NF-E2-related Factor-2 Mediates Neuroprotection against Mitochondrial Complex I Inhibitors and Increased Concentrations of Intracellular Calcium in Primary Cortical Neurons

NF-E2-related factor-2 (Nrf2) regulates the gene expression of phase II detoxification enzymes and antioxidant proteins through an enhancer sequence referred to as the antioxidant-responsive element (ARE). In this study, we demonstrate that Nrf2 protects neurons in mixed primary neuronal cultures containing both astrocytes (∼10%) and neurons (∼90%) through coordinate up-regulation of ARE-driven genes. Nrf2-/- neurons in this mixed culture system were more sensitive to mitochondrial toxin (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine or rotenone)-induced apoptosis compared with Nrf2+/+ neurons. To understand the underlying mechanism of this observed differential sensitivity, we compared the gene expression profiles using oligonucleotide microarrays. Microarray data showed that Nrf2+/+neuronal cultures had higher expression levels of genes encoding detoxification enzymes, antioxidant proteins, calcium homeostasis proteins, growth factors, neuron-specific proteins, and signaling molecules compared with Nrf2-/- neuronal cultures. As predicted from the microarray data, Nrf2-/- neurons were indeed more vulnerable to the cytotoxic effects of ionomycin- and 2,5-di-(t-butyl)-1,4-hydroquinone-induced increases in intracellular calcium. Finally, adenoviral vector-mediated overexpression of Nrf2 recovered ARE-driven gene expression in Nrf2-/- neuronal cultures and rescued Nrf2-/- neurons from rotenone- or ionomycin-induced cell death. Taken together, these findings suggest that Nrf2 plays an important role in protecting neurons from toxic insult. NF-E2-related factor-2 (Nrf2) regulates the gene expression of phase II detoxification enzymes and antioxidant proteins through an enhancer sequence referred to as the antioxidant-responsive element (ARE). In this study, we demonstrate that Nrf2 protects neurons in mixed primary neuronal cultures containing both astrocytes (∼10%) and neurons (∼90%) through coordinate up-regulation of ARE-driven genes. Nrf2-/- neurons in this mixed culture system were more sensitive to mitochondrial toxin (1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine or rotenone)-induced apoptosis compared with Nrf2+/+ neurons. To understand the underlying mechanism of this observed differential sensitivity, we compared the gene expression profiles using oligonucleotide microarrays. Microarray data showed that Nrf2+/+neuronal cultures had higher expression levels of genes encoding detoxification enzymes, antioxidant proteins, calcium homeostasis proteins, growth factors, neuron-specific proteins, and signaling molecules compared with Nrf2-/- neuronal cultures. As predicted from the microarray data, Nrf2-/- neurons were indeed more vulnerable to the cytotoxic effects of ionomycin- and 2,5-di-(t-butyl)-1,4-hydroquinone-induced increases in intracellular calcium. Finally, adenoviral vector-mediated overexpression of Nrf2 recovered ARE-driven gene expression in Nrf2-/- neuronal cultures and rescued Nrf2-/- neurons from rotenone- or ionomycin-induced cell death. Taken together, these findings suggest that Nrf2 plays an important role in protecting neurons from toxic insult. The antioxidant-responsive element (ARE) 1The abbreviations used are: ARE, antioxidant-responsive element; NQO1, NAD(P)H:quinone oxidoreductase-1; GST, glutathione S-transferase; Nrf2, NF-E2-related factor-2; PD, Parkinson's disease; MPP+, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine; DIV, days in vitro; GFAP, glial fibrillary acidic protein; MAP2, microtubule-associated protein-2; MTS, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling; GCLC, glutamatecysteine ligase catalytic subunit; GCLM, glutamate-cysteine ligase modifier subunit; RT, reverse transcription; Ad, adenovirus; GFP, green fluorescent protein; m.o.i., multiplicity of infection; dtBHQ, 2,5-di-(t-butyl)-1,4-hydroquinone; BAPTA-AM, 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) ester. plays an important role in the expression of genes encoding phase II detoxification enzymes and antioxidant proteins such as NAD(P)H: quinone oxidoreductase-1 (NQO1), glutathione S-transferases (GSTs), glutamate-cysteine ligase, and heme oxygenase-1 (1Rushmore T.H. 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A. 1994; 91: 9926-9930Crossref PubMed Scopus (1248) Google Scholar), is the principal component leading to ARE-driven gene expression. Recently, Nrf2 target genes were identified by oligonucleotide microarray analysis, and the gene lists suggest that Nrf2 is important in combating electrophiles and reactive oxygen species (11Lee J.-M. Calkins M.J. Chan K. Kan Y.W. Johnson J.A. J. Biol. Chem. 2003; 278: 12029-12038Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar, 13Thimmulappa R.K. Mai K.H. Srisuma S. Kensler T.W. Yamamoto M. Biswal S. Cancer Res. 2002; 62: 5196-5203PubMed Google Scholar, 14Shih A.Y. Johnson D.A. Wong G. Kraft A.D. Jiang L. Erb H. Johnson J.A. Murphy T.H. J. Neurosci. 2003; 23: 3394-3406Crossref PubMed Google Scholar). Many studies have shown that Nrf2 plays a critical role in protecting cells from oxidative stress. Chan et al. reported that Nrf2 protects liver from acetaminophen-induced injury (15Chan K. Han X.D. Kan Y.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 4611-4616Crossref PubMed Scopus (654) Google Scholar) and lung from butylated hydroxytoluene-induced toxicity (16Chan K. Kan Y.W. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 12731-12736Crossref PubMed Scopus (526) Google Scholar). Cho et al. (17Cho H.Y. Jedlicka A.E. Reddy S.P. Kensler T.W. Yamamoto M. Zhang L.Y. Kleeberger S.R. Am. J. Respir. Cell Mol. Biol. 2002; 26: 175-182Crossref PubMed Scopus (590) Google Scholar) demonstrated that Nrf2 knockout mice are more sensitive to hyperoxia-induced lung injury. Recently, our laboratory reported that Nrf2-/- primary astrocytes are more susceptible to oxidative stress and inflammation compared with Nrf2+/+ astrocytes (11Lee J.-M. Calkins M.J. Chan K. Kan Y.W. Johnson J.A. J. Biol. Chem. 2003; 278: 12029-12038Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar). Pretreatment of these Nrf2+/+ (but not Nrf2-/-) astrocytes with t-butylhydroquinone, which induces Nrf2 nuclear translocation resulting in coordinate up-regulation of ARE-driven genes, attenuates H2O2- and platelet-activating factor-induced cell death (11Lee J.-M. Calkins M.J. Chan K. Kan Y.W. Johnson J.A. J. Biol. Chem. 2003; 278: 12029-12038Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar). Similarly, t-butylhydroquinone-mediated protective effects have been shown in rodent and human neuroblastoma cells (18Duffy S. So A. Murphy T.H. J. Neurochem. 1998; 71: 69-77Crossref PubMed Scopus (121) Google Scholar, 19Li J. Lee J.-M. Johnson J.A. J. Biol. Chem. 2002; 277: 388-394Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). These observations suggest that the coordinate up-regulation of antioxidant genes is the key to protecting cells from oxidative stress and that Nrf2 is a master regulator of ARE-driven antioxidant gene expression, a process we refer to as programmed cell life (19Li J. Lee J.-M. Johnson J.A. J. Biol. Chem. 2002; 277: 388-394Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). Parkinson's disease (PD) is a progressive neurodegenerative disease caused by degeneration of dopaminergic neurons in the substantia nigra. Although the underlying mechanism by which dopaminergic neurons degenerate is not clear, oxidative stress has been implicated to play a role in the neuronal cell death associated with PD (20Adams Jr., J.D. Chang M.L. Klaidman L. Curr. Med. Chem. 2001; 8: 809-814Crossref PubMed Scopus (136) Google Scholar). In support of this, many studies have shown decreased antioxidant levels in PD patients as well as a protective effect of antioxidants in animal models of PD. For example, GSH and coenzyme Q10 have been reported to play an important role in protecting dopaminergic neurons not only in human PD patients, but also in animal PD models (21Nakamura K. Wang W. Kang U.J. J. Neurochem. 1997; 69: 1850-1858Crossref PubMed Scopus (78) Google Scholar, 22Beal M.F. Matthews R.T. Tieleman A. Shults C.W. Brain Res. 1998; 783: 109-114Crossref PubMed Scopus (228) Google Scholar, 23Shults C.W. Oakes D. Kieburtz K. Beal M.F. Haas R. Plumb S. Juncos J.L. Nutt J. Shoulson I. Carter J. Kompoliti K. Perlmutter J.S. Reich S. Stern M. Watts R.L. Kurlan R. Molho E. Harrison M. Lew M. the Parkinson Study GroupArch. Neurol. 2002; 59: 1541-1550Crossref PubMed Scopus (937) Google Scholar, 24Bharath S. Hsu M. Kaur D. Rajagopalan S. Andersen J.K. Biochem. Pharmacol. 2002; 64: 1037-1048Crossref PubMed Scopus (346) Google Scholar). In addition, iron metabolism and ferritin levels are involved in dopaminergic neuronal cell death in PD patients (25Dexter D.T. Carayon A. Vidailhet M. Ruberg M. Agid F. Agid Y. Lees A.J. Wells F.R. Jenner P. Marsden C.D. J. Neurochem. 1990; 55: 16-20Crossref PubMed Scopus (219) Google Scholar, 26Mann V.M. Cooper J.M. Daniel S.E. Srai K. Jenner P. Marsden C.D. Schapira A.H. Ann. Neurol. 1994; 36: 876-881Crossref PubMed Scopus (216) Google Scholar). A recent publication demonstrated that selective overexpression of human ferritin in dopaminergic neurons or administration of an iron chelator prevents 1-methyl-4-phenyl-1,2,3,6-tetrapyridine-induced death of dopaminergic neurons in vivo (27Kaur D. Yantiri F. Rajagopalan S. Kumar J. Mo J.Q. Boonplueang R. Viswanath V. Jacobs R. Yang L. Beal M.F. DiMonte D. Volitaskis I. Ellerby L. Cherny R.A. Bush A.I. Andersen J.K. Neuron. 2003; 37: 899-909Abstract Full Text Full Text PDF PubMed Scopus (561) Google Scholar). Furthermore, superoxide dismutase and glutathione peroxidase have been reported to play a protective role in animal models of PD (28Przedborski S. Kostic V. Jackson-Lewis V. Naini A.B. Simonetti S. Fahn S. Carlson E. Epstein C.J. Cadet J.L. J. Neurosci. 1992; 12: 1658-1667Crossref PubMed Google Scholar, 29Zhang J. Graham D.G. Montine T.J. Ho Y.S. J. Neurol. 2000; 59: PubMed Scopus Google Scholar, P. A. G. E. M. Andersen J.K. Jiang D. Beal M.F. J. Neurosci. 2000; PubMed Google Scholar). Interestingly, our recent oligonucleotide microarray with primary astrocytes showed that the expression of many of these protective antioxidant genes such as glutamate-cysteine ligase, superoxide glutathione and ferritin is these observations suggest that coordinate of these programmed cell life genes through an neurons from reactive oxygen neuronal cell death. In this study, we and the that decreased levels of detoxification enzymes and antioxidant proteins in Nrf2-/- neuronal cultures in to oxidative stress. To this we used Nrf2-/- and Nrf2+/+ neuronal cultures with or of these mitochondrial and are used in animal cell culture models of PD D. C.J. A. S. E. R. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, R. G. M. Neurosci. 2000; PubMed Scopus Google Scholar, R. A.K. S. M. J. Neurosci. 2002; PubMed Google Scholar). Furthermore, oligonucleotide microarray used to genes associated with this differential to of mitochondrial mice were with and primary neuronal cultures were from were in and in were with and in with containing and Cell were through cell and a of of the to with were in a and The Nrf2 of culture by a as (11Lee J.-M. Calkins M.J. Chan K. Kan Y.W. Johnson J.A. J. Biol. 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Chem. 2003; 278: 12029-12038Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar). by and using a reverse transcription system to the of were used with to gene are as Nrf2 and Nrf2 and NQO1, and and and and GCLM, and GCLC, and and and and and and and Microarray from Nrf2-/- and Nrf2+/+ primary neuronal cultures. and to (11Lee J.-M. Calkins M.J. Chan K. Kan Y.W. Johnson J.A. J. Biol. Chem. 2003; 278: 12029-12038Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar, 19Li J. Lee J.-M. Johnson J.A. J. Biol. Chem. 2002; 277: 388-394Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). Microarray used to and the of gene target and and and were by as (11Lee J.-M. Calkins M.J. Chan K. Kan Y.W. Johnson J.A. J. Biol. Chem. 2003; 278: 12029-12038Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar, 19Li J. Lee J.-M. Johnson J.A. J. Biol. Chem. 2002; 277: 388-394Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). The of the of the of genes. A of the used to a The were and genes and and decreased genes. the adenoviral and and were using the system of S. M. T. Y. M.L. J. 1997; 71: PubMed Google Scholar). The Nrf2 from J. Stewart D. Touchard C. Boinapally S. Choi A.M. Cook J.L. J. Biol. Chem. 1999; 274: 26071-26078Abstract Full Text Full Text PDF PubMed Scopus (1071) Google Scholar) by and of were Nrf2-/- primary neuronal cultures were with or a multiplicity of of of the neurons and of the astrocytes were with as by and and in we compared the of expression and of a known ARE-driven NQO1, in Nrf2+/+ and Nrf2-/- primary neuronal cultures. The expression of in Nrf2+/+ neuronal cultures Similarly, the of Nrf2+/+ neuronal cultures higher that of Nrf2-/- neuronal cultures with a of in the Nrf2-/- neuronal cultures and that the of Nrf2 the signaling in primary neuronal cultures. also as by our laboratory D.A. W. Johnson J.A. J. Neurochem. 2002; PubMed Scopus Google Scholar), that to the astrocytes in this mixed culture to this of gene expression of neurons to oxidative we primary neuronal cultures with the well known mitochondrial D. C.J. A. S. E. R. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar) and R. G. M. Neurosci. 2000; PubMed Scopus Google Scholar, R. A.K. S. M. J. Neurosci. 2002; PubMed Google Scholar). These neuronal cell death by mitochondrial resulting in decreased of reactive oxygen species and As shown in Nrf2-/- neuronal cultures were more sensitive to or and cell death to neuronal cell in Nrf2-/- neuronal cultures The is to the the of and or cell death in Nrf2+/+ neuronal is in the of cells in or Nrf2-/- neuronal cultures were of cells in the Nrf2-/- neuronal cultures in the Nrf2+/+ neuronal cultures with selective or neuronal that these cells were not astrocytes not and also the in Nrf2-/- neurons as shown by the of in Nrf2-/- neuronal cultures by mitochondrial neuronal cultures were with or cells were as of Nrf2 the Nrf2 target genes this observed we oligonucleotide microarray Nrf2+/+ and Nrf2-/- primary neuronal cultures. A of and decreased genes were identified using by and The of Nrf2 target genes in primary neuronal cultures are calcium growth factors, neuron-specific proteins, and of and decreased genes, genes of and sequence is Although many of the ARE-driven genes such as NQO1, and were by Nrf2 in primary neuronal the of Nrf2 target genes in these neuronal cultures from of cell (11Lee J.-M. Calkins M.J. Chan K. Kan Y.W. Johnson J.A. J. Biol. Chem. 2003; 278: 12029-12038Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar, 13Thimmulappa R.K. Mai K.H. Srisuma S. Kensler T.W. Yamamoto M. Biswal S. Cancer Res. 2002; 62: 5196-5203PubMed Google Scholar). The gene of calcium and neuron-specific proteins, were to the primary neuronal of Nrf2 target genes in primary neuronal of growth growth of signaling enhancer cell factor in a of Microarray and genes were to the microarray The in expression levels by well with the microarray data In addition, showed that the Nrf2+/+ neuronal cultures had higher and levels and the GSH in Nrf2+/+ neuronal cultures higher that in Nrf2-/- neuronal cultures of Nrf2 in microarray and and data that many genes an important role in calcium homeostasis were in an in primary neuronal cultures. gene and and and these genes have been reported to play an important role in neuronal cell death L. Y. D. J. 2000; PubMed Scopus Google Scholar, G. A. Neurol. 1998; PubMed Scopus Google Scholar), we neuronal cultures with or to the cells with an in intracellular calcium. and by of cells and by In with and more cell death in Nrf2-/- neuronal cultures compared with Nrf2+/+ neuronal cultures Pretreatment with the selective calcium chelator neuronal cultures Nrf2-/- and Nrf2+/+ neuronal not Interestingly, showed cytotoxic effects in Nrf2-/- neuronal that a Nrf2-/- neuronal cultures more sensitive to calcium Jr., Full Text PDF PubMed Scopus Google Scholar). as with and MPP+, the neurons (but not the the cell death in these cultures. ARE-driven that Nrf2 is important ARE-driven gene expression and we Nrf2-/- neuronal cultures with adenoviral and As shown in both cell and were by adenoviral and as by and and by the such that astrocytes were only of the neurons were of Nrf2-/- neuronal cultures with Nrf2 and such as and also showed that the expression levels of these genes were by in Nrf2-/- neuronal cultures and GCLC, not the expression levels of these genes not ARE-driven gene expression. Nrf2-/- neuronal cultures were with or and and were as were the Nrf2 Nrf2 we overexpression Nrf2 Nrf2-/- neurons from oxidative stress. neuronal cultures were with of and and we observed that Nrf2-/- neuronal cultures were more to these compared with Nrf2-/- neuronal cultures A and the of and or not only the neurons with in cultures with the or or most of the Nrf2-/- neurons in the cultures or In the of this effect with of the Nrf2-/- neurons in the cultures and neuronal cell death in the cultures. In this study, we have shown that ARE-driven gene expression is Nrf2 in primary neuronal cultures and that Nrf2-/- neurons are more sensitive to mitochondrial To Nrf2 target genes observed we oligonucleotide microarray Microarray data showed that Nrf2 is important the expression of many protective genes such as ARE-driven detoxification and antioxidant genes, calcium homeostasis genes, growth factors, signaling proteins, proteins, neuron-specific genes, and genes. the microarray data, we the that Nrf2-/- neurons are more susceptible to the cytotoxic effect of and that and more cell death in Nrf2-/- neurons compared with Nrf2+/+ neurons. Finally, we demonstrated that overexpression of Nrf2 ARE-driven gene expression in Nrf2-/- neuronal cultures and Nrf2-/- neurons from rotenone- or ionomycin-induced cell death. Taken together, these findings suggest that Nrf2 plays an important role in protecting neurons from toxic insult. In this study, we used mitochondrial and a calcium and an to the role of and MPP+, which are used in animal and cell culture models of PD, resulting in reactive oxygen species and neuronal cell death apoptosis D. C.J. A. S. E. R. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, R. G. M. Neurosci. 2000; PubMed Scopus Google Scholar, R. A.K. S. M. J. Neurosci. 2002; PubMed Google Scholar). the antioxidant and are important in protecting neurons from the effects of these In our study, Nrf2-/- primary neurons were sensitive to mitochondrial In addition, Nrf2-/- neurons were more susceptible to by or dtBHQ, an important role Nrf2 in the of calcium homeostasis as well as antioxidant In support of a role of Nrf2 in calcium our microarray identified proteins and calcium that play an important role in For example, protects neuronal cell and from ionomycin- or cell death by with neuronal apoptosis L. Y. D. J. 2000; PubMed Scopus Google Scholar). neurons G. A. Neurol. 1998; PubMed Scopus Google Scholar). these that calcium homeostasis genes to the observed our laboratory showed that coordinate up-regulation of ARE-driven genes by protects human neuroblastoma cells from apoptosis and identified ARE-driven genes by oligonucleotide microarray (19Li J. Lee J.-M. Johnson J.A. J. Biol. Chem. 2002; 277: 388-394Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). Furthermore, we reported that Nrf2 plays an important role in ARE-driven gene expression and in primary astrocytes (11Lee J.-M. Calkins M.J. Chan K. Kan Y.W. Johnson J.A. J. Biol. Chem. 2003; 278: 12029-12038Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar). R.K. Mai K.H. Srisuma S. Kensler T.W. Yamamoto M. Biswal S. Cancer Res. 2002; 62: 5196-5203PubMed Google Scholar), primary astrocytes (11Lee J.-M. Calkins M.J. Chan K. Kan Y.W. Johnson J.A. J. Biol. Chem. 2003; 278: 12029-12038Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar), liver K. H. Yamamoto M. Kensler T.W. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar), and primary neurons from Nrf2-/- mice have been used microarray analysis, and studies identified Nrf2 target genes primary and primary In these only genes were by Nrf2 and that these genes are by an of these genes, the lists of Nrf2 target genes are For example, genes encoding detoxification and enzymes are by Nrf2 in R.K. Mai K.H. Srisuma S. Kensler T.W. Yamamoto M. Biswal S. Cancer Res. 2002; 62: 5196-5203PubMed Google Scholar). In to detoxification genes, many antioxidant and genes are by Nrf2 in primary astrocytes (11Lee J.-M. Calkins M.J. Chan K. Kan Y.W. Johnson J.A. J. Biol. Chem. 2003; 278: 12029-12038Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar). with primary neurons Nrf2 target gene such as calcium homeostasis and neuron-specific genes. of Nrf2 target genes a of Nrf2 the or For example, Nrf2 target genes important in M. K. Yamamoto M. P. Kensler T.W. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: PubMed Scopus Google Scholar, Kensler T.W. I. P. A. Proc. Natl. Acad. Sci. U. S. A. 2002; PubMed Scopus Google Scholar). Nrf2 target gene play a role in antioxidant and effects in (11Lee J.-M. Calkins M.J. Chan K. Kan Y.W. Johnson J.A. J. Biol. Chem. 2003; 278: 12029-12038Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar). Finally, neuron-specific Nrf2 target genes calcium this play an important role in protecting neurons from oxidative stress or of calcium Although the of Nrf2 target genes cell these findings suggest that Nrf2 is critical to the mechanism in many studies have demonstrated that astrocytes and the and M. 2000; Google Scholar, J. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). Recently, we reported that Nrf2 regulates GSH and in neuronal cell A.Y. Johnson D.A. Wong G. Kraft A.D. Jiang L. Erb H. Johnson J.A. Murphy T.H. J. Neurosci. 2003; 23: 3394-3406Crossref PubMed Google Scholar). In the culture system used astrocytes the of cell that Nrf2 target genes in a of astrocytes to of the observed by antioxidants such as glutamate-cysteine ligase, heme and as identified by microarray (11Lee J.-M. Calkins M.J. Chan K. Kan Y.W. Johnson J.A. J. Biol. Chem. 2003; 278: 12029-12038Abstract Full Text Full Text PDF PubMed Scopus (643) Google Scholar, 14Shih A.Y. Johnson D.A. Wong G. Kraft A.D. Jiang L. Erb H. Johnson J.A. Murphy T.H. J. Neurosci. 2003; 23: 3394-3406Crossref PubMed Google Scholar). In to this showed that overexpression of Nrf2 rotenone- and ionomycin-induced in Nrf2-/- neurons. Furthermore, many Nrf2-/- neurons with higher of were that neurons are more to from these observations the that the effect of Nrf2 is by the ARE-driven gene of both astrocytes and neurons and that Nrf2 is a in the stress has been implicated in the neuronal cell death of many progressive neurodegenerative such as disease and Parkinson's the or neurons in these has with W. R. S. H. S. J.Q. D. Fahn S. J. Med. 2001; PubMed Scopus Google Scholar). to cell death to the of these neurodegenerative have in combating we have reported to neurons from oxidative stress through the coordinate up-regulation of ARE-driven genes that is referred to as programmed cell life (19Li J. Lee J.-M. Johnson J.A. J. Biol. Chem. 2002; 277: 388-394Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). Kan Nrf2 knockout and and the of the of the gene and also Jiang and Kraft

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