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Green tea catechins as brain-permeable, non toxic iron chelators to “iron out iron” from the brain

  • S. Mandel
  • O. Weinreb
  • L. Reznichenko
  • L. Kalfon
  • T. Amit
Part of the Journal of Neural Transmission. Supplementa book series (NEURALTRANS, volume 71)

Summary

Evidence to link abnormal metal (iron, copper and zinc) metabolism and handling with Parkinson’s and Alzheimer’s diseases pathology has frequently been reported. The capacity of free iron to enhance and promote the generation of toxic reactive oxygen radicals has been discussed numerous times. Metal chelation has the potential to prevent iron-induced oxidative stress and aggregation of alpha-synuclein and beta-amyloid peptides. The efficacy of iron chelators depends on their ability to penetrate the subcellular compartments and cellular membranes where iron dependent free radicals are generated. Thus, natural, non-toxic, brain permeable neuroprotective drugs, are preferentially advocated for “ironing out iron” from those brain areas where it preferentially accumulates in neurodegenerative diseases. This review will discuss the most recent findings from in vivo and in vitro studies concerning the transitional metal (iron and copper) chelating property of green tea and its major polyphenol, (−)-epigallocatechin-3-gallate with respect to their potential for the treatment of neurodegenerative diseases.

Keywords

Iron Regulatory Protein Amyloid Precursor Protein mRNA sAPPa Secretion Catechin Polyphenol Amyloid Precursor Protein mRNA Level 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Atwood CS, Obrenovich ME, Liu T, Chan H, Perry G, Smith MA, Martins RN (2003) Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta. Brain Res Brain Res Rev 43: 1–16PubMedCrossRefGoogle Scholar
  2. Beard JL, Connor JR, Jones BC (1993) Iron in the brain. Nutr Rev 51: 157–170PubMedCrossRefGoogle Scholar
  3. Ben-Shachar D, Eshel G, Finberg JP, Youdim MB (1991) The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J Neurochem 56: 1441–1444PubMedCrossRefGoogle Scholar
  4. Blalock EM, Geddes JW, Chen KC, Porter NM, Markesbery WR, Landfield PW (2004) Incipient Alzheimer’s disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc Natl Acad Sci USA 101: 2173–2178PubMedCrossRefGoogle Scholar
  5. Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, Verna JM (2001) Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 65: 135–172PubMedCrossRefGoogle Scholar
  6. Bravo L (1998) Polyphenols: chemistry, dietary sources, metabolism, and nutritional significance. Nutr Rev 56: 317–333PubMedCrossRefGoogle Scholar
  7. Cao X, Sudhof TC (2001) A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293: 115–120PubMedCrossRefGoogle Scholar
  8. Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, Barnham KJ, Volitakis I, Fraser FW, Kim Y, Huang X, Goldstein LE, Moir RD, Lim JT, Beyreuther K, Zheng H, Tanzi RE, Masters CL, Bush AI (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30: 665–676PubMedCrossRefGoogle Scholar
  9. Choi YT, Jung CH, Lee SR, Bae JH, Baek WK, Suh MH, Park J, Park CW, Suh SI (2001) The green tea polyphenol (−)-epigallocatechin gallate attenuates beta-amyloid-induced neurotoxicity in cultured hippocampal neurons. Life Sci 70: 603–614PubMedCrossRefGoogle Scholar
  10. Cooper R, Morre DJ, Morre DM (2005) Medicinal benefits of green tea: Part I. Review of noncancer health benefits. J Altern Complem Med 11: 521–528CrossRefGoogle Scholar
  11. Cuajungco MP, Frederickson CJ, Bush AI (2005) Amyloid-beta metal interaction and metal chelation. Subcell Biochem 38: 235–254PubMedGoogle Scholar
  12. De Strooper B, Annaert W (2000) Proteolytic processing and cell biological functions of the amyloid precursor protein. J Cell Sci 113: 1857–1870PubMedGoogle Scholar
  13. Esler WP, Wolfe MS (2001) A portrait of Alzheimer secretases — new features and familiar faces. Science 293: 1449–1454PubMedCrossRefGoogle Scholar
  14. Gal S, Zheng H, Fridkin M, Youdim MBH (2005) Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion. J Neurochem 95: 79–88PubMedCrossRefGoogle Scholar
  15. Galati G, O’Brien PJ (2004) Potential toxicity of flavonoids and other dietary phenolics: significance for their chemopreventive and anticancer properties. Free Radic Biol Med 37: 287–303PubMedCrossRefGoogle Scholar
  16. Gao Y, Pimplikar SW (2001) The gamma-secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus. Proc Natl Acad Sci USA 98: 14979–14984PubMedCrossRefGoogle Scholar
  17. Grinberg LN, Newmark H, Kitrossky N, Rahamim E, Chevion M, Rachmilewitz EA (1997) Protective effects of tea polyphenols against oxidative damage to red blood cells. Biochem Pharmacol 54: 973–978PubMedCrossRefGoogle Scholar
  18. Grunblatt E, Mandel S, Jacob-Hirsch J, Zeligson S, Amariglo N, Rechavi G, Li J, Ravid R, Roggendorf W, Riederer P, Youdim MBH (2004) Gene expression profiling of parkinsonian substantia nigra pars compacta; alterations in ubiquitin-proteasome, heat shock protein, iron and oxidative stress regulated proteins, cell adhesion=cellular matrix and vesicle trafficking genes. J Neural Transm 111: 1543–1573PubMedCrossRefGoogle Scholar
  19. Guo Q, Zhao B, Li M, Shen S, Xin W (1996) Studies on protective mechanisms of four components of green tea polyphenols against lipid peroxidation in synaptosomes. Biochim Biophys Acta 1304: 210–222PubMedGoogle Scholar
  20. Gutman RL, Ryu RH (1996) Rediscovering tea: an exploration of the scientific literature. Herbal Gram 37: 33–48Google Scholar
  21. Hanson ES, Rawlins ML, Leibold EA (2003) Oxygen and iron regulation of iron regulatory protein 2. J Biol Chem 278: 40337–40342PubMedCrossRefGoogle Scholar
  22. Hider RC, Liu ZD, Khodr HH (2001) Metal chelation of polyphenols. Methods Enzymol 335: 190–203PubMedCrossRefGoogle Scholar
  23. Higdon JV, Frei B (2003) Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. Crit Rev Food Sci Nutr 43: 89–143PubMedCrossRefGoogle Scholar
  24. Honda K, Smith MA, Zhu X, Baus D, Merrick WC, Tartakoff AM, Hattier T, Harris PL, Siedlak SL, Fujioka H, Liu Q, Moreira PI, Miller FP, Nunomura A, Shimohama S, Perry G (2005) Ribosomal RNA in Alzheimer disease is oxidized by bound redox-active iron. J Biol Chem 280: 20978–20986PubMedCrossRefGoogle Scholar
  25. Huang X, Moir RD, Tanzi RE, Bush AI, Rogers JT (2004) Redox-active metals, oxidative stress, and Alzheimer’s disease pathology. Ann N Y Acad Sci 1012: 153–163PubMedCrossRefGoogle Scholar
  26. Jellinger KA (2003) Neuropathological spectrum of synucleinopathies. Mov Disord 18[Suppl 6]: S2–S12PubMedCrossRefGoogle Scholar
  27. Joseph JA, Shukitt-Hale B, Casadesus G (2005) Reversing the deleterious effects of aging on neuronal communication and behavior: beneficial properties of fruit polyphenolic compounds. Am J Clin Nutr 81[Suppl 1]: 313S–316SPubMedGoogle Scholar
  28. Kaur D, Yantiri F, Rajagopalan S, Kumar J, Mo JQ, Boonplueang R, Viswanath V, Jacobs R, Yang L, Beal MF, DiMonte D, Volitaskis I, Ellerby L, Cherny RA, Bush AI, Andersen JK (2003) Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson’s disease. Neuron 37: 899–909PubMedCrossRefGoogle Scholar
  29. Kerry N, Rice-Evans C (1999) Inhibition of peroxynitrite-mediated oxidation of dopamine by flavonoid and phenolic antioxidants and their structural relationships. J Neurochem 73: 247–253PubMedCrossRefGoogle Scholar
  30. Kumamoto M, Sonda T, Nagayama K, Tabata M (2001) Effects of pH and metal ions on antioxidative activities of catechins. Biosci Biotechnol Biochem 65: 126–132PubMedCrossRefGoogle Scholar
  31. Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW (2004) Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med 36: 1–12PubMedGoogle Scholar
  32. Leissring MA, Murphy MP, Mead TR, Akbari Y, Sugarman MC, Jannatipour M, Anliker B, Muller U, Saftig P, De Strooper B, Wolfe MS, Golde TE, LaFerla FM (2002) A physiologic signaling role for the gamma-secretase-derived intracellular fragment of APP. Proc Natl Acad Sci USA 99: 4697–4702PubMedCrossRefGoogle Scholar
  33. Levites Y, Amit T, Youdim MBH, Mandel S (2002) Involvement of protein kinase C activation and cell survival=cell cycle genes in green tea polyphenol (−)-epigallocatechin-3-gallate neuroprotective action. J Biol Chem 277: 30574–30580PubMedCrossRefGoogle Scholar
  34. Levites Y, Amit T, Mandel S, Youdim MBH (2003) Neuroprotection and neurorescue against amyloid beta toxicity and PKC-dependent release of non-amyloidogenic soluble precusor protein by green tea polyphenol (−)-epigallocatechin-3-gallate. Faseb J 17: 952–954PubMedGoogle Scholar
  35. Linazasoro G (2002) Neuroprotection in Parkinson’s disease: love story or mission impossible? Expert Rev Neurotherapeutics 2: 403–416CrossRefGoogle Scholar
  36. Mandel S, Youdim MBH (2004) Catechin polyphenols: neurodegeneration and neuroprotection in neurodegenerative diseases. Free Radical Bio Med 37: 304–317CrossRefGoogle Scholar
  37. Mandel S, Maor G, Youdim MBH (2004a) Iron and alpha-synuclein in the substantia nigra of MPTP-treated mice: effect of neuroprotective drugs R-apomorphine and green tea polyphenol (−)-epigallocatechin-3-gallate. J Mol Neurosci 24: 401–416PubMedCrossRefGoogle Scholar
  38. Mandel S, Weinreb O, Amit T, Youdim MBH (2004b) 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
  39. Mandel SA, Avramovich-Tirosh Y, Reznichenko L, Zheng H, Weinreb O, Amit T, Youdim MBH (2005) Multifunctional activities of green tea catechins in neuroprotection. Neurosignals 14: 46–60PubMedCrossRefGoogle Scholar
  40. Marambaud P, Zhao H, Davies P (2005) Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J Biol Chem 280: 37377–37382PubMedCrossRefGoogle Scholar
  41. Mattson MP (1997) Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev 77: 1081–1132PubMedGoogle Scholar
  42. McNaught KS, Belizaire R, Jenner P, Olanow CW, Isacson O (2002) Selective loss of 20S proteasome alpha-subunits in the substantia nigra pars compacta in Parkinson’s disease. Neurosci Lett 326: 155–158PubMedCrossRefGoogle Scholar
  43. Meade TW (1975) Subacute myelo-optic neuropathy and clioquinol. An epidemiological case-history for diagnosis. Br J Prev Soc Med 29: 157–169PubMedGoogle Scholar
  44. Morel I, Lescoat G, Cogrel P, Sergent O, Pasdeloup N, Brissot P, Cillard P, Cillard J (1999) Antioxidant and iron-chelating activities of the flavonoids catechin, quercetin and diosmetin on iron-loaded rat hepatocyte cultures. Biochem Pharmacol 45: 13–19CrossRefGoogle Scholar
  45. Nakagawa K, Miyazawa T (1997) Absorption and distribution of tea catechin, (−)-epigallocatechin-3-gallate, in the rat. J Nutr Sci Vitaminol (Tokyo) 43: 679–684PubMedGoogle Scholar
  46. Ono K, Hasegawa K, Naiki H, Yamada M (2004) Anti-amyloidogenic activity of tannic acid and its activity to destabilize Alzheimer’s betaamyloid fibrils in vitro. Biochim Biophys Acta 1690: 193–202PubMedGoogle Scholar
  47. Ono K, Yoshiike Y, Takashima A, Hasegawa K, Naiki H, Yamada M (2003) Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer’s disease. J Neurochem 87: 172–181PubMedCrossRefGoogle Scholar
  48. Pannala AS, Razaq R, Halliwell B, Singh S, Rice-Evans CA (1998) Inhibition of peroxynitrite dependent tyrosine nitration by hydroxycinnamates: nitration or electron donation? Free Radical Bio Med 24: 594–606CrossRefGoogle Scholar
  49. Payton S, Cahill CM, Randall JD, Gullans SR, Rogers JT (2003) Drug discovery targeted to the Alzheimer’s APP mRNA 5′-untranslated region: the action of paroxetine and dimercaptopropanol. J Mol Neurosci 20: 267–275PubMedCrossRefGoogle Scholar
  50. Poon HF, Shepherd HM, Reed TT, Calabrese V, Stella AM, Pennisi G, Cai J, Pierce WM, Klein JB, Butterfield DA (2005) Proteomics analysis provides insight into caloric restriction mediated oxidation and expression of brain proteins associated with age-related impaired cellular processes: Mitochondrial dysfunction, glutamate dysregulation and impaired protein synthesis. Neurobiol Ageing: Epub ahead of printGoogle Scholar
  51. Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, Ehrhart J, Townsend K, Zeng J, Morgan D, Hardy J, Town T, Tan J (2005) Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. J Neurosci 25: 8807–8814PubMedCrossRefGoogle Scholar
  52. Reznichenko L, Amit T, Youdim MBH, Mandel S (2005) Green tea polyphenol (−)-epigallocatechin-3-gallate induces neurorescue of long-term serum-deprived PC12 cells and promotes neurite outgrowth. J Neurochem 93: 1157–1167PubMedCrossRefGoogle Scholar
  53. Reznichenko L, Amit T, Zheng H, Weinreb O, Avramovich-Tirosh Y, Youdim MBH, Mandel S (2006) Reduction of the iron-regulated beta-amyloid precursor protein and toxic beta-amyloid peptides expression by green tea polyphenol (−)-epigallocatechin-3-gallate: implication of iron chelation in Alzheimer’s disease. J Neurochem 97: 27–36CrossRefGoogle Scholar
  54. Rice-Evans C (2001) Flavonoid antioxidants. Curr Med Chem 8: 797–807PubMedGoogle Scholar
  55. Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, Youdim MBH (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 52: 515–520PubMedCrossRefGoogle Scholar
  56. Rogers JT, Lahiri DK (2004) Metal and inflammatory targets for Alzheimer’s disease. Curr Drug Targets 5: 535–551PubMedCrossRefGoogle Scholar
  57. Rogers JT, Randall JD, Cahill CM, Eder PS, Huang X, Gunshin H, Leiter L, McPhee J, Sarang SS, Utsuki T, Greig NH, Lahiri DK, Tanzi RE, Bush AI, Giordano T, Gullans SR (2002) An iron-responsive element type II in the 5′-untranslated region of the Alzheimer’s amyloid precursor protein transcript. J Biol Chem 277: 45518–45528PubMedCrossRefGoogle Scholar
  58. Schroeter H, Boyd C, Spencer JP, Williams RJ, Cadenas E, Rice-Evans C (2002) MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide. Neurobiol Ageing 23: 861–880CrossRefGoogle Scholar
  59. Sharp FR, Bernaudin M (2004) HIF1 and oxygen sensing in the brain. Nat Rev Neurosci 5: 437–448PubMedCrossRefGoogle Scholar
  60. Sipe JC, Lee P, Beutler E (2002) Brain iron metabolism and neurodegenerative disorders. Dev Neurosci 24: 188–196PubMedCrossRefGoogle Scholar
  61. Sorond FA, Ratan RR (2000) Ironing-out mechanisms of neuronal injury under hypoxic-ischemic conditions and potential role of iron chelators as neuroprotective agents. Antioxidants and Redox Signaling 2: 421–436PubMedCrossRefGoogle Scholar
  62. Suganuma M, Okabe S, Oniyama M, Tada Y, Ito H, Fujiki H (1998) Wide distribution of [3H](−)-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue. Carcinogenesis 19: 1771–1776.PubMedCrossRefGoogle Scholar
  63. Templeton DM, Liu Y (2003) Genetic regulation of cell function in response to iron overload or chelation. Biochim Biophys Acta 1619: 113–124PubMedGoogle Scholar
  64. Thomas R, Kim MH (2005) Epigallocatechin gallate inhibits HIF-1alpha degradation in prostate cancer cells. Biochem Biophys Res Commun 334: 543–548PubMedCrossRefGoogle Scholar
  65. Tournaire C, Croux S, Maurette MT, Beck I, Hocquaux M, Braun AM, Oliveros E (1993) Antioxidant activity of flavonoids: efficiency of singlet oxygen (1 delta g) quenching. Journal of Photochemistry and Photobiology B 19: 205–215CrossRefGoogle Scholar
  66. Townsend PA, Scarabelli TM, Davidson SM, Knight RA, Latchman DS, Stephanou A (2004) STAT-1 interacts with p53 to enhance DNA damage-induced apoptosis. J Biol Chem 279: 5811–5820PubMedCrossRefGoogle Scholar
  67. Wang J, Chen G, Muckenthaler M, Galy B, Hentze MW, Pantopoulos K (2004) Iron-mediated degradation of IRP2, an unexpected pathway involving a 2-oxoglutarate-dependent oxygenase activity. Mol Cell Biol 24: 954–965PubMedCrossRefGoogle Scholar
  68. Wang ZY, Huang MT, Lou YR, Xie JG, Reuhl KR, Newmark HL, Ho CT, Yang CS, Conney AH (1994) Inhibitory effects of black tea, green tea, decaffeinated black tea, and decaffeinated green tea on ultraviolet B light-induced skin carcinogenesis in 7,12-dimethylbenz [a]anthracene-initiated SKH-1 mice. Cancer Res 54: 3428–3455PubMedGoogle Scholar
  69. Weinreb O, Mandel S, Youdim MBH (2003) cDNA gene expression profile homology of antioxidants and their anti-apoptotic and pro-apoptotic activities in human neuroblastoma cells. Faseb J 17: 935–937PubMedGoogle Scholar
  70. Wiseman S, Mulder T, Rietveld A (2001) Tea flavonoids: bioavailability in vivo and effects on cell signaling pathways in vitro. Antioxid Redox Signal 3: 1009–1021PubMedCrossRefGoogle Scholar
  71. Wiseman SA, Balentine DA, Frei B (1997) Antioxidants in tea. Crit Rev Food Sci Nutr 37: 705–718PubMedCrossRefGoogle Scholar
  72. Yang CS, Wang ZY (1993) Tea and cancer. J Natl Cancer Inst 85: 1038–1049.PubMedGoogle Scholar
  73. Youdim MBH, Riederer P (2004) Iron in the brain, normal and pathological, In: Adelman G, Smith B (eds) Encyclopedia of Neuroscience, ElsevierGoogle Scholar
  74. Youdim MBH, Buccafusco JJ (2005) Multi-functional Drugs for Various CNS Targets in the Treatment of Neurodegenerative Disorders. Trends Pharmacol Sci 26: 27–35PubMedCrossRefGoogle Scholar
  75. Youdim MBH, Fridkin M, Zheng H (2004) Novel bifunctional drugs targeting monoamine oxidase inhibition and iron chelation as an approach to neuroprotection in Parkinson’s disease and other neurodegenerative diseases. J Neural Transm 111: 1455–1471PubMedCrossRefGoogle Scholar
  76. Zecca L, Youdim MBH, Riederer P, Connor JR, Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5: 863–873PubMedCrossRefGoogle Scholar
  77. Zhang Y, James M, Middleton FA, Davis RL (2005) Transcriptional analysis of multiple brain regions in Parkinson’s disease supports the involvement of specific protein processing, energy metabolism, and signaling pathways, and suggests novel disease mechanisms. Am J Med Genet B Neuropsychiatr Genet 137: 5–16PubMedGoogle Scholar
  78. Zheng H, Gal S, Weiner LM, Bar-Am O, Warshawsky A, Fridkin M, Youdim MBH (2005a) Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases: in vitro studies on antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition. J Neurochem 95: 68–78PubMedCrossRefGoogle Scholar
  79. Zheng H, Weiner LM, Bar-Am O, Epsztejn S, Cabantchik ZI, Warshawsky A, Youdim MBH, Fridkin M (2005b) Design, synthesis, and evaluation of novel bifunctional iron-chelators as potential agents for neuroprotection in Alzheimer’s, Parkinson’s, and other neurodegenerative diseases. Bioorg Med Chem 13: 773–783PubMedCrossRefGoogle Scholar
  80. Zhou YD, Kim YP, Li XC, Baerson SR, Agarwal AK, Hodges TW, Ferreira D, Nagle DG (2004) Hypoxia-inducible factor-1 activation by (−)-epicatechin gallate: potential adverse effects of cancer chemoprevention with high-dose green tea extracts. J Nat Prod 67: 2063–2069PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • S. Mandel
    • 1
    • 2
  • O. Weinreb
    • 1
  • L. Reznichenko
    • 1
  • L. Kalfon
    • 1
  • T. Amit
    • 1
  1. 1.Department of Pharmacology, Faculty of Medicine, TechnionEve Topf and US NPF Centers for Neurodegenerative DiseasesHaifaIsrael
  2. 2.HaifaIsrael

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