The Nrf2–ARE cytoprotective pathway in astrocytes

Marcelo R. Vargas; Jeffrey A. Johnson

doi:10.1017/S1462399409001094

The Nrf2–ARE cytoprotective pathway in astrocytes

Published online by Cambridge University Press: 03 June 2009

Marcelo R. Vargas and

Jeffrey A. Johnson

Show author details

Marcelo R. Vargas: Affiliation:
Division of Pharmaceutical Sciences, University of Wisconsin, Madison, WI, USA.
Jeffrey A. Johnson*: Affiliation:
Division of Pharmaceutical Sciences, University of Wisconsin, Madison, WI, USA. Waisman Center, Molecular and Environmental Toxicology Center, and Center for Neuroscience, University of Wisconsin, Madison, WI, USA.
*: *Corresponding author: Jeffrey A. Johnson, School of Pharmacy, 6125 Rennebohm Hall, 777 Highland Avenue, University of Wisconsin, Madison, WI 53705, USA. Tel.: +1 608 262 2893; Fax: +1 608 262 5345; E-mail: jajohnson@pharmacy.wisc.edu

Article contents

Abstract
References

Get access

Rights & Permissions

Abstract

The expression of phase-II detoxification and antioxidant enzymes is governed by a cis-acting regulatory element named the antioxidant response element (ARE). ARE-containing genes are regulated by the nuclear factor erythroid-2-related factor 2 (Nrf2), a member of the Cap'n'Collar basic-leucine-zipper family of transcription factors. ARE-regulated genes are preferentially activated in astrocytes, which consequently have more efficient detoxification and antioxidant defences than neurons. Astrocytes closely interact with neurons to provide structural, metabolic and trophic support, as well as actively participating in the modulation of neuronal excitability and neurotransmission. Therefore, functional alterations in astrocytes can shape the interaction with surrounding cells, such as neurons and microglia. Activation of Nrf2 in astrocytes protects neurons from a wide array of insults in different in vitro and in vivo paradigms, confirming the role of astrocytes in determining the vulnerability of neurons to noxious stimuli. Here, we review the current data supporting Nrf2 activation in astrocytes as a viable therapeutic approach, not only in acute neuronal damage, but also in chronic neurodegeneration related to oxidative stress.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 11 , July 2009 , e17

DOI: https://doi.org/10.1017/S1462399409001094 [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1Chance, B., Sies, H. and Boveris, A. (1979) Hydroperoxide metabolism in mammalian organs. Physiological Reviews 59, 527-605CrossRef Google Scholar PubMed

2Palmer, 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, 1251-1256CrossRef Google Scholar PubMed

3Pacher, P., Beckman, J.S. and Liaudet, L. (2007) Nitric oxide and peroxynitrite in health and disease. Physiological Reviews 87, 315-424CrossRef Google Scholar PubMed

4Gutteridge, 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, 136-147Google Scholar PubMed

5Goodall, 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, 1-22CrossRef Google Scholar PubMed

6Halliwell, B. (2006) Oxidative stress and neurodegeneration: where are we now? Journal of Neurochemistry 97, 1634-1658CrossRef Google Scholar PubMed

7Lin, M.T. and Beal, M.F. (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787-795CrossRef Google Scholar PubMed

8Browne, S.E. and Beal, M.F. (2006) Oxidative damage in Huntington's disease pathogenesis. Antioxidants and Redox Signalling 8, 2061-2073CrossRef Google Scholar PubMed

9Moi, 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, 9926-9930CrossRef Google Scholar

10Itoh, 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, 4184-4193CrossRef Google Scholar

11Rushmore, 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, 14648-14653CrossRef Google Scholar PubMed

12Andrews, 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, 722-728CrossRef Google Scholar PubMed

13Ney, 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, 6011-6017CrossRef Google Scholar

14Strauss, 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, 5809-5813CrossRef Google Scholar PubMed

15Itoh, 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, 313-322CrossRef Google Scholar PubMed

16Motohashi, 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, 1-12CrossRef Google Scholar PubMed

17Itoh, 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, 76-86CrossRef Google Scholar

18Wakabayashi, N., Itoh, K., Wakabayashi, J. et al. (2003) Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nature Genetics 35, 238-245CrossRef Google Scholar PubMed

19Stewart, 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, 2396-2402CrossRef Google Scholar PubMed

20Alam, 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-F752CrossRef Google Scholar PubMed

21McMahon, 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, 31556-31567CrossRef Google Scholar PubMed

22Cullinan, 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, 8477-8486CrossRef Google Scholar PubMed

23Kobayashi, 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, 7130-7139CrossRef Google Scholar PubMed

24McMahon, 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, 24756-24768CrossRef Google Scholar PubMed

25Dinkova-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, 11908-11913CrossRef Google Scholar PubMed

26Zhang, 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, 8137-8151CrossRef Google Scholar PubMed

27Levonen, 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, 373-382CrossRef Google Scholar PubMed

28Wakabayashi, 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, 2040-2045CrossRef Google Scholar PubMed

29Yamamoto, 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, 2758-2770CrossRef Google Scholar PubMed

30Kobayashi, M. and Yamamoto, M. (2006) Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Advances in Enzyme Regulation 46, 113-140CrossRef Google Scholar PubMed

31Sun, 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, 6334-6349CrossRef Google Scholar PubMed

32Nguyen, 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, 32485-32492CrossRef Google Scholar PubMed

33Velichkova, 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, 4501-4513CrossRef Google Scholar

34Watai, Y., Kobayashi, A., Nagase, H. et al. (2007) Subcellular localization and cytoplasmic complex status of endogenous Keap1. Genes to Cells 12, 1163-1178CrossRef Google Scholar PubMed

35Braun, 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, 5492-5505CrossRef Google Scholar PubMed

36Vargas, 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, 25571-25579CrossRef Google Scholar PubMed

37Lee, J.M., Li, J., Johnson, D.A. et al. (2005) Nrf2, a multi-organ protector? The FASEB Journal 19, 1061-1066CrossRef Google Scholar PubMed

38Tenhunen, 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, 748-755CrossRef Google Scholar PubMed

39Maines, M.D. (1988) Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. The FASEB Journal 2, 2557-2568CrossRef Google Scholar PubMed

40Shibahara, 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, 7865-7869CrossRef Google Scholar PubMed

41Maines, 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, 411-419CrossRef Google Scholar PubMed

42Barañano, 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, 10996-11002CrossRef Google Scholar PubMed

43Poss, 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, 10925-10930CrossRef Google Scholar PubMed

44Yachie, 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, 129-135CrossRef Google Scholar PubMed

45Chen, K., Gunter, K. and Maines, M.D. (2000) Neurons overexpressing heme oxygenase-1 resist oxidative stress-mediated cell death. Journal of Neurochemistry 75, 304-313CrossRef Google Scholar PubMed

46Dwyer, 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, 300-305CrossRef Google Scholar PubMed

47Dwyer, 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, 37-47CrossRef Google Scholar PubMed

48Kitamura, 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, 138-1483.0.CO;2-3>CrossRef Google Scholar PubMed

49Schipper, 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, 1802-1811CrossRef Google Scholar PubMed

50Regan, R.F., Guo, Y. and Kumar, N. (2000) Heme oxygenase-1 induction protects murine cortical astrocytes from hemoglobin toxicity. Neuroscience Letters 282, 1-4CrossRef Google Scholar PubMed

51Mehindate, 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, 1386-1395CrossRef Google Scholar PubMed

52Fauconneau, 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, 1338-1348CrossRef Google Scholar PubMed

53Stocker, R., Yamamoto, Y., McDonagh, A.F. et al. (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235, 1043-1046CrossRef Google Scholar PubMed

54Doré, 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, 167-172CrossRef Google Scholar PubMed

55Ferris, C.D., Jaffrey, S.R., Sawa, A. et al. (1999) Haem oxygenase-1 prevents cell death by regulating cellular iron. Nature Cell Biology 1, 152-157CrossRef Google Scholar PubMed

56Song, 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, 655-663CrossRef Google Scholar PubMed

57Schipper, H.M. (2004) Brain iron deposition and the free radical-mitochondrial theory of ageing. Ageing Research Reviews 3, 265-301CrossRef Google Scholar PubMed

58Takeda, A., Itoyama, Y., Kimpara, T. et al. (2004) Heme catabolism and heme oxygenase in neurodegenerative disease. Antioxidants and Redox Signalling 6, 888-894CrossRef Google Scholar PubMed

59Schipper, H.M. (2004) Heme oxygenase expression in human central nervous system disorders. Free Radical Biology and Medicine 37, 1995-2011CrossRef Google Scholar PubMed

60van 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, 1729-1737CrossRef Google Scholar PubMed

61Ferrante, 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, 326-334CrossRef Google Scholar PubMed

62Cuadrado, A. and Rojo, A.I. (2008) Heme oxygenase-1 as a therapeutic target in neurodegenerative diseases and brain infections. Current Pharmaceutical Design 14, 429-442CrossRef Google Scholar PubMed

63Ho, 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, 16644-16651CrossRef Google Scholar PubMed

64Ho, 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, 32804-32812CrossRef Google Scholar PubMed

65Lash, L.H. (2006) Mitochondrial glutathione transport: physiological, pathological and toxicological implications. Chemico-Biological Interactions 163, 54-67CrossRef Google Scholar PubMed

66Dringen, R., Pawlowski, P.G. and Hirrlinger, J. (2005) Peroxide detoxification by brain cells. Journal of Neuroscience Research 79, 157-165CrossRef Google Scholar PubMed

67Hayes, J.D., Flanagan, J.U. and Jowsey, I.R. (2005) Glutathione transferases. Annual Review of Pharmacology and Toxicology 45, 51-88CrossRef Google Scholar PubMed

68Cole, S.P. and Deeley, R.G. (2006) Transport of glutathione and glutathione conjugates by MRP1. Trends in Pharmacological Sciences 27, 438-446CrossRef Google Scholar PubMed

69Meister, A. (1988) Glutathione metabolism and its selective modification. Journal of Biological Chemistry 263, 17205-17208CrossRef Google Scholar PubMed

70Moinova, 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, 661-668CrossRef Google Scholar

71Wild, 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, 33627-33636CrossRef Google Scholar PubMed

72Chan, 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, 19-26CrossRef Google Scholar PubMed

73Harvey, 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, 443-453CrossRef Google Scholar PubMed

74Chanas, 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, 405-416CrossRef Google Scholar PubMed

75Hayashi, 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, 824-829CrossRef Google Scholar PubMed

76Sasaki, 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, 44765-44771CrossRef Google Scholar PubMed

77Shih, 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, 10514–10523CrossRef Google Scholar PubMed

78Yoh, K., Itoh, K., Enomoto, A. et al. (2001) Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Kidney International 60, 1343-1353CrossRef Google Scholar PubMed

79Li, J., Stein, T.D. and Johnson, J.A. (2004) Genetic dissection of systemic autoimmune disease in Nrf2-deficient mice. Physiological Genomics 18, 261-272CrossRef Google Scholar PubMed

80Thimmulappa, 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, 984-995CrossRef Google Scholar PubMed

81Hirayama, 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, 1236-1242CrossRef Google Scholar PubMed

82Kensler, 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, 89-116CrossRef Google Scholar PubMed

83Suh, 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, 3381-3386CrossRef Google Scholar PubMed

84Kotlo, 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, 797-806CrossRef Google Scholar

85Morito, N., Yoh, K., Itoh, K. et al. (2003) Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels. Oncogene 22, 9275-9281CrossRef Google Scholar PubMed

86Raoul, 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, 1067-1083CrossRef Google Scholar PubMed

87Pehar, 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, 464-473CrossRef Google Scholar PubMed

88Pehar, 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, 7777-7785CrossRef Google Scholar PubMed

89Bronstein, D.M., Perez-Otano, I., Sun, V. et al. (1995) Glia-dependent neurotoxicity and neuroprotection in mesencephalic cultures. Brain Research 704, 112-116CrossRef Google Scholar PubMed

90Desagher, S., Glowinski, J. and Premont, J. (1996) Astrocytes protect neurons from hydrogen peroxide toxicity. Journal of Neuroscience 16, 2553-2562CrossRef Google Scholar PubMed

91Tanaka, J., Toku, K., Zhang, B. et al. (1999) Astrocytes prevent neuronal death induced by reactive oxygen and nitrogen species. Glia 28, 85-963.0.CO;2-Y>CrossRef Google Scholar PubMed

92Drukarch, B., Schepens, E., Jongenelen, C.A. et al. (1997) Astrocyte-mediated enhancement of neuronal survival is abolished by glutathione deficiency. Brain Research 770, 123-130CrossRef Google Scholar PubMed

93Gegg, 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, 1-6CrossRef Google Scholar PubMed

94Sagara, 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, 1667-1671CrossRef Google Scholar PubMed

95Sagara, J., Makino, N. and Bannai, S. (1996) Glutathione efflux from cultured astrocytes. Journal of Neurochemistry 66, 1876-1881CrossRef Google Scholar PubMed

96Dringen, R. (2000) Metabolism and functions of glutathione in brain. Progress in Neurobiology 62, 649-671CrossRef Google Scholar PubMed

97Sun, 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, 17420-17431CrossRef Google Scholar PubMed

98Lee, 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, 12029-12038CrossRef Google Scholar PubMed

99Shih, 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, 3394-3406CrossRef Google Scholar PubMed

100Kraft, 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, 1101-1112CrossRef Google Scholar PubMed

101Vargas, 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, 687-696CrossRef Google Scholar PubMed

102Drukarch, 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, 217-220CrossRef Google Scholar PubMed

103Guo, N. and Shaw, C. (1992) Characterization and localization of glutathione binding sites on cultured astrocytes. Brain Research Molecular Brain Research 15, 207-215CrossRef Google Scholar PubMed

104Janáky, R., Ogita, K., Pasqualotto, B.A. et al. (1999) Glutathione and signal transduction in the mammalian CNS. Journal of Neurochemistry 73, 889-902CrossRef Google Scholar PubMed

105Hermann, 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, 389-394CrossRef Google Scholar PubMed

106Bolaños, 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, 995-1001CrossRef Google Scholar

107Dringen, 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, 562-569CrossRef Google Scholar PubMed

108Meister, A. (1995) Glutathione metabolism. Methods in Enzymology 251, 3-7CrossRef Google Scholar PubMed

109Hirrlinger, J., König, 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, 627-636CrossRef Google Scholar PubMed

110Hirrlinger, J. and Dringen, R. (2005) Multidrug resistance protein 1-mediated export of glutathione and glutathione disulfide from brain astrocytes. Methods in Enzymology 400, 395-409CrossRef Google Scholar PubMed

111Minich, 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 from brain astrocytes. Journal of Neurochemistry 97, 373-384CrossRef Google Scholar

112Dringen, R., Kranich, O. and Hamprecht, B. (1997) The gamma-glutamyl transpeptidase inhibitor acivicin preserves glutathione released by astroglial cells in culture. Neurochemical Research 22, 727-733CrossRef Google Scholar PubMed

113Dringen, 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, 1003-1008CrossRef Google Scholar PubMed

114Vargas, 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, 13574-13581CrossRef Google Scholar PubMed

115Ischiropoulos, H. and Beckman, J.S. (2003) Oxidative stress and nitration in neurodegeneration: cause, effect, or association? Journal of Clinical Investigation 111, 163-169CrossRef Google Scholar PubMed

116Nunomura, 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, 411-423CrossRef Google Scholar PubMed

117van 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 Targets CNS and Neurological Disorders 4, 267-281CrossRef Google Scholar PubMed

118Calkins, 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, 497-508CrossRef Google Scholar PubMed

119de 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, 1375-1383CrossRef Google Scholar PubMed

120Johnson, 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, 61-69CrossRef Google Scholar PubMed

121Rowland, L.P. and Shneider, N.A. (2001) Amyotrophic lateral sclerosis. New England Journal of Medicine 344, 1688-1700CrossRef Google Scholar PubMed

122Rosen, 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, 59-62CrossRef Google Scholar PubMed

123Gurney, 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, 1772-1775CrossRef Google Scholar PubMed

124Howland, D.S., Liu, J., She, Y. et al. (2002) Focal loss of the glutamate transporter EAAT2 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, 1604-1609CrossRef Google Scholar

125Beckman, 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-S20CrossRef Google Scholar PubMed

126Cleveland, D.W. and Rothstein, J.D. (2001) From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nature Reviews Neuroscience 2, 806-819CrossRef Google Scholar PubMed

127Bruijn, 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, 723-479CrossRef Google Scholar PubMed

128Manfredi, G. and Xu, Z. (2005) Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion 5, 77-87CrossRef Google Scholar PubMed

129Boillée, S., Yamanaka, K., Lobsiger, C.S. et al. (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389-1392CrossRef Google Scholar PubMed

130Beers, 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, 16021-16026CrossRef Google Scholar

131Yamanaka, K., Chun, S.J., Boillee, S. et al. (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nature Neuroscience 11, 251-253CrossRef Google Scholar PubMed

132Estévez, 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, 923-931CrossRef Google Scholar PubMed

133Barbeito, 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, 263-274CrossRef Google Scholar PubMed

134Sarlette, 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, 1055-1062CrossRef Google Scholar PubMed

135Ferraiuolo, 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, 9201-9219CrossRef Google Scholar PubMed

136Kraft, 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, 107-117CrossRef Google Scholar PubMed

137Gong, 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, 660-665CrossRef Google Scholar

138Nagai, 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, 615-622CrossRef Google Scholar PubMed

139Thomas, B. and Beal, M.F. (2007) Parkinson's disease. Human Molecular Genetics 16, R183-R194CrossRef Google Scholar PubMed

140Alam, 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, 1326-1329CrossRef Google Scholar

141Alam, 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, 1196-1203CrossRef Google Scholar

142Dexter, 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, 92-97CrossRef Google Scholar PubMed

143Valente, E.M., Abou-Sleiman, P.M., Caputo, V. et al. (2004) Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158-1160CrossRef Google Scholar PubMed

144Clements, 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, 15091-15096CrossRef Google Scholar PubMed

145van 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, 1253-1262CrossRef Google Scholar PubMed

146Schipper, H.M. (2004) Heme oxygenase expression in human central nervous system disorders. Free Radical Biology and Medicine 37, 1995-2011CrossRef Google Scholar PubMed

147Ramsey, C.P., Glass, C.A., Montgomery, M.B. et al. (2007) Expression of Nrf2 in neurodegenerative diseases. Journal of Neuropathology and Experimental Neurology 66, 75-85CrossRef Google Scholar PubMed

148Yamamoto, 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, 4364-4372CrossRef Google Scholar PubMed

149Jakel, R.J., Townsend, J.A., Kraft, A.D. and Johnson, J.A. (2007) Nrf2-mediated protection against 6-hydroxydopamine. Brain Research 1144, 192-201CrossRef Google Scholar PubMed

150Wruck, 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, 57-67Google Scholar

151Burton, N.C., Kensler, T.W. and Guilarte, T.R. (2006) In vivo modulation of the Parkinsonian phenotype by Nrf2. Neurotoxicology 27, 1094-1100CrossRef Google Scholar PubMed

152Chen, 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, 2933-2938CrossRef Google Scholar PubMed

153Bertram, L. and Tanzi, R.E. (2008) Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nature Reviews Neuroscience 9, 768-778CrossRef Google Scholar PubMed

154Marshak, 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, 1-7CrossRef Google Scholar PubMed

155Smith, 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, 9866-9868CrossRef Google Scholar PubMed

156Schipper, 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, 252-261CrossRef Google Scholar PubMed

157Wang, X., Su, B., Perry, G. et al. (2007) Insights into amyloid-beta-induced mitochondrial dysfunction in Alzheimer disease. Free Radical Biology and Medicine 43, 1569-1573CrossRef Google Scholar PubMed

158Shaftel, 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, 7CrossRef Google Scholar PubMed

159Raina, 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, 23-27CrossRef Google Scholar PubMed

160Wang, 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, 525-531CrossRef Google Scholar

161SantaCruz, K.S., Yazlovitskaya, E., Collins, J. et al. (2004) Regional NAD(P)H:quinone oxidoreductase activity in Alzheimer's disease. Neurobiology of Aging 25, 63-69CrossRef Google Scholar PubMed

162Kanninen, 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, 302-313CrossRef Google Scholar PubMed

163Resende, 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, 2051-2057CrossRef Google Scholar

164Wruck, 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, 1785-1795CrossRef Google Scholar PubMed

165Brennan, W.A. Jr., Bird, E.D. and Aprille, J.R. (1985) Regional mitochondrial respiratory activity in Huntington's disease brain. Journal of Neurochemistry 44, 1948-1950CrossRef Google Scholar PubMed

166Gu, M., Gash, M.T., Mann, V.M. et al. (1996) Mitochondrial defect in Huntington's disease caudate nucleus. Annals of Neurology 39, 385-389CrossRef Google Scholar PubMed

167Tabrizi, 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, 80-863.0.CO;2-K>CrossRef Google Scholar PubMed

168Bogdanov, 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, 1246-1249CrossRef Google Scholar

169Schapira, A.H. (1996) Oxidative stress and mitochondrial dysfunction in neurodegeneration. Current Opinion in Neurology 9, 260-264CrossRef Google Scholar PubMed

170Brouillet, E., Condé, F., Beal, M.F. and Hantraye, P. (1999) Replicating Huntington's disease phenotype in experimental animals. Progress in Neurobiology 59, 427-468CrossRef Google Scholar PubMed

171Shih, 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, 22925-22936CrossRef Google Scholar PubMed

172Calkins, 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, 244-249CrossRef Google Scholar PubMed

173Shih, 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, 10321-10335CrossRef Google Scholar PubMed

174Zhao, J., Kobori, N., Aronowski, J. and Dash, P.K. (2006) Sulforaphane reduces infarct volume following focal cerebral ischemia in rodents. Neuroscience Letters 393, 108-112CrossRef Google Scholar PubMed

175Zhao, X., Sun, G., Zhang, J. et al. (2007) Transcription factor Nrf2 protects the brain from damage produced by intracerebral hemorrhage. Stroke 38, 3280-3286CrossRef Google Scholar PubMed

176Wang, 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, 408-414CrossRef Google Scholar PubMed

177Satoh, 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, 768-773CrossRef Google Scholar PubMed

178Satoh, 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, 1116-1131CrossRef Google Scholar PubMed

179Zhao, 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, 10240-10248CrossRef Google Scholar PubMed

180Zhao, 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, 499-506CrossRef Google Scholar PubMed

181Qiang, 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, 3273-3284CrossRef Google Scholar PubMed

182Jiang, 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, 4557-4569CrossRef Google Scholar PubMed

183Min, 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, 1880-1887CrossRef Google Scholar PubMed

184Innamorato, 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, 680-689CrossRef Google Scholar PubMed

Article contents

The Nrf2–ARE cytoprotective pathway in astrocytes

Abstract

Access options

References

References

Further reading, resources and contacts

This article has been cited by the following publications. This list is generated based on data provided by Crossref.

Article contents

The Nrf2–ARE cytoprotective pathway in astrocytes

Abstract

Access options

References

References

Further reading, resources and contacts

Save article to Kindle

Save article to Dropbox

Save article to Google Drive

Reply to: Submit a response

Your details

You have entered the maximum number of contributors

Conflicting interests