Many lines of evidence suggest that oxidative stress resulting in reactive oxygen species (ROS) generation and inflammation play a pivotal role in the age-associated cognitive decline and neuronal loss in neurodegenerative diseases including Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s diseases. One cardinal chemical pathology observed in these disorders is the accumulation of iron at sites where the neurons die. The buildup of an iron gradient in conjunction with ROS (superoxide, hydroxyl radical and nitric oxide) are thought to constitute a major trigger in neuronal toxicity and demise in all these diseases. Thus, promising future treatment of neurodegenerative diseases and aging depends on availability of effective brain permeable, iron-chelatable/radical scavenger neuroprotective drugs that would prevent the progression of neurodegeneration. Tea flavonoids (catechins) have been reported to possess potent iron- chelating, radical-scavenging and anti-inflammatory activities and to protect neuronal death in a wide array of cellular and animal models of neurological diseases. Recent studies have indicated that in addition to the known antioxidant activity of catechins, other mechanisms such as modulation of signal transduction pathways, cell survival/death genes and mitochondrial function, contribute significantly to the induction of cell viability. This review will focus on the multifunctional properties of green tea and its major component (–)-epigallocatechin-3-gallate (EGCG) and their ability to induce neuroprotection and neurorescue in vitro and in vivo. In particular, their transitional metal (iron and copper) chelating property and inhibition of oxidative stress.
© 2005 S. Karger AG, Basel
- Parkinson’s disease
- Neurite outgrowth
- Green tea catechins
- Iron chelation
- Cell signaling
- Protein kinase C
- Butterfield D, Castegna A, Pocernich C, Drake J, Scapagnini G, Calabrese V: Nutritional approaches to combat oxidative stress in Alzheimer’s disease. J Nutr Biochem 2002;13:444.
- Wang ZY, Huang MT, Lou YR, Xie JG, Reuhl KR, Newmark HL, Ho CT, Yang CS, Conney AH: 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 1994;54:3428–3455.
- Yang CS, Wang ZY: Tea and cancer. J Natl Cancer Inst 1993;85:1038–1049.
- Wiseman SA, Balentine DA, Frei B: Antioxidants in tea. Crit Rev Food Sci Nutr 1997;37:705–718.
- Higdon JV, Frei B: Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. Crit Rev Food Sci Nutr 2003;43:89–143.
- Jiang F, Dusting GJ: Natural phenolic compounds as cardiovascular therapeutics: Potential role of their anti-inflammatory effects. Curr Vasc Pharmacol 2003;1:135–156.
- Guo Q, Zhao B, Shen S, Hou J, Hu J, Xin W: ESR study on the structure-antioxidant activity relationship of tea catechins and their epimers. Biochim Biophys Acta 1999;1427:13–23.
- Hider RC, Liu ZD, Khodr HH: Metal chelation of polyphenols. Methods Enzymol 2001;335:190–203.
- Guo Q, Zhao B, Li M, Shen S, Xin W: Studies on protective mechanisms of four components of green tea polyphenols against lipid peroxidation in synaptosomes. Biochim Biophys Acta 1996;1304:210–222.
- Kumamoto M, Sonda T, Nagayama K, Tabata M: Effects of pH and metal ions on antioxidative activities of catechins. Biosci Biotechnol Biochem 2001;65:126–132.
- Grinberg LN, Newmark H, Kitrossky N, Rahamim E, Chevion M, Rachmilewitz EA: Protective effects of tea polyphenols against oxidative damage to red blood cells. Biochem Pharmacol 1997;54:973–978.
- Mandel S, Weinreb O, Amit T, Youdim MBH: Cell signaling pathways in the neuroprotective actions of the green tea polyphenol (–)-epigallocatechin-3-gallate: implications for neurodegenerative diseases. J Neurochem 2004;88:1555–1569.
- Weinreb O, Mandel S, Amit T, Youdim MB: Neurological mechanisms of green tea polyphenols in Alzheimer’s and Parkinson’s diseases. J Nutr Biochem 2004;15:506–516.
- Suganuma M, Okabe S, Oniyama M, Tada Y, Ito H, Fujiki H: Wide distribution of [3H](–)-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue. Carcinogenesis 1998;19:1771–1776.
- Nakagawa K, Miyazawa T: Absorption and distribution of tea catechin, (–)-epigallocatechin-3-gallate, in the rat. J Nutr Sci Vitaminol (Tokyo) 1997;43:679–684.
- Abd El Mohsen MM, Kuhnle G, Rechner AR, Schroeter H, Rose S, Jenner P, Rice-Evans CA: Uptake and metabolism of epicatechin and its access to the brain after oral ingestion. Free Rad Biol Med 2002;33:1693–1702.
- Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR: Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 2004;5:863–873.
- Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R, Verna JM: Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: Contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 2001;65:135–172.
- Linazasoro G: Neuroprotection in Parkinson’s disease: Love story or mission impossible? Expert Rev Neurotherapeut 2002;2:403–416.
- McNaught KS, Belizaire R, Jenner P, Olanow CW, Isacson O: Selective loss of 20S proteasome alpha-subunits in the substantia nigra pars compacta in Parkinson’s disease. Neurosci Lett 2002;326:155–158.
- Olanow CW, Youdim MB: Iron and neurodegeneration: Prospects for neuroprotection; in Olanow CW, Jenner P, Youdim MB (eds): Neurodegeneration and Neuroprotection in Parkinson’s Disease. London, Academic Press, 1996, pp 55–69.
- Mandel S, Grunblatt E, Youdim MBH: cDNA microarray to study gene expression of dopaminergic neurodegeneration and neuroprotection in MPTP and 6-hydroxydopamine models: Implications for idiopathic Parkinson’s disease. J Neural Transm Suppl 2000;60:117–124.
- Dauer W, Przedborski S: Parkinson’s disease: Mechanisms and models. Neuron 2003;39:889–909.
- Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, Dekker MC, Squitieri F, Ibanez P, Joosse M, van Dongen JW, Vanacore N, van Swieten JC, Brice A, Meco G, van Duijn CM, Oostra BA, Heutink P: Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science 2003;299:256–259.
- Valente EM, Abou-Sleiman PM, Caputo V, Muqit MM, Harvey K, Gispert S, Ali Z, Del Turco D, Bentivoglio AR, Healy DG, Albanese A, Nussbaum R, Gonzalez-Maldonado R, Deller T, Salvi S, Cortelli P, Gilks WP, Latchman DS, Harvey RJ, Dallapiccola B, Auburger G, Wood NW: Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 2004;304:1158–1160.
- Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, Juncos JL, Nutt J, Shoulson I, Carter J, Kompoliti K, Perlmutter JS, Reich S, Stern M, Watts RL, Kurlan R, Molho E, Harrison M, Lew M: Effects of coenzyme Q10 in early Parkinson disease: Evidence of slowing of the functional decline. Arch Neurol 2002;59:1541–1550.
- Riederer P, Sofic E, Rausch WD, Schmidt B, Reynolds GP, Jellinger K, Youdim MBH: Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem 1989;52:515–520.
- Jenner P, Olanow CW: Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology 1996;47:S161–170.
- Grunblatt E, Mandel S, Jacob-Hirsch J, Zeligson S, Amariglo N, Rechavi G, Li J, Ravid R, Roggendorf W, Riederer P, Youdim MB: 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 2004;111:1543–1573.
- Levites Y, Weinreb O, Maor G, Youdim MBH, Mandel S: Green tea polyphenol (–)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. J Neurochem 2001;78:1073–1082.
- Komatsu M, Hiramatsu M: The efficacy of an antioxidant cocktail on lipid peroxide level and superoxide dismutase activity in aged rat brain and DNA damage in iron-induced epileptogenic foci. Toxicology 2000;148:143–148.
- Pan T, Fei J, Zhou X, Jankovic J, Le W: Effects of green tea polyphenols on dopamine uptake and on MPP+-induced dopamine neuron injury. Life Sci 2003;72:1073–1083.
- Lu H, Meng X, Yang CS: Enzymology of methylation of tea catechins and inhibition of catechol-O-methyltransferase by (–)-epigallocatechin gallate. Drug Metab Dispos 2003;31:572–579.
- Lee S, Suh S, Kim S: Protective effects of the green tea polyphenol (-)-epigallocatechin gallate against hippocampal neuronal damage after transient global ischemia in gerbils. Neurosci Lett 2000;287:191–194.
- Lee H, Bae JH, Lee SR: Protective effect of green tea polyphenol EGCG against neuronal damage and brain edema after unilateral cerebral ischemia in gerbils. J Neurosci Res 2004;77:892–900.
- Suzuki M, Tabuchi M, Ikeda M, Umegaki K, Tomita T: Protective effects of green tea catechins on cerebral ischemic damage. Med Sci Monit 2004;10:BR166–174.
- Sutherland BA, Shaw OM, Clarkson AN, Jackson DM, Sammut IA, Appleton I: Neuroprotective effects of (–)-epigallocatechin gallate after hypoxia-ischemia-induced brain damage: novel mechanisms of action. Faseb J 2004.
- Townsend PA, Scarabelli TM, Davidson SM, Knight RA, Latchman DS, Stephanou A: STAT-1 interacts with p53 to enhance DNA damage-induced apoptosis. J Biol Chem 2004;279:5811–5820.
- Aktas O, Prozorovski T, Smorodchenko A, Savaskan NE, Lauster R, Kloetzel PM, Infante-Duarte C, Brocke S, Zipp F: Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol 2004;173:5794–5800.
- Schroeter H, Spencer JP, Rice-Evans C, Williams RJ: Flavonoids protect neurons from oxidized low-density-lipoprotein-induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3. Biochem J 2001;358:547–557.
- Spencer JP, Schroeter H, Kuhnle G, Srai SK, Tyrrell RM, Hahn U, Rice-Evans C: Epicatechin and its in vivo metabolite, 3′-O-methyl epicatechin, protect human fibroblasts from oxidative-stress-induced cell death involving caspase-3 activation. Biochem J 2001;354:493–500.
- Nobre Junior HV, Cunha GM, Maia FD, Oliveira RA, Moraes MO, Rao VS: Catechin attenuates 6-hydroxydopamine (6-OHDA)-induced cell death in primary cultures of mesencephalic cells. Comp Biochem Physiol [C] 2003;136:175–180.
- Mercer LD, Kelly BL, Horne MK, Beart PM: Dietary polyphenols protect dopamine neurons from oxidative insults and apoptosis: Investigations in primary rat mesencephalic cultures. Biochem Pharmacol 2005;69:339–345.
- Levites Y, Amit T, Youdim MBH, Mandel S: Involvement of protein kinase C activation and cell survival/cell cycle genes in green tea polyphenol (–)-epigallocatechin-3-gallate neuroprotective action. J Biol Chem 2002;277:30574–30580.
- Choi YT, Jung CH, Lee SR, Bae JH, Baek WK, Suh MH, Park J, Park CW, Suh SI: The green tea polyphenol (–)-epigallocatechin gallate attenuates beta-amyloid-induced neurotoxicity in cultured hippocampal neurons. Life Sci 2001;70:603–614.
- Levites Y, Amit T, Mandel S, Youdim MBH: 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 2003;17:952–954.
- Reznichenko L, Amit T, Youdim MB, Mandel S: Green tea polyphenol (–)-epigallocatechin-3-gallate induces neurorescue of long-term serum-deprived PC12 cells and promotes neurite outgrowth. J Neurochem 2005;in press.
- Weinreb O, Mandel S, Youdim MBH: cDNA gene expression profile homology of antioxidants and their anti-apoptotic and pro-apoptotic activities in human neuroblastoma cells. FASEB J 2003;17:935–937.
- Halliwell B: Vitamin C: antioxidant or pro-oxidant in vivo? Free Rad Res 1996;25:439–454.
- Gassen M, Pinchasi B, Youdim MB: Apomorphine is a potent radical scavenger and protects cultured pheochromocytoma cells from 6-OHDA and H2O2-induced cell death. Adv Pharmacol 1998;42:320–324.
- Gassen M, Gross A, Youdim MB: Apomorphine enantiomers protect cultured pheochromocytoma (PC12) cells from oxidative stress induced by H2O2 and 6-hydroxydopamine. Mov Disord 1998;13:242–248.
- Galati G, O’Brien PJ: Potential toxicity of flavonoids and other dietary phenolics: Significance for their chemopreventive and anticancer properties. Free Radic Biol Med 2004;37:287–303.
- Wiseman S, Mulder T, Rietveld A: Tea flavonoids: Bioavailability in vivo and effects on cell signaling pathways in vitro. Antioxid Redox Signal 2001;3:1009–1021.
- Durkin JP, Tremblay R, Chakravarthy B, Mealing G, Morley P, Small D, Song D: Evidence that the early loss of membrane protein kinase C is a necessary step in the excitatory amino acid-induced death of primary cortical neurons. J Neurochem 1997;68:1400–1412.
- Maher P: How protein kinase C activation protects nerve cells from oxidative stress-induced cell death. J Neurosci 2001;21:2929–2938.
- Vianna MR, Barros DM, Silva T, Choi H, Madche C, Rodrigues C, Medina JH, Izquierdo I: Pharmacological demonstration of the differential involvement of protein kinase C isoforms in short- and long-term memory formation and retrieval of one-trial avoidance in rats. Psychopharmacology (Berl) 2000;150:77–84.
- Lange-Asschenfeldt C, Raval AP, Dave KR, Mochly-Rosen D, Sick TJ, Perez-Pinzon MA: Epsilon protein kinase C mediated ischemic tolerance requires activation of the extracellular regulated kinase pathway in the organotypic hippocampal slice. J Cereb Blood Flow Metab 2004;24:636–645.
- Cordey M, Gundimeda U, Gopalakrishna R, Pike CJ: Estrogen activates protein kinase C in neurons: Role in neuroprotection. J Neurochem 2003;84:1340–1348.
- Han YS, Zheng WH, Bastianetto S, Chabot JG, Quirion R: Neuroprotective effects of resveratrol against beta-amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C. Br J Pharmacol 2004;141:997–1005.
- Youdim MBH: Rasagiline: An anti-Parkinson drug with neuroprotective activity. Expert Rev Neurotherapeut 2003;3:737–749.
- Weinreb O, Bar-Am O, Amit T, Chillag-Talmor O, Youdim MB: Neuroprotection via pro-survival protein kinase C isoforms associated with Bcl-2 family members. FASEB J 2004;18:1471–1473.
- Mandel S, Maor G, Youdim MBH: 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 2004;24:401–416.
- Ruvolo PP, Deng X, Carr BK, May WS: A functional role for mitochondrial protein kinase Calpha in Bcl2 phosphorylation and suppression of apoptosis. J Biol Chem 1998;273:25436–25442.
- Jiffar T, Kurinna S, Suck G, Carlson-Bremer D, Ricciardi MR, Konopleva M, Andreeff M, Ruvolo PP: PKC alpha mediates chemoresistance in acute lymphoblastic leukemia through effects on Bcl2 phosphorylation. Leukemia 2004;18:505–512.
- Kim SY, Ahn BH, Kim J, Bae YS, Kwak JY, Min G, Kwon TK, Chang JS, Lee YH, Yoon SH, Min do S: Phospholipase C, protein kinase C, Ca2+/calmodulin-dependent protein kinase II, and redox state are involved in epigallocatechin gallate-induced phospholipase D activation in human astroglioma cells. Eur J Biochem 2004;271:3470–3480.
- Kumazawa S, Kajiya K, Naito A, Saito H, Tuzi S, Tanio M, Suzuki M, Nanjo F, Suzuki E, Nakayama T: Direct evidence of interaction of a green tea polyphenol, epigallocatechin gallate, with lipid bilayers by solid-state nuclear magnetic resonance. Biosci Biotechnol Biochem 2004;68:1743–1747.
- Saito H, Tabeta R, Kodama M, Nagata C, Sato Y: Direct evidence of incorporation of 12-O-[20-2H1]tetradecanoylphorbol-13-acetate into artificial membranes as determined by deuterium magnetic resonance. Cancer Lett 1984;22:65–69.
- Gary DS, Milhavet O, Camandola S, Mattson MP: Essential role for integrin linked kinase in Akt-mediated integrin survival signaling in hippocampal neurons. J Neurochem 2003;84:878–890.
- Kermer P, Klocker N, Labes M, Bahr M: Insulin-like growth factor-I protects axotomized rat retinal ganglion cells from secondary death via PI3-K-dependent Akt phosphorylation and inhibition of caspase-3 in vivo. J Neurosci 2000;20:2–8.
- Singer CA, Figueroa-Masot XA, Batchelor RH, Dorsa DM: The mitogen-activated protein kinase pathway mediates estrogen neuroprotection after glutamate toxicity in primary cortical neurons. J Neurosci 1999;19:2455–2463.
- Schroeter H, Boyd C, Spencer JP, Williams RJ, Cadenas E, Rice-Evans C: MAPK signaling in neurodegeneration: Influences of flavonoids and of nitric oxide. Neurobiol Aging 2002;23:861–880.
- Vaudry D, Stork PJ, Lazarovici P, Eiden LE: Signaling pathways for PC12 cell differentiation: Making the right connections. Science 2002;296:1648–1649.
- Harris CA, Deshmukh M, Tsui-Pierchala B, Maroney AC, Johnson EM Jr: Inhibition of the c-Jun N-terminal kinase signaling pathway by the mixed lineage kinase inhibitor CEP-1347 (KT7515) preserves metabolism and growth of trophic factor-deprived neurons. J Neurosci 2002;22:103–113.
- Alessandrini A, Namura S, Moskowitz MA, Bonventre JV: MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci USA 1999;96:12866–12869.
- Yun HY, Gonzalez-Zulueta M, Dawson VL, Dawson TM: Nitric oxide mediates N-methyl-D-aspartate receptor-induced activation of p21ras. Proc Natl Acad Sci USA 1998;95:5773–5778.
- Yu R, Jiao JJ, Duh JL, Gudehithlu K, Tan TH, Kong AN: Activation of mitogen-activated protein kinases by green tea polyphenols: Potential signaling pathways in the regulation of antioxidant-responsive element-mediated phase II enzyme gene expression. Carcinogenesis 1997;18:451–456.
- Chen C, Yu R, Owuor ED, Kong AN: Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death. Arch Pharm Res 2000;23:605–612.
- Owuor ED, Kong AN: Antioxidants and oxidants regulated signal transduction pathways. Biochem Pharmacol 2002;64:765–770.
- Chung JH, Han JH, Hwang EJ, Seo JY, Cho KH, Kim KH, Youn JI, Eun HC: Dual mechanisms of green tea extract-induced cell survival in human epidermal keratinocytes. FASEB J 2003;17:1913–1915
- Lorenz M, Wessler S, Follmann E, Michaelis W, Dusterhoft T, Baumann G, Stangl K, Stangl V: A constituent of green tea, epigallocatechin-3-gallate, activates endothelial nitric oxide synthase by a PI3K-, PKA-, and Akt-dependent pathway, and leads to endothelial-dependent vasorelaxation. J Biol Chem 2003.
- Tedeschi E, Menegazzi M, Yao Y, Suzuki H, Forstermann U, Kleinert H: Green tea inhibits human inducible nitric-oxide synthase expression by down-regulating signal transducer and activator of transcription-1alpha activation. Mol Pharmacol 2004;65:111–120.
- Bernardi P, Petronilli V, Di Lisa F, Forte M: A mitochondrial perspective on cell death. Trends Biochem Sci 2001;26:112–117.
- Cory S, Adams JM: The Bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer 2002;2:647–656.
- Merry DE, Korsmeyer SJ: Bcl-2 gene family in the nervous system. Annu Rev Neurosci 1997;20:245–267.
- DeFeudis FV, Drieu K: Ginkgo biloba extract (EGb 761) and CNS functions: Basic studies and clinical applications. Curr Drug Targets 2000;1:25–58.
- Ishige K, Schubert D, Sagara Y: Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med 2001;30:433–446.
- Lee JH, Song DK, Jung CH, Shin DH, Park J, Kwon TK, Jang BC, Mun KC, Kim SP, Suh SI, Bae JH: (–)-Epigallocatechin gallate attenuates glutamate-induced cytotoxicity via intracellular Ca modulation in PC12 cells. Clin Exp Pharmacol Physiol 2004;31:530–536.
- Bush AI: The metallobiology of Alzheimer’s disease. Trends Neurosci 2003;26:207–214.
- Atwood CS, Obrenovich ME, Liu T, Chan H, Perry G, Smith MA, Martins RN: Amyloid-beta: A chameleon walking in two worlds: A review of the trophic and toxic properties of amyloid-beta. Brain Res Brain Res Rev 2003;43:1–16.
- 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: An iron-responsive element type II in the 5′-untranslated region of the Alzheimer’s amyloid precursor protein transcript. J Biol Chem 2002;277:45518–45528.
- Sharp FR, Bernaudin M: HIF1 and oxygen sensing in the brain. Nat Rev Neurosci 2004;5:437–448.
- Lee JW, Bae SH, Jeong JW, Kim SH, Kim KW: Hypoxia-inducible factor (HIF-1)alpha: Its protein stability and biological functions. Exp Mol Med 2004;36:1–12.
- Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ: Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001;292:468–472.
- Minchenko O, Opentanova I, Caro J: Hypoxic regulation of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene family (PFKFB-1-4) expression in vivo. FEBS Lett 2003;554:264–270.
- Hanson ES, Leibold EA: Regulation of the iron regulatory proteins by reactive nitrogen and oxygen species. Gene Expr 1999;7:367–376.
- Wang J, Chen G, Muckenthaler M, Galy B, Hentze MW, Pantopoulos K: Iron-mediated degradation of IRP2, an unexpected pathway involving a 2-oxoglutarate-dependent oxygenase activity. Mol Cell Biol 2004;24:954–965.
- Crapper McLachlan DR, Dalton AJ, Kruck TP, Bell MY, Smith WL, Kalow W, Andrews DF: Intramuscular desferrioxamine in patients with Alzheimer’s disease. Lancet 1991;337:1304–1308.
- Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R, Li QX, Tammer A, Carrington D, Mavros C, Volitakis I, Xilinas M, Ames D, Davis S, Beyreuther K, Tanzi RE, Masters CL: Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting a beta amyloid deposition and toxicity in Alzheimer disease: A pilot phase 2 clinical trial. Arch Neurol 2003;60:1685–1691.
- Meade TW: Subacute myelo-optic neuropathy and clioquinol: An epidemiological case-history for diagnosis. Br J Prev Soc Med 1975;29:157–169.
- Baum L, Ng A: Curcumin interaction with copper and iron suggests one possible mechanism of action in Alzheimer’s disease animal models. J Alzheimers Dis 2004;6:367–377; discussion 443–369.
- Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM: The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. J Neurosci 2001;21:8370–8377.
- Dedeoglu A, Cormier K, Payton S, Tseitlin KA, Kremsky JN, Lai L, Li X, Moir RD, Tanzi RE, Bush AI, Kowall NW, Rogers JT, Huang X: Preliminary studies of a novel bifunctional metal chelator targeting Alzheimer’s amyloidogenesis. Exp Gerontol 2004;39:1641–1649.
- Youdim MB, Fridkin M, Zheng H: Bifunctional drug derivatives of MAO-B inhibitor rasagiline and iron chelator VK-28 as a more effective approach to treatment of brain ageing and ageing neurodegenerative diseases. Mech Age Dev 2005;126:317–326.
- Shachar DB, Kahana N, Kampel V, Warshawsky A, Youdim MB: Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lesion in rats. Neuropharmacology 2004;46:254–263.
- Youdim MB, Fridkin M, Zheng H: 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 2004;111:1455–1471.
- Youdim MBH, Buccafusco JJ: Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol Sci 2005;26:27–35.
- Zheng H, Weiner LM, Bar-Am O, Epsztejn S, Cabantchik ZI, Warshawsky A, Youdim MB, Fridkin M: 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 2005;13:773–783.
- Ono K, Yoshiike Y, Takashima A, Hasegawa K, Naiki H, Yamada M: Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: Implications for the prevention and therapeutics of Alzheimer’s disease. J Neurochem 2003;87:172–181.
- Mattson MP, Barger SW, Furukawa K, Bruce AJ, Wyss-Coray T, Mark RJ, Mucke L: Cellular signaling roles of TGF beta, TNF alpha and beta APP in brain injury responses and Alzheimer’s disease. Brain Res Rev 1997;23:47–61.
- Xu X, Yang D, Wyss-Coray T, Yan J, Gan L, Sun Y, Mucke L: Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis. Proc Natl Acad Sci USA 1999;96:7547–7552.
- Small DH, Nurcombe V, Reed G, Clarris H, Moir R, Beyreuther K, Masters CL: A heparin-binding domain in the amyloid protein precursor of Alzheimer’s disease is involved in the regulation of neurite outgrowth. J Neurosci 1994;14:2117–2127.
- Morimoto T, Ohsawa I, Takamura C, Ishiguro M, Kohsaka S: Involvement of amyloid precursor protein in functional synapse formation in cultured hippocampal neurons. J Neurosci Res 1998;51:185–195.
- Yamamoto A, Shin RW, Hasegawa K, Naiki H, Sato H, Yoshimasu F, Kitamoto T: Iron (III) induces aggregation of hyperphosphorylated tau and its reduction to iron (II) reverses the aggregation: implications in the formation of neurofibrillary tangles of Alzheimer’s disease. J Neurochem 2002;82:1137–1147.
- Gerlach M, Ben-Shachar D, Riederer P, Youdim MB: Altered brain metabolism of iron as a cause of neurodegenerative diseases? J Neurochem 1994;63:793–807.
- Jellinger KA: Neuropathological spectrum of synucleinopathies. Mov Disord 2003;18 (suppl 6):2–12.
- Turnbull S, Tabner BJ, El-Agnaf OM, Moore S, Davies Y, Allsop D: Alpha-Synuclein implicated in Parkinson’s disease catalyses the formation of hydrogen peroxide in vitro. Free Radic Biol Med 2001;30:1163–1170.
- Ostrerova-Golts N, Petrucelli L, Hardy J, Lee JM, Farer M, Wolozin B: The A53T alpha-synuclein mutation increases iron-dependent aggregation and toxicity. J Neurosci 2000;20:6048–6054.
- Ebadi M, Govitrapong P, Sharma S, Muralikrishnan D, Shavali S, Pellett L, Schafer R, Albano C, Eken J: Ubiquinone (coenzyme q10) and mitochondria in oxidative stress of Parkinson’s disease. Biol Signals Recept 2001;10:224–253.
- Ponka P: Hereditary causes of disturbed iron homeostasis in the central nervous system. Ann NY Acad Sci 2004;1012:267–281.
- Meyron-Holtz EG, Ghosh MC, Iwai K, LaVaute T, Brazzolotto X, Berger UV, Land W, Ollivierre-Wilson H, Grinberg A, Love P, Rouault TA: Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. EMBO J 2004;23:386–395.
- LaVaute T, Smith S, Cooperman S, Iwai K, Land W, Meyron-Holtz E, Drake SK, Miller G, Abu-Asab M, Tsokos M, Switzer R 3rd, Grinberg A, Love P, Tresser N, Rouault TA: Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet 2001;27:209–214.
- Hashimoto M, Takeda A, Hsu LJ, Takenouchi T, Masliah E: Role of cytochrome c as a stimulator of alpha-synuclein aggregation in Lewy body disease. J Biol Chem 1999;274:28849–28852.
- Ben-Shachar D, Eshel G, Finberg JP, Youdim MB: The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J Neurochem 1991;56:1441–1444.
- Lan J, Jiang DH: Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice. J Neural Transm (Budapest) 1997;104:469–481.
- Checkoway H, Powers K, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD: Parkinson’s disease risks associated with cigarette smoking, alcohol consumption, and caffeine intake. Am J Epidemiol 2002;155:732–738.
- Li SC, Schoenberg BS, Wang CC, Cheng XM, Rui DY, Bolis CL, Schoenberg DG: A prevalence survey of Parkinson’s disease and other movement disorders in the People’s Republic of China. Arch Neurol 1985;42:655–657.
- Zhang ZX, Roman GC: Worldwide occurrence of Parkinson’s disease: An updated review. Neuroepidemiology 1993;12:195–208.
- 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: Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: A novel therapy for Parkinson’s disease. Neuron 2003;37:899–909.
- Shoham S, Youdim MB: Nutritional iron deprivation attenuates kainate-induced neurotoxicity in rats: implications for involvement of iron in neurodegeneration. Ann NY Acad Sci 2004;1012:94–114.
Prof. M.B.H. Youdim
Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research, Technion-Faculty of Medicine
POB 9697, 31096 Haifa (Israel)
Tel. +972 4 8295290, Fax +972 4 8513145, E-Mail Youdim@Tx.Technion.ac.il
Received: January 28, 2005
Accepted after revision: March 1, 2005
Number of Print Pages : 15
Number of Figures : 6, Number of Tables : 0, Number of References : 129
Vol. 14, No. 1-2, Year 2005 (Cover Date: Released June 2005)
Journal Editor: Ip, N.Y. (Hong Kong)
ISSN: 1424–862X (print), 1424–8638 (Online)
For additional information: http://www.karger.com/nsg
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.