Skip to main content

Advertisement

SpringerLink
Log in

Targeting the NF-E2-Related Factor 2 Pathway: a Novel Strategy for Traumatic Brain Injury

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

As an essential component of cellular defense against a variety of endogenous and exogenous stresses, nuclear factor erythroid 2-related factor 2 (Nrf2) has received increased attention in the past decades. Multiple studies indicate that Nrf2 acts not only as an important protective factor in injury models but also as a downstream target of therapeutic agents. Activation of Nrf2 has increasingly been linked to many human diseases, especially in central nervous system (CNS) injury such as traumatic brain injury (TBI). Several researches have deciphered that activation of Nrf2 exerts antioxidative stress, antiapoptosis, and antiinflammation influence in TBI via different molecules and pathways including heme oxygenase-1 (HO-1), NADPH:quinine oxidoreductase-1 (NQO-1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2). Hence, Nrf2 shows great promise as a molecular target in TBI. In the present article, we provide an updated review of the current state of our knowledge about relationship between Nrf2 and TBI, highlighting the specific roles of Nrf2 in TBI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Reference

  1. Brooks JC, Strauss DJ, Shavelle RM, Paculdo DR, Hammond FM, Harrison-Felix CL (2013) Long-term disability and survival in traumatic brain injury: results from the National Institute on Disability and Rehabilitation Research model systems. Arch Phys Med Rehabil 94:2203–2209

    Article  PubMed  Google Scholar 

  2. Cornelius C, Crupi R, Calabrese V, Graziano A, Milone P, Pennisi G, Radak Z, Calabrese EJ et al (2013) Traumatic brain injury: oxidative stress and neuroprotection. Antioxid Redox Signal 19:836–853

    Article  CAS  PubMed  Google Scholar 

  3. Ding K, Wang H, Xu J, Li T, Zhang L, Ding Y, Zhu L, He J et al (2014) Melatonin stimulates antioxidant enzymes and reduces oxidative stress in experimental traumatic brain injury: the Nrf2-ARE signaling pathway as a potential mechanism. Free Radic Biol Med 73:1–11

    Article  CAS  PubMed  Google Scholar 

  4. Brown SL, Sekhar KR, Rachakonda G, Sasi S, Freeman ML (2008) Activating transcription factor 3 is a novel repressor of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)-regulated stress pathway. Cancer Res 68:364–368

    Article  CAS  PubMed  Google Scholar 

  5. Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, Yamamoto M (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang DD, Lo SC, Sun Z, Habib GM, Lieberman MW, Hannink M (2005) Ubiquitination of Keap1, a BTB-Kelch substrate adaptor protein for Cul3, targets Keap1 for degradation by a proteasome-independent pathway. J Biol Chem 280:30091–30099

    Article  CAS  PubMed  Google Scholar 

  7. Lo SC, Hannink M (2006) CAND1-mediated substrate adaptor recycling is required for efficient repression of Nrf2 by Keap1. Mol Cell Biol 26:1235–1244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Satoh T, McKercher SR, Lipton SA (2013) Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs. Free Radic Biol Med 65:645–657

    Article  CAS  PubMed  Google Scholar 

  9. Chen G, Fang Q, Zhang J, Zhou D, Wang Z (2011) Role of the Nrf2-ARE pathway in early brain injury after experimental subarachnoid hemorrhage. J Neurosci Res 89:515–523

    Article  CAS  PubMed  Google Scholar 

  10. Wang J, Fields J, Zhao C, Langer J, Thimmulappa RK, Kensler TW, Yamamoto M, Biswal S et al (2007) Role of Nrf2 in protection against intracerebral hemorrhage injury in mice. Free Radic Biol Med 43:408–414

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Yan W, Wang HD, Hu ZG, Wang QF, Yin HX (2008) Activation of Nrf2-ARE pathway in brain after traumatic brain injury. Neurosci Lett 431:150–154

    Article  CAS  PubMed  Google Scholar 

  12. Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O’Connor T, Harada T, Yamamoto M (2001) High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicological sciences : an official journal of the Society of Toxicology 59:169–177

    Article  CAS  Google Scholar 

  13. Zhao J, Moore AN, Redell JB, Dash PK (2007) Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 27:10240–10248

    Article  CAS  Google Scholar 

  14. Jin W, Wang H, Yan W, Zhu L, Hu Z, Ding Y, Tang K (2009) Role of Nrf2 in protection against traumatic brain injury in mice. J Neurotrauma 26:131–139

    Article  PubMed  Google Scholar 

  15. Jin W, Kong J, Wang H, Wu J, Lu T, Jiang J, Ni H, Liang W (2011) Protective effect of tert-butylhydroquinone on cerebral inflammatory response following traumatic brain injury in mice. Injury 42:714–718

    Article  PubMed  Google Scholar 

  16. Lu XY, Wang HD, Xu JG, Ding K, Li T (2014) Pretreatment with tert-butylhydroquinone attenuates cerebral oxidative stress in mice after traumatic brain injury. J Surg Res 188:206–212

    Article  CAS  PubMed  Google Scholar 

  17. Miller DM, Singh IN, Wang JA, Hall ED (2015) Nrf2-ARE activator carnosic acid decreases mitochondrial dysfunction, oxidative damage and neuronal cytoskeletal degradation following traumatic brain injury in mice. Exp Neurol 264:103–110

    Article  CAS  PubMed  Google Scholar 

  18. Xu J, Wang H, Ding K, Zhang L, Wang C, Li T, Wei W, Lu X (2014) Luteolin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE pathway. Free Radic Biol Med 71:186–195

    Article  CAS  PubMed  Google Scholar 

  19. Li X, Wang H, Gao Y, Li L, Tang C, Wen G, Zhou Y, Zhou M et al (2016) Protective effects of quercetin on mitochondrial biogenesis in experimental traumatic brain injury via the Nrf2 signaling pathway. PLoS One 11:e0164237

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Ding H, Wang H, Zhu L, Wei W (2016) Ursolic acid ameliorates early brain injury after experimental traumatic brain injury in mice by activating the Nrf2 pathway. Neurochemical research

  21. Wood RL, Rutterford NA (2006) Demographic and cognitive predictors of long-term psychosocial outcome following traumatic brain injury. Journal of the International Neuropsychological Society : JINS 12:350–358

    Article  PubMed  Google Scholar 

  22. Shin SS, Dixon CE (2015) Alterations in cholinergic pathways and therapeutic strategies targeting cholinergic system after traumatic brain injury. J Neurotrauma 32:1429–1440

    Article  PubMed  PubMed Central  Google Scholar 

  23. Cardenas DD, McLean A Jr, Farrell-Roberts L, Baker L, Brooke M, Haselkorn J (1994) Oral physostigmine and impaired memory in adults with brain injury. Brain Inj 8:579–587

    Article  CAS  PubMed  Google Scholar 

  24. McLean A Jr, Stanton KM, Cardenas DD, Bergerud DB (1987) Memory training combined with the use of oral physostigmine. Brain Inj 1:145–159

    Article  PubMed  Google Scholar 

  25. Benedictus MR, Spikman JM, van der Naalt J (2010) Cognitive and behavioral impairment in traumatic brain injury related to outcome and return to work. Arch Phys Med Rehabil 91:1436–1441

    Article  PubMed  Google Scholar 

  26. Kenne E, Erlandsson A, Lindbom L, Hillered L, Clausen F (2012) Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice. J Neuroinflammation 9:17

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wang Z, Ji C, Wu L, Qiu J, Li Q, Shao Z, Chen G (2014) Tert-butylhydroquinone alleviates early brain injury and cognitive dysfunction after experimental subarachnoid hemorrhage: role of Keap1/Nrf2/ARE pathway. PLoS One 9:e97685

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Naseem M, Parvez S (2014) Role of melatonin in traumatic brain injury and spinal cord injury. TheScientificWorldJOURNAL 586270:2014

    Google Scholar 

  29. Pun PB, Lu J, Moochhala S (2009) Involvement of ROS in BBB dysfunction. Free Radic Res 43:348–364

    Article  CAS  PubMed  Google Scholar 

  30. Hanafy KA, Selim MH (2012) Antioxidant strategies in neurocritical care. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 9:44–55

    Article  CAS  Google Scholar 

  31. Mendes Arent A, de Souza LF, Walz R, Dafre AL (2014) Perspectives on molecular biomarkers of oxidative stress and antioxidant strategies in traumatic brain injury. Biomed Res Int 723060:2014

    Google Scholar 

  32. Tebay LE, Robertson H, Durant ST, Vitale SR, Penning TM, Dinkova-Kostova AT, Hayes JD (2015) Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic Biol Med 88:108–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24:7130–7139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. de Vries HE, Witte M, Hondius D, Rozemuller AJ, Drukarch B, Hoozemans J, van Horssen J (2008) Nrf2-induced antioxidant protection: a promising target to counteract ROS-mediated damage in neurodegenerative disease? Free Radic Biol Med 45:1375–1383

    Article  PubMed  CAS  Google Scholar 

  35. Lu XY, Wang HD, Xu JG, Ding K, Li T (2015) Deletion of Nrf2 exacerbates oxidative stress after traumatic brain injury in mice. Cell Mol Neurobiol 35:713–721

    Article  CAS  PubMed  Google Scholar 

  36. Tumer N, Svetlov S, Whidden M, Kirichenko N, Prima V, Erdos B, Sherman A, Kobeissy F et al (2013) Overpressure blast-wave induced brain injury elevates oxidative stress in the hypothalamus and catecholamine biosynthesis in the rat adrenal medulla. Neurosci Lett 544:62–67

    Article  CAS  PubMed  Google Scholar 

  37. Shu L, Wang C, Wang J, Zhang Y, Zhang X, Yang Y, Zhuo J, Liu J (2016) The neuroprotection of hypoxic preconditioning on rat brain against traumatic brain injury by up-regulated transcription factor Nrf2 and HO-1 expression. Neurosci Lett 611:74–80

    Article  CAS  PubMed  Google Scholar 

  38. Czabotar PE, Lessene G, Strasser A, Adams JM (2014) Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol 15:49–63

    Article  CAS  PubMed  Google Scholar 

  39. Ghirnikar RS, Lee YL, Eng LF (1998) Inflammation in traumatic brain injury: role of cytokines and chemokines. Neurochem Res 23:329–340

    Article  CAS  PubMed  Google Scholar 

  40. Merrill JE, Benveniste EN (1996) Cytokines in inflammatory brain lesions: helpful and harmful. Trends Neurosci 19:331–338

    Article  CAS  PubMed  Google Scholar 

  41. Campbell SJ, Hughes PM, Iredale JP, Wilcockson DC, Waters S, Docagne F, Perry VH, Anthony DC (2003) CINC-1 is an acute-phase protein induced by focal brain injury causing leukocyte mobilization and liver injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17:1168–1170

    Article  CAS  Google Scholar 

  42. Wilcockson DC, Campbell SJ, Anthony DC, Perry VH (2002) The systemic and local acute phase response following acute brain injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 22:318–326

    Article  CAS  Google Scholar 

  43. Gruber A, Reinprecht A, Illievich UM, Fitzgerald R, Dietrich W, Czech T, Richling B (1999) Extracerebral organ dysfunction and neurologic outcome after aneurysmal subarachnoid hemorrhage. Crit Care Med 27:505–514

    Article  CAS  PubMed  Google Scholar 

  44. Kalsotra A, Turman CM, Dash PK, Strobel HW (2003) Differential effects of traumatic brain injury on the cytochrome p450 system: a perspective into hepatic and renal drug metabolism. J Neurotrauma 20:1339–1350

    Article  PubMed  Google Scholar 

  45. Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, Yamamoto M, Kensler TW et al (2005) Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med 202:47–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sandberg M, Patil J, D’Angelo B, Weber SG, Mallard C (2014) NRF2-regulation in brain health and disease: implication of cerebral inflammation. Neuropharmacology 79:298–306

    Article  CAS  PubMed  Google Scholar 

  47. Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS, Kong AN (2006) Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res 66:11580–11584

    Article  CAS  PubMed  Google Scholar 

  48. Osburn WO, Karim B, Dolan PM, Liu G, Yamamoto M, Huso DL, Kensler TW (2007) Increased colonic inflammatory injury and formation of aberrant crypt foci in Nrf2-deficient mice upon dextran sulfate treatment. International journal of cancer Journal international du cancer 121:1883–1891

    Article  CAS  PubMed  Google Scholar 

  49. Jin W, Zhu L, Guan Q, Chen G, Wang QF, Yin HX, Hang CH, Shi JX et al (2008) Influence of Nrf2 genotype on pulmonary NF-kappaB activity and inflammatory response after traumatic brain injury. Ann Clin Lab Sci 38:221–227

    CAS  PubMed  Google Scholar 

  50. Jin W, Wang H, Ji Y, Zhu L, Yan W, Qiao L, Yin H (2009) Genetic ablation of Nrf2 enhances susceptibility to acute lung injury after traumatic brain injury in mice. Exp Biol Med 234:181–189

    Article  CAS  Google Scholar 

  51. Jin W, Wang H, Ji Y, Hu Q, Yan W, Chen G, Yin H (2008) Increased intestinal inflammatory response and gut barrier dysfunction in Nrf2-deficient mice after traumatic brain injury. Cytokine 44:135–140

    Article  CAS  PubMed  Google Scholar 

  52. Pan H, Wang H, Wang X, Zhu L, Mao L (2012) The absence of Nrf2 enhances NF-kappaB-dependent inflammation following scratch injury in mouse primary cultured astrocytes. Mediat Inflamm 217580:2012

    Google Scholar 

  53. Petty MA, Lo EH (2002) Junctional complexes of the blood-brain barrier: permeability changes in neuroinflammation. Prog Neurobiol 68:311–323

    Article  CAS  PubMed  Google Scholar 

  54. DeWitt DS, Prough DS (2003) Traumatic cerebral vascular injury: the effects of concussive brain injury on the cerebral vasculature. J Neurotrauma 20:795–825

    Article  PubMed  Google Scholar 

  55. Oby E, Janigro D (2006) The blood-brain barrier and epilepsy. Epilepsia 47:1761–1774

    Article  CAS  PubMed  Google Scholar 

  56. Fishman RA (1975) Brain edema. N Engl J Med 293:706–711

    Article  CAS  PubMed  Google Scholar 

  57. Lyeth BG, Liu S, Hamm RJ (1993) Combined scopolamine and morphine treatment of traumatic brain injury in the rat. Brain Res 617:69–75

    Article  CAS  PubMed  Google Scholar 

  58. Hong Y, Yan W, Chen S, Sun CR, Zhang JM (2010) The role of Nrf2 signaling in the regulation of antioxidants and detoxifying enzymes after traumatic brain injury in rats and mice. Acta Pharmacol Sin 31:1421–1430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. De Groote B, Van Laer P, Maurus K, Van Biervliet JP, Meeus L (1990) Embolization of ectopic kidney to control incontinence. Pediatrics 85:217–219

    CAS  PubMed  Google Scholar 

  60. Tong KI, Katoh Y, Kusunoki H, Itoh K, Tanaka T, Yamamoto M (2006) Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol Cell Biol 26:2887–2900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hayes JD, McMahon M (2009) NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci 34:176–188

    Article  CAS  PubMed  Google Scholar 

  62. Kim JH, Yu S, Chen JD, Kong AN (2013) The nuclear cofactor RAC3/AIB1/SRC-3 enhances Nrf2 signaling by interacting with transactivation domains. Oncogene 32:514–527

    Article  CAS  PubMed  Google Scholar 

  63. Rada P, Rojo AI, Chowdhry S, McMahon M, Hayes JD, Cuadrado A (2011) SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol Cell Biol 31:1121–1133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wang H, Liu K, Geng M, Gao P, Wu X, Hai Y, Li Y, Li Y et al (2013) RXRalpha inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2. Cancer Res 73:3097–3108

    Article  CAS  PubMed  Google Scholar 

  65. Alam J, Shibahara S, Smith A (1989) Transcriptional activation of the heme oxygenase gene by heme and cadmium in mouse hepatoma cells. J Biol Chem 264:6371–6375

    CAS  PubMed  Google Scholar 

  66. Keyse SM, Tyrrell RM (1989) Heme oxygenase2016 is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proceedings of the National Academy of Sciences of the United States of America 86:99–103

  67. Foresti R, Clark JE, Green CJ, Motterlini R (1997) Thiol compounds interact with nitric oxide in regulating heme oxygenase-1 induction in endothelial cells. Involvement of superoxide and peroxynitrite anions. J Biol Chem 272:18411–18417

    Article  CAS  PubMed  Google Scholar 

  68. Terry CM, Clikeman JA, Hoidal JR, Callahan KS (1998) Effect of tumor necrosis factor-alpha and interleukin-1 alpha on heme oxygenase-1 expression in human endothelial cells. Am J Phys 274:H883–H891

    Article  CAS  Google Scholar 

  69. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235:1043–1046

    Article  CAS  PubMed  Google Scholar 

  70. Brouard S, Otterbein LE, Anrather J, Tobiasch E, Bach FH, Choi AM, Soares MP (2000) Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med 192:1015–1026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ward RJ, Wilmet S, Legssyer R, Crichton RR (2002) The influence of iron homoeostasis on macrophage function. Biochem Soc Trans 30:762–765

    Article  CAS  PubMed  Google Scholar 

  72. Ryter SW, Choi AM (2005) Heme oxygenase-1: redox regulation of a stress protein in lung and cell culture models. Antioxid Redox Signal 7:80–91

    Article  CAS  PubMed  Google Scholar 

  73. Prawan A, Kundu JK, Surh YJ (2005) Molecular basis of heme oxygenase-1 induction: implications for chemoprevention and chemoprotection. Antioxid Redox Signal 7:1688–1703

    Article  CAS  PubMed  Google Scholar 

  74. Calabrese V, Butterfield DA, Scapagnini G, Stella AM, Maines MD (2006) Redox regulation of heat shock protein expression by signaling involving nitric oxide and carbon monoxide: relevance to brain aging, neurodegenerative disorders, and longevity. Antioxid Redox Signal 8:444–477

    Article  CAS  PubMed  Google Scholar 

  75. Siegel D, Bolton EM, Burr JA, Liebler DC, Ross D (1997) The reduction of alpha-tocopherolquinone by human NAD(P)H: quinone oxidoreductase: the role of alpha-tocopherolhydroquinone as a cellular antioxidant. Mol Pharmacol 52:300–305

    Article  CAS  PubMed  Google Scholar 

  76. Beyer RE, Segura-Aguilar J, Di Bernardo S, Cavazzoni M, Fato R, Fiorentini D, Galli MC, Setti M et al (1996) The role of DT-diaphorase in the maintenance of the reduced antioxidant form of coenzyme Q in membrane systems. Proc Natl Acad Sci U S A 93:2528–2532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Siegel D, Gustafson DL, Dehn DL, Han JY, Boonchoong P, Berliner LJ, Ross D (2004) NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. Mol Pharmacol 65:1238–1247

    Article  CAS  PubMed  Google Scholar 

  78. Katsuoka F, Motohashi H, Ishii T, Aburatani H, Engel JD, Yamamoto M (2005) Genetic evidence that small maf proteins are essential for the activation of antioxidant response element-dependent genes. Mol Cell Biol 25:8044–8051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hayes JD, McMahon M, Chowdhry S, Dinkova-Kostova AT (2010) Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid Redox Signal 13:1713–1748

    Article  CAS  PubMed  Google Scholar 

  80. Zhu J, Wang H, Fan Y, Lin Y, Zhang L, Ji X, Zhou M (2014) Targeting the NF-E2-related factor 2 pathway: a novel strategy for glioblastoma (review). Oncol Rep 32:443–450

    Article  PubMed  Google Scholar 

  81. Nair S, Doh ST, Chan JY, Kong AN, Cai L (2008) Regulatory potential for concerted modulation of Nrf2- and Nfkb1-mediated gene expression in inflammation and carcinogenesis. Br J Cancer 99:2070–2082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chen F, Castranova V, Shi X, Demers LM (1999) New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases. Clin Chem 45:7–17

    CAS  PubMed  Google Scholar 

  83. Baeuerle PA, Baltimore D (1996) NF-kappa B: ten years after. Cell 87:13–20

    Article  CAS  PubMed  Google Scholar 

  84. Neurath M (1996) F.; Pettersson, S.; Meyer zum Buschenfelde, K. H.; Strober, W. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice. Nat Med 2:998–1004

    Article  CAS  PubMed  Google Scholar 

  85. Kim JE, You DJ, Lee C, Ahn C, Seong JY, Hwang JI (2010) Suppression of NF-kappaB signaling by KEAP1 regulation of IKKbeta activity through autophagic degradation and inhibition of phosphorylation. Cell Signal 22:1645–1654

    Article  CAS  PubMed  Google Scholar 

  86. Yu M, Li H, Liu Q, Liu F, Tang L, Li C, Yuan Y, Zhan Y et al (2011) Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway. Cell Signal 23:883–892

    Article  CAS  PubMed  Google Scholar 

  87. Ahmad R, Raina D, Meyer C, Kharbanda S, Kufe D (2006) Triterpenoid CDDO-Me blocks the NF-kappaB pathway by direct inhibition of IKKbeta on Cys-179. J Biol Chem 281:35764–35769

    Article  CAS  PubMed  Google Scholar 

  88. Sriram N, Kalayarasan S, Sudhandiran G (2009) Epigallocatechin-3-gallate augments antioxidant activities and inhibits inflammation during bleomycin-induced experimental pulmonary fibrosis through Nrf2-Keap1 signaling. Pulm Pharmacol Ther 22:221–236

    Article  CAS  PubMed  Google Scholar 

  89. Liu YC, Hsieh CW, Wu CC, Wung BS (2007) Chalcone inhibits the activation of NF-kappaB and STAT3 in endothelial cells via endogenous electrophile. Life Sci 80:1420–1430

    Article  CAS  PubMed  Google Scholar 

  90. Wakabayashi N, Slocum SL, Skoko JJ, Shin S, Kensler TW (2010) When NRF2 talks, who’s listening? Antioxid Redox Signal 13:1649–1663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Cairns B, Kim JY, Tang XN, Yenari M (2012) A. NOX inhibitors as a therapeutic strategy for stroke and neurodegenerative disease. Curr Drug Targets 13:199–206

    Article  CAS  PubMed  Google Scholar 

  92. Pendyala S, Natarajan V (2010) Redox regulation of Nox proteins. Respir Physiol Neurobiol 174:265–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zhang QG, Laird MD, Han D, Nguyen K, Scott E, Dong Y, Dhandapani KM, Brann DW (2012) Critical role of NADPH oxidase in neuronal oxidative damage and microglia activation following traumatic brain injury. PLoS One 7:e34504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Lu XY, Wang HD, Xu JG, Ding K, Li T (2014) NADPH oxidase inhibition improves neurological outcome in experimental traumatic brain injury. Neurochem Int 69:14–19

    Article  CAS  PubMed  Google Scholar 

  95. Dohi K, Ohtaki H, Nakamachi T, Yofu S, Satoh K, Miyamoto K, Song D, Tsunawaki S et al (2010) Gp91phox (NOX2) in classically activated microglia exacerbates traumatic brain injury. J Neuroinflammation 7:41

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Pendyala S, Usatyuk PV, Gorshkova IA, Garcia JG, Natarajan V (2009) Regulation of NADPH oxidase in vascular endothelium: the role of phospholipases, protein kinases, and cytoskeletal proteins. Antioxid Redox Signal 11:841–860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Alves-Lopes R, Neves KB, Montezano AC, Harvey A, Carneiro FS, Touyz RM, Tostes RC (2016) Internal pudental artery dysfunction in diabetes mellitus is mediated by NOX1-derived ROS-, Nrf2-, and rho kinase-dependent mechanisms. Hypertension 68:1056–1064

    Article  CAS  PubMed  Google Scholar 

  98. Liu B, Cao B, Zhang D, Xiao N, Chen H, Li GQ, Peng SC, Wei LQ (2016) Salvianolic acid B protects against paraquat-induced pulmonary injury by mediating Nrf2/Nox4 redox balance and TGF-beta1/Smad3 signaling. Toxicol Appl Pharmacol 309:111–120

    Article  CAS  PubMed  Google Scholar 

  99. Lin C, Zhao X, Sun D, Zhang L, Fang W, Zhu T, Wang Q, Liu B et al (2016) Transcriptional activation of follistatin by Nrf2 protects pulmonary epithelial cells against silica nanoparticle-induced oxidative stress. Scientific reports 6:21133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Pendyala S, Moitra J, Kalari S, Kleeberger SR, Zhao Y, Reddy SP, Garcia JG, Natarajan V (2011) Nrf2 regulates hyperoxia-induced Nox4 expression in human lung endothelium: identification of functional antioxidant response elements on the Nox4 promoter. Free Radic Biol Med 50:1749–1759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Powis G, Montfort WR (2001) Properties and biological activities of thioredoxins. Annu Rev Biophys Biomol Struct 30:421–455

    Article  CAS  PubMed  Google Scholar 

  102. Arner ES, Holmgren A (2000) Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem 267:6102–6109

    Article  CAS  PubMed  Google Scholar 

  103. Hattori I, Takagi Y, Nozaki K, Kondo N, Bai J, Nakamura H, Hashimoto N, Yodoi J (2002) Hypoxia-ischemia induces thioredoxin expression and nitrotyrosine formation in new-born rat brain. Redox report : communications in free radical research 7:256–259

    Article  CAS  PubMed  Google Scholar 

  104. Hatic H, Kane MJ, Saykally JN, Citron BA (2012) Modulation of transcription factor Nrf2 in an in vitro model of traumatic brain injury. J Neurotrauma 29:1188–1196

    Article  PubMed  Google Scholar 

  105. Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K et al (1998) Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J 17:2596–2606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Masutani H, Ueda S, Yodoi J (2005) The thioredoxin system in retroviral infection and apoptosis. Cell Death Differ 12(Suppl 1):991–998

    Article  CAS  PubMed  Google Scholar 

  107. Tavaria M, Gabriele T, Anderson RL, Mirault ME, Baker E, Sutherland G, Kola I (1995) Localization of the gene encoding the human heat shock cognate protein, HSP73, to chromosome 11. Genomics 29:266–268

    Article  CAS  PubMed  Google Scholar 

  108. Turturici G, Sconzo G, Geraci F (2011) Hsp70 and its molecular role in nervous system diseases. Biochem Res Int 618127:2011

    Google Scholar 

  109. Calabrese V, Signorile A, Cornelius C, Mancuso C, Scapagnini G, Ventimiglia B, Ragusa N, Dinkova-Kostova A (2008) Practical approaches to investigate redox regulation of heat shock protein expression and intracellular glutathione redox state. Methods Enzymol 441:83–110

    Article  CAS  PubMed  Google Scholar 

  110. Foster JA, Brown IR (1997) Differential induction of heat shock mRNA in oligodendrocytes, microglia, and astrocytes following hyperthermia. Brain Res Mol Brain Res 45:207–218

    Article  CAS  PubMed  Google Scholar 

  111. Huang G, Diao J, Yi H, Xu L, Xu J, Xu W (2016) Signaling pathways involved in HSP32 induction by hyperbaric oxygen in rat spinal neurons. Redox Biol 10:108–118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Dinkova-Kostova AT, Talalay P (2008) Direct and indirect antioxidant properties of inducers of cytoprotective proteins. Mol Nutr Food Res 52(Suppl 1):S128–S138

    PubMed  Google Scholar 

  113. Dash PK, Zhao J, Orsi SA, Zhang M, Moore AN (2009) Sulforaphane improves cognitive function administered following traumatic brain injury. Neurosci Lett 460:103–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Wang X, de Rivero Vaccari JP, Wang H, Diaz P, German R, Marcillo AE, Keane RW (2012) Activation of the nuclear factor E2-related factor 2/antioxidant response element pathway is neuroprotective after spinal cord injury. J Neurotrauma 29:936–945

    Article  PubMed  PubMed Central  Google Scholar 

  115. Jin W, Ni H, Dai Y, Wang H, Lu T, Wu J, Jiang J, Liang W (2010) Effects of tert-butylhydroquinone on intestinal inflammatory response and apoptosis following traumatic brain injury in mice. Mediat Inflamm 502564:2010

    Google Scholar 

  116. Nguyen T, Sherratt PJ, Huang HC, Yang CS, Pickett CB (2003) Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26 S proteasome. J Biol Chem 278:4536–4541

    Article  CAS  PubMed  Google Scholar 

  117. Li Z, Dong X, Zhang J, Zeng G, Zhao H, Liu Y, Qiu R, Mo L et al (2014) Formononetin protects TBI rats against neurological lesions and the underlying mechanism. J Neurol Sci 338:112–117

    Article  CAS  PubMed  Google Scholar 

  118. Lo YL, Wang W (2013) Formononetin potentiates epirubicin-induced apoptosis via ROS production in HeLa cells in vitro. Chem Biol Interact 205:188–197

    Article  CAS  PubMed  Google Scholar 

  119. Dajas F, Andres AC, Florencia A, Carolina E, Felicia RM (2013) Neuroprotective actions of flavones and flavonols: mechanisms and relationship to flavonoid structural features. Cent Nerv Syst Agents Med Chem 13:30–35

    Article  CAS  PubMed  Google Scholar 

  120. Tsai MC, Chen WJ, Tsai MS, Ching CH, Chuang JI (2011) Melatonin attenuates brain contusion-induced oxidative insult, inactivation of signal transducers and activators of transcription 1, and upregulation of suppressor of cytokine signaling-3 in rats. J Pineal Res 51:233–245

    Article  CAS  PubMed  Google Scholar 

  121. Ozarowski M, Mikolajczak PL, Bogacz A, Gryszczynska A, Kujawska M, Jodynis-Liebert J, Piasecka A, Napieczynska H et al (2013) Rosmarinus officinalis L. leaf extract improves memory impairment and affects acetylcholinesterase and butyrylcholinesterase activities in rat brain. Fitoterapia 91:261–271

    Article  CAS  PubMed  Google Scholar 

  122. Satoh T, Kosaka K, Itoh K, Kobayashi A, Yamamoto M, Shimojo Y, Kitajima C, Cui J 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. J Neurochem 104:1116–1131

    Article  CAS  PubMed  Google Scholar 

  123. Meng XE, Zhang Y, Li N, Fan DF, Yang C, Li H, Guo DZ, Pan SY (2016) Effects of hyperbaric oxygen on the Nrf2 signaling pathway in secondary injury following traumatic brain injury. Genetics and molecular research : GMR 15

  124. Zhang M, Wu J, Ding H, Wu W, Xiao G (2016) Progesterone provides the pleiotropic neuroprotective effect on traumatic brain injury through the Nrf2/ARE signaling pathway. Neurocritical care

  125. Yang Y, Wang H, Li L, Li X, Wang Q, Ding H, Wang X, Ye Z et al (2016) Sinomenine provides neuroprotection in model of traumatic brain injury via the Nrf2-ARE pathway. Front Neurosci 10:580

    PubMed  PubMed Central  Google Scholar 

  126. Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290:1717–1721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Luo CL, Li BX, Li QQ, Chen XP, Sun YX, Bao HJ, Dai DK, Shen YW et al (2011) Autophagy is involved in traumatic brain injury-induced cell death and contributes to functional outcome deficits in mice. Neuroscience 184:54–63

    Article  CAS  PubMed  Google Scholar 

  128. Zhang YB, Li SX, Chen XP, Yang L, Zhang YG, Liu R, Tao LY (2008) Autophagy is activated and might protect neurons from degeneration after traumatic brain injury. Neurosci Bull 24:143–149

    Article  PubMed  PubMed Central  Google Scholar 

  129. Joshi G, Gan KA, Johnson DA, Johnson JA (2015) Increased Alzheimer’s disease-like pathology in the APP/PS1DeltaE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol Aging 36:664–679

    Article  CAS  PubMed  Google Scholar 

  130. Pajares M, Jimenez-Moreno N, Garcia-Yague AJ, Escoll M, de Ceballos ML, Van Leuven F, Rabano A, Yamamoto M et al (2016) Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes. Autophagy 12:1902–1916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Faden AI, Demediuk P, Panter SS, Vink R (1989) The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798–800

    Article  CAS  PubMed  Google Scholar 

  132. Palmer AM, Marion DW, Botscheller ML, Bowen DM, DeKosky ST (1994) Increased transmitter amino acid concentration in human ventricular CSF after brain trauma. Neuroreport 6:153–156

    Article  CAS  PubMed  Google Scholar 

  133. Zhang H, Zhang X, Zhang T, Chen L (2001) Excitatory amino acids in cerebrospinal fluid of patients with acute head injuries. Clin Chem 47:1458–1462

    CAS  PubMed  Google Scholar 

  134. Baker AJ, Moulton RJ, MacMillan VH, Shedden PM (1993) Excitatory amino acids in cerebrospinal fluid following traumatic brain injury in humans. J Neurosurg 79:369–372

    Article  CAS  PubMed  Google Scholar 

  135. Feng S, Xu Z, Wang F, Yang T, Liu W, Deng Y, Xu B (2016) Sulforaphane prevents methylmercury-induced oxidative damage and excitotoxicity through activation of the Nrf2-ARE pathway. Molecular neurobiology

  136. Carmona-Ramirez I, Santamaria A, Tobon-Velasco JC, Orozco-Ibarra M, Gonzalez-Herrera IG, Pedraza-Chaverri J, Maldonado PD (2013) Curcumin restores Nrf2 levels and prevents quinolinic acid-induced neurotoxicity. J Nutr Biochem 24:14–24

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (no. 81672503) and the Jiangsu Provincial Key Subject (no. X4200722).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, Jinling Hospital, 305 East Zhongshan Road, Nanjing, Jiangsu Province, China

    Li Zhang & Handong Wang

Authors
  1. Li Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Handong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Handong Wang.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, L., Wang, H. Targeting the NF-E2-Related Factor 2 Pathway: a Novel Strategy for Traumatic Brain Injury. Mol Neurobiol 55, 1773–1785 (2018). https://doi.org/10.1007/s12035-017-0456-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-017-0456-z

Keywords

Search

Navigation