Molecular Neurobiology

, Volume 44, Issue 2, pp 192–201 | Cite as

Modulation of Nrf2/ARE Pathway by Food Polyphenols: A Nutritional Neuroprotective Strategy for Cognitive and Neurodegenerative Disorders

  • Giovanni Scapagnini
  • Vasto Sonya
  • Abraham G. Nader
  • Caruso Calogero
  • Davide Zella
  • Galvano Fabio


In recent years, there has been a growing interest, supported by a large number of experimental and epidemiological studies, for the beneficial effects of some phenolic substances, contained in commonly used spices and herbs, in preventing various age-related pathologic conditions, ranging from cancer to neurodegenerative diseases. Although the exact mechanisms by which polyphenols promote these effects remain to be elucidated, several reports have shown their ability to stimulate a general xenobiotic response in the target cells, activating multiple defense genes. Data from our and other laboratories have previously demonstrated that curcumin, the yellow pigment of curry, strongly induces heme-oxygenase-1 (HO-1) expression and activity in different brain cells via the activation of heterodimers of NF-E2-related factors 2 (Nrf2)/antioxidant responsive element (ARE) pathway. Many studies clearly demonstrate that activation ofNrf2 target genes, and particularly HO-1, in astrocytes and neurons is strongly protective against inflammation, oxidative damage, and cell death. In the central nervous system, the HO system has been reported to be very active, and its modulation seems to play a crucial role in the pathogenesis of neurodegenerative disorders. Recent and unpublished data from our group revealed that low concentrations of epigallocatechin-3-gallate, the major green tea catechin, induces HO-1 by ARE/Nrf2 pathway in hippocampal neurons, and by this induction, it is able to protect neurons against different models of oxidative damages. Furthermore, we have demonstrated that other phenolics, such as caffeic acid phenethyl ester and ethyl ferulate, are also able to protect neurons via HO-1 induction. These studies identify a novel class of compounds that could be used for therapeutic purposes as preventive agents against cognitive decline.


Heterodimers of NF-E2-related factors 2 (Nrf2) Antioxidant responsive element (ARE) Heme oxygenase 1 (HO-1) Neurodegenerative disorders Alzheimer’s disease Polyphenols Curcumin (-)- epigallocatechin-3- gallate (EGCG) Brain ageing 


  1. 1.
    Alzheimer’s Association (2009) Alzheimer’s disease facts and figures. Alzheimers Dement 5:234–270CrossRefGoogle Scholar
  2. 2.
    Rojo LE et al (2008) Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res 39:1–16PubMedCrossRefGoogle Scholar
  3. 3.
    Butterfield DA et al (2001) Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol Med 7:548–554PubMedCrossRefGoogle Scholar
  4. 4.
    Halliwell B (2007) Biochemistry of oxidative stress. Biochem Soc Trans 35:1147–1150PubMedCrossRefGoogle Scholar
  5. 5.
    Butterfield DA, Sultana R (2007) Redox proteomics identification of oxidatively modified brain proteins in Alzheimer’s disease and mild cognitive impairment: insights into the progression of this dementing disorder. J Alzheimers Dis 12:61–72PubMedGoogle Scholar
  6. 6.
    Katzman R, Saitoh T (1991) Advances in Alzheimer’s disease. FASEB J 5:278–286PubMedGoogle Scholar
  7. 7.
    Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of aging. Nature 408:239–247PubMedCrossRefGoogle Scholar
  8. 8.
    Calabrese V et al (2004) Nitric oxide and cellular stress response in brain aging and neurodegenerative disorders: the role of vitagenes. In Vivo 18:245–267PubMedGoogle Scholar
  9. 9.
    Skovronsky DM, Lee VM, Trojanowski JQ (2006) Neurodegenerative diseases: new concepts of pathogenesis and their therapeutic implications. Annu Rev Pathol 1:151–170PubMedCrossRefGoogle Scholar
  10. 10.
    Racchi M et al (2008) Alzheimer’s disease; new diagnostic and therapeutic tools. Immun Ageing 5:7PubMedCrossRefGoogle Scholar
  11. 11.
    Vatassery GT, Fahn S, Kuskowski MA (1998) The Parkinson Study Group. Alpha tocopherol in CSF of subjects taking high‑dose vitamin E in the DATATOP study. Neurology 50:1900–1902PubMedGoogle Scholar
  12. 12.
    Johnson JA et al (2008) The Nrf2-ARE pathway: An indicator and modulator of oxidative stress in neurodegeneration. Ann NY Acad Sci 1147:61–69PubMedCrossRefGoogle Scholar
  13. 13.
    Innamorato NG et al (2008) The transcription factor Nrf2 is a therapeutic target against brain inflammation. J Immunol 181(1):680–689PubMedGoogle Scholar
  14. 14.
    Sun Z et al (2007) Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2. Mol Cell Biol 27:6334–6349PubMedCrossRefGoogle Scholar
  15. 15.
    Yamamoto T et al (2008) Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol 28:2758–2770PubMedCrossRefGoogle Scholar
  16. 16.
    Malhotra D et al (2010) Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res 38(17):5718–5734PubMedCrossRefGoogle Scholar
  17. 17.
    Jakel RJ et al (2007) Nrf2-mediated protection against 6-hydroxydopamine. Brain Res 1144:192–201PubMedCrossRefGoogle Scholar
  18. 18.
    Innamorato NG et al (2010) Different susceptibility to the Parkinson’s toxin MPTP in mice lacking the redox master regulator Nrf2 or its target gene heme oxygenase-1. PLoS ONE 5(7):e11838PubMedCrossRefGoogle Scholar
  19. 19.
    Rojo AI et al (2010) Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease. Glia 58(5):588–598PubMedGoogle Scholar
  20. 20.
    Vargas MR et al (2006) Increased glutathione biosynthesis by Nrf2 activation in astrocytes prevents p75NTR-dependent motor neuron apoptosis. J Neurochem 97(3):687–696PubMedCrossRefGoogle Scholar
  21. 21.
    Vargas MR et al (2008) Nrf2 activation in astrocytes protects against neurodegeneration in mouse models of familial amyotrophic lateral sclerosis. J Neurosci 28(50):13574–13581PubMedCrossRefGoogle Scholar
  22. 22.
    Ramsey CP et al (2007) Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol 66:75–85PubMedCrossRefGoogle Scholar
  23. 23.
    Kanninen K et al (2008) Nuclear factor erythroid 2-related factor 2 protects against beta amyloid. Mol Cell Neurosci 39:302–313PubMedCrossRefGoogle Scholar
  24. 24.
    Wruck CJ et al (2008) Kavalactones protect neural cells against amyloid beta peptideinduced neurotoxicity via extracellular signal-regulated kinase 1/2-dependent nuclear factor erythroid 2-related factor 2 activation. Mol Pharmacol 73:1785–1795PubMedCrossRefGoogle Scholar
  25. 25.
    Kanninen K et al (2009) Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 106:16505–16510PubMedCrossRefGoogle Scholar
  26. 26.
    Chen PC et al (2009) Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: Critical role for the astrocyte. Proc Natl Acad Sci USA 106:2933–2938PubMedCrossRefGoogle Scholar
  27. 27.
    Abraham NG, Kappas A (2008) Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev 60(1):79–127PubMedCrossRefGoogle Scholar
  28. 28.
    Takahashi M et al (2002) Amyloid precursor proteins inhibit heme oxygenase activity and augment neurotoxicity in Alzheimer’s disease. Neuron 28:461–473CrossRefGoogle Scholar
  29. 29.
    Schipper HM (2000) Heme oxygenase-1: role in brain aging and neurodegeneration. Exp Gerontol 35:821–830PubMedCrossRefGoogle Scholar
  30. 30.
    Colombrita C et al (2003) Regional rat brain distribution of heme oxygenase-1 and manganese superoxide dismutase mRNA: relevance of redox homeostasis in the aging processes. Exp Biol Med 228:517–524Google Scholar
  31. 31.
    Chen K, Gunter K, Maines MD (2000) Neurons overexpressing heme oxygenase-1 resist oxidative stress-mediated cell death. J Neurochem 75:304–312PubMedCrossRefGoogle Scholar
  32. 32.
    Le WD, Xie WJ, Appel SH (1999) Protective role of heme oxygenase-1 in oxidative stress-induced neuronal injury. J Neurosci Res 56:652–658PubMedCrossRefGoogle Scholar
  33. 33.
    Willis D et al (1996) Heme oxygenase: a novel target for the modulation of the inflammatory response. Nat Med 2:87–90PubMedCrossRefGoogle Scholar
  34. 34.
    Poss KD, Tonegawa S (1997) Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci USA 94:10925–10930PubMedCrossRefGoogle Scholar
  35. 35.
    Yachie A et al (1999) Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 defi- ciency. J Clin Invest 103:129–135PubMedCrossRefGoogle Scholar
  36. 36.
    Paine A et al (2010) Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential. Biochem Pharmacol 80(12):1895–1903PubMedCrossRefGoogle Scholar
  37. 37.
    Pamplona A et al (2007) Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med 13(6):703–710PubMedCrossRefGoogle Scholar
  38. 38.
    Chora AA et al (2007) Heme oxygenase-1 and carbon monoxide suppress autoimmune neuroinflammation. J Clin Invest 117(2):438–47PubMedCrossRefGoogle Scholar
  39. 39.
    Dumont M et al (2009) Triterpenoid CDDOmethylamide improves memory and decreases amyloid plaques in a transgenic mouse model of Alzheimer’s disease. J Neurochem 109(2):502–512PubMedCrossRefGoogle Scholar
  40. 40.
    Son TG et al (2010) Plumbagin, a novel Nrf2/ARE activator, protects against cerebral ischemia. J Neurochem 112(5):1316–1326PubMedCrossRefGoogle Scholar
  41. 41.
    Morrison CD et al (2010) High fat diet increases hippocampal oxidative stress and cognitive impairment in aged mice: implications for decreased Nrf2 signaling. J Neurochem 114(6):1581–1589PubMedCrossRefGoogle Scholar
  42. 42.
    Zhao J et al (2007) Enhancing expression of Nrf2-driven genes protects the blood brain barrier after brain injury. J Neurosci 27:10240–10248PubMedCrossRefGoogle Scholar
  43. 43.
    Dash P et al (2009) Sulforaphane improves cognitive function administered following traumatic brain injury. Neurosci Lett 460(2):103–107PubMedCrossRefGoogle Scholar
  44. 44.
    Ping Z et al (2010) Sulforaphane protects brains against hypoxic-ischemic injury <!– through induction of Nrf2-dependent phase 2 enzyme. Brain Res 1343:178–185PubMedCrossRefGoogle Scholar
  45. 45.
    Gomez-Pinilla F (2008) Brain foods: the effects of nutrients on brain function. Nat Rev Neurosci 9:568–578PubMedCrossRefGoogle Scholar
  46. 46.
    Nakatani N (2000) Phenolic antioxidants from herbs and spices. Biofactors 13:141–146PubMedCrossRefGoogle Scholar
  47. 47.
    Butterfield D et al (2002) Nutritional approaches to combat oxidative stress in Alzheimer’s disease. J Nutr Biochem 13:444–461PubMedCrossRefGoogle Scholar
  48. 48.
    Sun AY et al (2008) Botanical phenolics and brain health. Neuromolecular Med 10:259–274PubMedCrossRefGoogle Scholar
  49. 49.
    Van Dyk K, Sano M (2007) The impact of nutrition on cognition in the elderly. Neurochem Res 32:893–904PubMedCrossRefGoogle Scholar
  50. 50.
    Letenneur L et al (2007) Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol 165:1364–1371PubMedCrossRefGoogle Scholar
  51. 51.
    Barberger-Gateau P et al (2007) Dietary patterns and risk of dementia: the Three-City cohort study. Neurology 69:921–930CrossRefGoogle Scholar
  52. 52.
    Scarmeas N et al (2006) Mediterranean diet, alzheimer disease, and vascular mediation. Arch Neurol 63:1709–1717PubMedCrossRefGoogle Scholar
  53. 53.
    Kang JH, Ascherio A, Grodstein F (2005) Fruit and vegetable consumption andcognitive decline in aging women. Ann Neurol 57:713–720PubMedCrossRefGoogle Scholar
  54. 54.
    Commenges D et al (2000) Intake of flavonoids and risk of dementia. Eur J Epidemiol 16:357–363PubMedCrossRefGoogle Scholar
  55. 55.
    Kim J, Lee HJ, Lee KW (2010) Naturally occurring phytochemicals for the prevention of Alzheimer’s disease. J Neurochem 112(6):1415–30PubMedCrossRefGoogle Scholar
  56. 56.
    Mattson MP, Son TG, Camandola S (2007) Viewpoint: mechanisms of action and therapeutic potential of neurohormetic phytochemicals. Dose Response 5(3):174–186PubMedCrossRefGoogle Scholar
  57. 57.
    Calabrese EJ (2008) Neuroscience and hormesis: overview and general findings. Crit Rev Toxicol 38(4):249–52PubMedCrossRefGoogle Scholar
  58. 58.
    Rattan SI, Fernandes RA, Demirovic D, Dymek B, Lima CF (2009) Heat stress and hormetin-induced hormesis in human cells: effects on aging, wound healing, angiogenesis, and differentiation. Dose Response 7(1):90–103PubMedCrossRefGoogle Scholar
  59. 59.
    Martin D et al (2004) Regulation of heme oxygenase-1 expression through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in response to the antioxidant phytochemical carnosol. J Biol Chem 279:8919–8929PubMedCrossRefGoogle Scholar
  60. 60.
    Surh YJ, Kundu JK, Na HK (2008) Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 74(13):1526–1539PubMedCrossRefGoogle Scholar
  61. 61.
    Foresti R et al (2005) Differential activation of heme oxygenase-1 by chalcones and rosolic acid in endothelial cells. J Pharmacol Exp Ther 312:686–693PubMedCrossRefGoogle Scholar
  62. 62.
    Ammon HPT, Wahl MA (1991) Pharmacology of Curcuma Longa. Planta Med 57:1–7PubMedCrossRefGoogle Scholar
  63. 63.
    Priyadarsini KI, Guha SN, Rao MN (1998) Physicochemical properties and antioxidant activities of methoxy phenols. Free Radic Biol Med 24:933–941PubMedCrossRefGoogle Scholar
  64. 64.
    Martin-Aragon S, Benedi JM, Villar AM (1997) Modifications on antioxidant capacity and lipid peroxidation in mice under fraxetin treatment. J Pharm Pharmacol 49:49–52PubMedCrossRefGoogle Scholar
  65. 65.
    Sreejayan A, Rao MN (1997) Nitric oxide scavenging by curcuminoids. J Pharm Pharmacol 49:105–107PubMedCrossRefGoogle Scholar
  66. 66.
    Zhao BL et al (1989) Scavenging effect of extracts of green tea and natural antioxidants on active oxygen radicals. Cell Biophys 14:175–185PubMedGoogle Scholar
  67. 67.
    Masuda T et al (1999) Chemical studies on antioxidant mechanism of curcuminoid: analysis of radical reaction products from curcumin. J Agric Food Chem 47:71–77PubMedCrossRefGoogle Scholar
  68. 68.
    Jovanovic SV et al (2001) How curcumin works preferentially with soluble antioxidants. J Am Chem Soc 123:3064–3068PubMedCrossRefGoogle Scholar
  69. 69.
    Pun PB et al (2010) Ageing in nematodes: do antioxidants extend lifespan in Caenorhabditis elegans? Biogerontology 11:17–30PubMedCrossRefGoogle Scholar
  70. 70.
    Ramos-Gomez M et al (2001) Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 98:3410–3415PubMedCrossRefGoogle Scholar
  71. 71.
    Singh S, Aggarwal BB (1995) Activation of transcription factor NF–κB is suppressed by curcumin (diferuloylmethane). J Biol Chem 270:24995–25000PubMedCrossRefGoogle Scholar
  72. 72.
    Huang MT, Newmark HL, Frenkel K (1997) Inhibitory effects of curcumin on tumorigenesis in mice. J Cell Biochem Suppl 27:26–34PubMedCrossRefGoogle Scholar
  73. 73.
    Abe Y, Hashimoto S, Horie T (1999) Curcumin inhibition of inflammatory cytokine production by human peripheral blood monocytes and alveolar macrophages. Pharmacol Res 39:41–47PubMedCrossRefGoogle Scholar
  74. 74.
    Awasthi S et al (2000) Curcumin-glutathione interactions and the role of human glutathione S-transferase P1-1. Chem Biol Interact 128:19–38PubMedCrossRefGoogle Scholar
  75. 75.
    Dinkova-Kostova AT, Talalay P (1999) Relation of structure of curcumin analogs to their potencies as inducers of Phase 2 detoxification enzymes. Carcinogenesis 20:911–914PubMedCrossRefGoogle Scholar
  76. 76.
    Dinkova-Kostova AT et al (2001) Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proc Natl Acad Sci USA 98:3404–3409PubMedCrossRefGoogle Scholar
  77. 77.
    Balogun E et al (2003) Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J 371:887–895PubMedCrossRefGoogle Scholar
  78. 78.
    Singhal SS et al (1999) The effect of curcumin on glutathione-linked enzymes in K562 human leukemia cells. Toxicol Lett 109:87–95PubMedCrossRefGoogle Scholar
  79. 79.
    Motterlini R et al (2000) Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress. Free Radic Biol Med 28:1303–1312PubMedCrossRefGoogle Scholar
  80. 80.
    Scapagnini G et al (2002) Caffeic acid phenethyl ester and curcumin: a novel class of heme oxygenase-1 inducers. Mol Pharmacol 61:554–561PubMedCrossRefGoogle Scholar
  81. 81.
    Scapagnini G et al (2006) Curcumin activates defensive genes and protects neurons against oxidative stress. Antioxid Redox Signal 8:395–403PubMedCrossRefGoogle Scholar
  82. 82.
    Scapagnini G et al. (2004) Use of curcumin derivatives or CAPE in the manufacture of a medicament for the treatment of neuroprotective disorders. World Patent Number: WO 2004/075883 A1Google Scholar
  83. 83.
    Goel A, Kunnumakkara AB, Aggarwal BB (2008) Curcumin as ―Curecumin||: from kitchen to clinic. Biochem Pharmacol 75:787–809PubMedCrossRefGoogle Scholar
  84. 84.
    Yang C, Zhang X, Fan H, Liu Y (2009) Curcumin upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia. Brain Res 1282:133–41PubMedCrossRefGoogle Scholar
  85. 85.
    Sikora E, Scapagnini G, Barbagallo M (2010) Curcumin, inflammation, ageing and age-related diseases. Immun Ageing 7(1):1PubMedCrossRefGoogle Scholar
  86. 86.
    Rajakrishnan V et al (1999) Neuroprotective role of curcumin from curcuma longa on ethanol induced brain damage. Phytother Res 13:571–574PubMedCrossRefGoogle Scholar
  87. 87.
    Chandra V et al (2001) Incidence of Alzheimer’s disease in a rural community in India: the Indo-US study. Neurology 57:985–989PubMedGoogle Scholar
  88. 88.
    Ng TP et al (2006) Curry consumption and cognitive function in the elderly. Am J Epidemiol 164:898–906PubMedCrossRefGoogle Scholar
  89. 89.
    Lim GP et al (2001) The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 21:8370–8377PubMedGoogle Scholar
  90. 90.
    Frautschy SA et al (2001) Phenolic anti-inflammatory antioxidant reversal of Abeta induced cognitive deficits and neuropathology. Neurobiol Aging 22:993–1005PubMedCrossRefGoogle Scholar
  91. 91.
    Yang F et al (2005) Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques and reduces amyloid in vivo. J Biol Chem 280:5892–5901PubMedCrossRefGoogle Scholar
  92. 92.
    Cole GM, Teter B, Frautschy SA (2007) Neuroprotective effects of curcumin. Adv Exp Med Biol 595:197–212PubMedCrossRefGoogle Scholar
  93. 93.
    Begum AN et al (2008) Curcumin structure-function, bioavailability and efficacy in models of neuroinflammation and Alzheimer’s disease. J Pharmacol Exp Ther 326:196–208PubMedCrossRefGoogle Scholar
  94. 94.
    Baum L et al (2008) Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol 28:110–113PubMedCrossRefGoogle Scholar
  95. 95.
    Michaluart P et al (1999) Inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation. Cancer Res 59:2347–2352PubMedGoogle Scholar
  96. 96.
    Natarajan K et al (1996) Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci USA 93:9090–9095PubMedCrossRefGoogle Scholar
  97. 97.
    Chen YJ, Shiao MS, Wang SY (2001) The antioxidant caffeic acid phenethyl ester induces apoptosis associated with selective scavenging of hydrogen peroxide in human leukemic HL-60 cells. Anticancer Drugs 12:143–149PubMedCrossRefGoogle Scholar
  98. 98.
    Huang MT et al (1996) Inhibitory effects of caffeic acid phenethyl ester (CAPE) on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion in mouse skin and the synthesis of DNA, RNA and protein in HeLa cells. Carcinogenesis 17:761–765PubMedCrossRefGoogle Scholar
  99. 99.
    Graf E (1992) Antioxidant potential of ferulic acid. Free Radic Biol Med 13:435–448PubMedCrossRefGoogle Scholar
  100. 100.
    Qureshi MJ, Blain JA (1976) Antioxidant activity in tomato extracts. Nucleus Karachi 13:29–33Google Scholar
  101. 101.
    Bourne LC, Rice-Evans C (1998) Biovailability of ferulic acid. Biochem Biophys Res Commun 253:222–227PubMedCrossRefGoogle Scholar
  102. 102.
    Pannala R et al (1998) Inhibition of peroxynitrite dependent tyrosine nitration by hydroxycinnamates: nitration or electron donation. Free Radic Biol Med 24:594–606PubMedCrossRefGoogle Scholar
  103. 103.
    Castelluccio C et al (1995) Antioxidant potential of intermediates in phenylpropanoid metabolism in higher plants. FEBS Lett 368:188–192PubMedCrossRefGoogle Scholar
  104. 104.
    Bourne L, Rice-Evans C (1997) The effect of the phenolic antioxidant ferulic acid on the oxidation of low density lipoprotein depends on the pro-oxidant used. Free Radic Res 27:337–344PubMedCrossRefGoogle Scholar
  105. 105.
    Kanski J et al (2002) Ferulic acid antioxidant protection against hydroxyl and peroxyl radical oxidation in synaptosomal and neuronal cell culture systems in vitro: structure—activity studies. J Nutr Biochem 13:273–281PubMedCrossRefGoogle Scholar
  106. 106.
    Clifford MN (1999) Chlorogenic acids and other cinnamates—nature, occurrence and dietary burden. J Sci Food Agric 79:362–372CrossRefGoogle Scholar
  107. 107.
    Kroon PA, Williamson G (1999) Hydroxycinnamates in plants and food: current and future perspectives. J Sci Food Agric 79:355–361CrossRefGoogle Scholar
  108. 108.
    Kikuzaki H et al (2002) Antioxidant properties of ferulic acid and its related compounds. J Agric Food Chem 50:2161–2168PubMedCrossRefGoogle Scholar
  109. 109.
    Scapagnini G et al (2004) Ethyl ferulate, a lipophilic polyphenol, induces HO-1 and protects rat neurons against oxidative stress. Antioxid Redox Signal 6:811–818PubMedGoogle Scholar
  110. 110.
    Perluigi M et al (2009) In vivo protective effects of ferulic acid ethyl ester against amyloid-beta peptide 1–42-induced oxidative stress. J Neurosci Res 84:418–26CrossRefGoogle Scholar
  111. 111.
    Sano J et al (2004) Effects of green tea intake on the development of coronary artery disease. Circ J 68:665–670PubMedCrossRefGoogle Scholar
  112. 112.
    Wolfram S (2007) Effects of green tea and EGCG on cardiovascular and metabolic health. J Am Coll Nutr 26:373–388Google Scholar
  113. 113.
    Moyers SB, Kumar NB (2004) Green tea polyphenols and cancer chemoprevention: multiple mechanisms and endpoints for phase II trials. Nutr Rev 62:204–211PubMedCrossRefGoogle Scholar
  114. 114.
    Boschmann M, Thielecke F (2007) The effects of epigallocatechin-3-gallate on thermogenesis and fat oxidation in obese men: a pilot study. J Am Coll Nutr 26:389–395Google Scholar
  115. 115.
    Potenza MA et al (2007) Epigallocatechin gallate, a green tea polyphenol, improves endothelial function and insulin sensitivity, reduces bood pressure and protects against myocardial ischemia/reperfusion injury in spontaneously hypertensive rats (SHR). Am J Physiol Endocrinol Metab 292:1378–1387CrossRefGoogle Scholar
  116. 116.
    Mandel S et al (2004) Cell signaling pathways in the neuroprotective actions of the green tea polyphenol (−)-epigallocatechin-3-gallate: implications for neurodegenerative diseases. J Neurochem 88:1555–1569PubMedCrossRefGoogle Scholar
  117. 117.
    Khan N, Mukhtar H (2007) Tea polyphenols for health promotion. Life Sci 81:519–533PubMedCrossRefGoogle Scholar
  118. 118.
    Ahmed S et al (2002) Green tea polyphenol epigallocatechin-3-gallate inhibits the IL-1 beta-induced activity and expression of cyclooxygenase-2 and nitric oxide synthase-2 in human chondrocytes. Free Radic Biol Med 33:1097–1105PubMedCrossRefGoogle Scholar
  119. 119.
    Kim SJ et al (2007) Epigallocatechin-3-gallate suppresses NF-kappaB activation and phosphorylation of p38 MAPK and JNK in human astrocytoma U373MG cells. J Nutr Biochem 18:587–596PubMedCrossRefGoogle Scholar
  120. 120.
    Khan N, Mukhtar H (2008) Multitargeted therapy of cancer by green tea polyphenols. Cancer Lett 269:269–280PubMedCrossRefGoogle Scholar
  121. 121.
    Srividhya R et al (2008) Attenuation of senescence-induced oxidative exacerbations in aged rat brain by (-)-epigallocatechin-3-gallate. Int J Dev Neurosci 26:217–223PubMedCrossRefGoogle Scholar
  122. 122.
    Kweon MH et al (2006) Constitutive overexpression of Nrf2-dependent heme oxygenase-1 in A549 cells contributes to resistance to apoptosis induced by epigallocatechin 3-gallate. J Biol Chem 281:33761–33772PubMedCrossRefGoogle Scholar
  123. 123.
    Romeo L et al (2009) The major green tea polyphenol, (−)-epigallocatechin-3-gallate, induces heme oxygenase in rat neurons and acts as an effective neuroprotective agent against oxidative stress. J Am Coll Nutr 28:492S–499SPubMedGoogle Scholar
  124. 124.
    Shah ZA, Li RC, Ahmad AS, Kensler TW, Yamamoto M, Biswal S, Doré S (2010) The flavanol (−)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway. J Cereb Blood Flow Metab 30(12):1951–1961PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Giovanni Scapagnini
    • 1
  • Vasto Sonya
    • 2
  • Abraham G. Nader
    • 3
  • Caruso Calogero
    • 2
  • Davide Zella
    • 5
  • Galvano Fabio
    • 4
  1. 1.Department of Health SciencesUniversity of MoliseCampobassoItaly
  2. 2.Immunosenescence Unit, Department of Pathobiology and Biomedical MethodologiesUniversity of PalermoPalermoItaly
  3. 3.Department of Physiology and Pharmacology, College of MedicineUniversity of ToledoToledoUSA
  4. 4.Department of Biological Chemistry, Medical Chemistry and Molecular BiologyUniversity of CataniaCataniaItaly
  5. 5.Department of Biochemistry and Molecular Biology, Institute of Human Virology-School of MedicineUniversity of MarylandBaltimoreUSA

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