brain. Journal of Neurochemistry 44, 1948-1950 (Pubitemid 15047284)
166. Gu, M., Gash, M.T., Mann, V.M. et al. (1996) Mitochondrial defect in Huntington's disease caudate nucleus. Annals of Neurology 39, 385-389 (Pubitemid 26100764)
167. Tabrizi, S.J., Workman, J., Hart, P.E. et al. (2000) Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse. Annals of Neurology 47, 80-86 (Pubitemid 30033653)
168. Bogdanov, M.B., Andreassen, O.A. et al. (2001) Increased oxidative damage to DNA in a transgenic mouse model of Huntington's disease. Journal of Neurochemistry 79, 1246-1249 (Pubitemid 34019802)
169. Schapira, A.H. (1996) Oxidative stress and mitochondrial dysfunction in neurodegeneration. Current Opinion in Neurology 9, 260-264
170. Brouillet, E., Condé, F., Beal, M.F. and Hantraye, P. (1999) Replicating Huntington's disease phenotype in experimental animals. Progress in Neurobiology 59, 427-468 (Pubitemid 29392967)
171. Shih, A.Y., Imbeault, S., Barakauskas,V. et al. (2005) Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. Journal of Biological Chemistry 280, 22925-22936 (Pubitemid 40853201)
172. Calkins, M.J., Jakel, R.J., Johnson, D.A. et al. (2005) Protection from mitochondrial complex II inhibition in vitro and in vivo by Nrf2-mediated transcription. Proceedings of the National Academy of Sciences of the United States of America 102, 244-249 (Pubitemid 40094460)
173. Shih, A.Y., Li, P. and Murphy, T.H. (2005) A small-molecule-inducible Nrf2-mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo. Journal of Neuroscience 25, 10321-10335 (Pubitemid 41636229)
174. Zhao, J., Kobori, N., Aronowski, J. and Dash, P.K. (2006) Sulforaphane reduces infarct volume following focal cerebral ischemia in rodents. Neuroscience Letters 393, 108-112 (Pubitemid 41821089)
175. Zhao, X., Sun, G., Zhang, J. et al. (2007) Transcription factor Nrf2 protects the brain from damage produced by intracerebral hemorrhage. Stroke 38, 3280-3286 (Pubitemid 350175749)
176. Wang, J., Fields, J., Zhao, C. et al. (2007) Role of Nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radical Biology and Medicine 43, 408-414 (Pubitemid 46977628)
177. Satoh, T., Okamoto, S.I., Cui, J. et al. (2006) Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic [correction of electrophillic] phase II inducers. Proceedings of the National Academy of Sciences of the United States of America 103, 768-773 (Pubitemid 43153100)
178. Satoh, T., Kosaka, K., Itoh, K. et al. (2008) Carnosic acid, a catechol-type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S-alkylation of targeted cysteines on Keap1. Journal of Neurochemistry 104, 1116-1131 (Pubitemid 351143643)
179. Zhao, J., Moore, A.N., Redell, J.B. and Dash, P.K. (2007) Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. Journal of Neuroscience 27, 10240-10248 (Pubitemid 47450456)
180. Zhao, J., Moore, A.N., Clifton, G.L. and Dash, P.K. (2005) Sulforaphane enhances aquaporin-4 expression and decreases cerebral edema following traumatic brain injury. Journal of Neuroscience Research 82, 499-506 (Pubitemid 41579349)
181. Qiang,W., Kuang, X., Liu, J. et al. (2006) Astrocytes survive chronic infection and cytopathic effects of the ts1 mutant of the retrovirus Moloney murine leukemia virus by upregulation of antioxidant defenses. Journal of Virology 80, 3273-3284
182. Jiang, Y., Scofield, V.L., Yan, M. et al. (2006) Retrovirus-induced oxidative stress with neuroimmunodegeneration is suppressed by antioxidant treatment with a refined monosodium alpha-luminol (Galavit). Journal of Virology 80, 4557-4569
183. Min, K.J., Yang, M.S., Kim, S.U. et al. (2006) Astrocytes induce hemeoxygenase-1 expression in microglia: a feasible mechanism for preventing excessive brain inflammation. Journal of Neuroscience 26, 1880-1887
184. Innamorato, N.G., Rojo, A.I., García-Yagüe, A.J. et al. (2008) The transcription factor Nrf2 is a therapeutic target against brain inflammation. Journal of Immunology 181, 680-689