From Anti-Parkinson’s Drug Rasagiline to Novel Multitarget Iron Chelators with Acetylcholinesterase and Monoamine Oxidase Inhibitory and Neuroprotective Properties for Alzheimer’s Disease

Living reference work entry


Alzheimer’s disease (AD) is a multifactorial syndrome involving a complex array of different, while related factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel multimodal compounds, as follows: the brain selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity, M30; the chelating with neuroprotective activity, HLA20; the acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity, HLA20A; the AChE-MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity, M30D; and neuroprotective peptide NAPVSIPQ analogs. Among them, HLA20A and M30D act as pro-chelators and can be activated to liberate their respective active chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on antioxidant-chelating potency, AchE and MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including the major role of oxidative stress (OS) due to accumulation of iron in AD brains and formation of free oxygen radicals, modulation of amyloid-β (Aβ) and amyloid precursor protein expression/processing and tau, induction of cell cycle arrest; inhibition of neuronal death markers, upregulation of neurotrophic factors, as well as activation of protein kinase C and mitogen-activated protein kinase signaling pathways.


AChE-MAO-A and -B inhibitors M30 Multitarget chelators Site-activated Alzheimer’s disease 


  1. Abdipranoto A, Wu S, Stayte S, Vissel B. The role of neurogenesis in neurodegenerative diseases and its implications for therapeutic development. CNS Neurol Disord Drug Targets. 2008;7(2):187–210.CrossRefGoogle Scholar
  2. Anantharaman M, Tangpong J, Keller JN, Murphy MP, Markesbery WR, Kiningham KK, St Clair DK. Beta-amyloid mediated nitration of manganese superoxide dismutase: implication for oxidative stress in a APPNLH/NLH X PS-1P264L/P264L double knock-in mouse model of Alzheimer’s disease. Am J Pathol. 2006;168(5):1608–18. S0002-9440(10)62183-9 [pii]CrossRefGoogle Scholar
  3. Atri A, Shaughnessy LW, Locascio JJ, Growdon JH. Long-term course and effectiveness of combination therapy in Alzheimer disease. Alzheimer Dis Assoc Disord. 2008;22(3):209–21. Scholar
  4. Avramovich-Tirosh Y, Amit T, Bar-Am O, Zheng H, Fridkin M, Youdim MB. Therapeutic targets and potential of the novel brain- permeable multifunctional iron chelator-monoamine oxidase inhibitor drug, M-30, for the treatment of Alzheimer’s disease. J Neurochem. 2007a;100(2): 490–502. JNC4258 [pii]. Scholar
  5. Avramovich-Tirosh Y, Reznichenko L, Mit T, Zheng H, Fridkin M, Weinreb O, Mandel S, Youdim MB. Neurorescue activity, APP regulation and amyloid-beta peptide reduction by novel multi-functional brain permeable iron- chelating- antioxidants, M-30 and green tea polyphenol, EGCG. Curr Alzheimer Res. 2007b;4(4):403–11.CrossRefGoogle Scholar
  6. Avramovich-Tirosh Y, Bar-Am O, Amit T, Youdim MB, Weinreb O. Up-regulation of hypoxia-inducible factor (HIF)-1alpha and HIF-target genes in cortical neurons by the novel multifunctional iron chelator anti-Alzheimer drug, M30. Curr Alzheimer Res. 2010;7(4):300–6. CAR -54 [pii]CrossRefGoogle Scholar
  7. Bar-Am O, Weinreb O, Amit T, Youdim MB. Regulation of Bcl-2 family proteins, neurotrophic factors, and APP processing in the neurorescue activity of propargylamine. FASEB J. 2005;19(13):1899–901. 05-3794fje [pii]. Scholar
  8. Belluti F, Rampa A, Piazzi L, Bisi A, Gobbi S, Bartolini M, Andrisano V, Cavalli A, Recanatini M, Valenti P. Cholinesterase inhibitors: xanthostigmine derivatives blocking the acetylcholinesterase-induced beta-amyloid aggregation. J Med Chem. 2005;48(13):4444–56. Scholar
  9. Blat D, Weiner L, Youdim MB, Fridkin M. A novel iron-chelating derivative of the neuroprotective peptide NAPVSIPQ shows superior antioxidant and antineurodegenerative capabilities. J Med Chem. 2008;51(1):126–34. Scholar
  10. Borchardt T, Schmidt C, Camarkis J, Cappai R, Masters CL, Beyreuther K, Multhaup G. Differential effects of zinc on amyloid precursor protein (APP) processing in copper-resistant variants of cultured Chinese hamster ovary cells. Cell Mol Biol (Noisy-le-Grand). 2000;46(4):785–95.Google Scholar
  11. Borghi R, Patriarca S, Traverso N, Piccini A, Storace D, Garuti A, Gabriella C, Patrizio O, Massimo T. The increased activity of BACE1 correlates with oxidative stress in Alzheimer’s disease. Neurobiol Aging. 2007;28(7):1009–14. S0197-4580(06)00145-X [pii]. Scholar
  12. Brenneman DE, Spong CY, Hauser JM, Abebe D, Pinhasov A, Golian T, Gozes I. Protective peptides that are orally active and mechanistically nonchiral. J Pharmacol Exp Ther. 2004;309(3):1190–7. jpet.103.063891 [pii]CrossRefPubMedGoogle Scholar
  13. Bullock R, Dengiz A. Cognitive performance in patients with Alzheimer’s disease receiving cholinesterase inhibitors for up to 5 years. Int J Clin Pract. 2005;59(7):817–22. IJCP562 [pii]. Scholar
  14. Cavalli A, Bolognesi ML, Minarini A, Rosini M, Tumiatti V, Recanatini M, Melchiorre C. Multi-target-directed ligands to combat neurodegenerative diseases. J Med Chem. 2008;51(3):347–72. Scholar
  15. Cheng SY, Trombetta LD. The induction of amyloid precursor protein and alpha-synuclein in rat hippocampal astrocytes by diethyldithiocarbamate and copper with or without glutathione. Toxicol Lett. 2004;146(2):139–49. S0378427403003588 [pii]CrossRefGoogle Scholar
  16. Chow VW, Savonenko AV, Melnikova T, Kim H, Price DL, Li T, Wong PC. Modeling an anti-amyloid combination therapy for Alzheimer’s disease. Sci Transl Med. 2010;2(13):13ra11. 2/13/13ra1 [pii]CrossRefGoogle Scholar
  17. Correia SC, Moreira PI. Hypoxia-inducible factor 1: a new hope to counteract neurodegeneration? J Neurochem. 2010;112(1):1–12. JNC6443 [pii]CrossRefPubMedGoogle Scholar
  18. Cuajungco MP, Faget KY. Zinc takes the center stage: its paradoxical role in Alzheimer’s disease. Brain Res Brain Res Rev. 2003;41(1):44–56. S0165017302002199 [pii]CrossRefGoogle Scholar
  19. Diamant S, Podoly E, Friedler A, Ligumsky H, Livnah O, Soreq H. Butyrylcholinesterase attenuates amyloid fibril formation in vitro. Proc Natl Acad Sci U S A. 2006;103(23):8628–33. 0602922103 [pii]. Scholar
  20. Drake J, Link CD, Butterfield DA. Oxidative stress precedes fibrillar deposition of Alzheimer’s disease amyloid beta-peptide (1-42) in a transgenic Caenorhabditis elegans model. Neurobiol Aging. 2003;24(3):415–20. S0197458002002257 [pii]CrossRefGoogle Scholar
  21. Duce JA, Bush AI. Biological metals and Alzheimer’s disease: implications for therapeutics and diagnostics. Prog Neurobiol. 2010;92(1):1–18. S0301-0082(10)00093-6 [pii]CrossRefPubMedGoogle Scholar
  22. Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI. Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell. 2010;142(6):857–67. S0092-8674(10)00938-4 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  23. Fowler JS, Volkow ND, Wang GJ, Logan J, Pappas N, Shea C, MacGregor R. Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiol Aging. 1997;18(4):431–5. S0197-4580(97)00037-7 [pii]CrossRefGoogle Scholar
  24. Gal S, Zheng H, Fridkin M, Youdim MB. 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. 2005;95(1):79–88. JNC3341 [pii]. Scholar
  25. Gal S, Zheng H, Fridkin M, Youdim MB. Restoration of nigrostriatal dopamine neurons in post-MPTP treatment by the novel multifunctional brain-permeable iron chelator-monoamine oxidase inhibitor drug, M30. Neurotox Res. 2010;17(1):15–27. Scholar
  26. Geldenhuys WJ, Youdim MB, Carroll RT, Van der Schyf CJ. The emergence of designed multiple ligands for neurodegenerative disorders. Prog Neurobiol. 2011;94(4):347–59. S0301-0082(11)00061-X [pii]CrossRefPubMedGoogle Scholar
  27. Gozes I. NAP (davunetide) provides functional and structural neuroprotection. Curr Pharm Des. 2011;17(10):1040–4. BSP/CPD/E-Pub/000374 [pii]CrossRefGoogle Scholar
  28. Gozes I, Bardea A, Bechar M, Pearl O, Reshef A, Zamostiano R, Davidson A, Rubinraut S, Giladi E, Fridkin M, Brenneman DE. Neuropeptides and neuronal survival: neuroprotective strategy for Alzheimer’s disease. Ann N Y Acad Sci. 1997;814:161–6.CrossRefGoogle Scholar
  29. Gozes I, Giladi E, Pinhasov A, Bardea A, Brenneman DE. Activity-dependent neurotrophic factor: intranasal administration of femtomolar-acting peptides improve performance in a water maze. J Pharmacol Exp Ther. 2000;293(3):1091–8.PubMedGoogle Scholar
  30. Gozes I, Divinsky I, Pilzer I, Fridkin M, Brenneman DE, Spier AD. From vasoactive intestinal peptide (VIP) through activity-dependent neuroprotective protein (ADNP) to NAP: a view of neuroprotection and cell division. J Mol Neurosci. 2003;20(3):315–22. JMN:20:3:315 [pii]. Scholar
  31. Guglielmotto M, Giliberto L, Tamagno E, Tabaton M. Oxidative stress mediates the pathogenic effect of different Alzheimer’s disease risk factors. Front Aging Neurosci. 2010;2:3. Scholar
  32. Hamrick SE, McQuillen PS, Jiang X, Mu D, Madan A, Ferriero DM. A role for hypoxia-inducible factor-1alpha in desferoxamine neuroprotection. Neurosci Lett. 2005;379(2):96–100. S0304-3940(05)00009-1 [pii]. Scholar
  33. Hegde ML, Bharathi P, Suram A, Venugopal C, Jagannathan R, Poddar P, Srinivas P, Sambamurti K, Rao KJ, Scancar J, Messori L, Zecca L, Zatta P. Challenges associated with metal chelation therapy in Alzheimer’s disease. J Alzheimers Dis. 2009;17(3):457–68. Q3510L74N8003871 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  34. Hensley K, Carney JM, Mattson MP, Aksenova M, Harris M, Wu JF, Floyd RA, Butterfield DA. A model for beta-amyloid aggregation and neurotoxicity based on free radical generation by the peptide: relevance to Alzheimer disease. Proc Natl Acad Sci U S A. 1994;91(8):3270–4.CrossRefGoogle Scholar
  35. Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008;4(11):682–90. nchembio.118 [pii]CrossRefPubMedGoogle Scholar
  36. Huang X, Atwood CS, Hartshorn MA, Multhaup G, Goldstein LE, Scarpa RC, Cuajungco MP, Gray DN, Lim J, Moir RD, Tanzi RE, Bush AI. The A beta peptide of Alzheimer’s disease directly produces hydrogen peroxide through metal ion reduction. Biochemistry. 1999a;38(24): 7609–16. bi990438f [pii]CrossRefPubMedGoogle Scholar
  37. Huang X, Cuajungco MP, Atwood CS, Hartshorn MA, Tyndall JD, Hanson GR, Stokes KC, Leopold M, Multhaup G, Goldstein LE, Scarpa RC, Saunders AJ, Lim J, Moir RD, Glabe C, Bowden EF, Masters CL, Fairlie DP, Tanzi RE, Bush AI. Cu(II) potentiation of alzheimer abeta neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem. 1999b;274(52):37111–6.CrossRefGoogle Scholar
  38. Inestrosa NC, Alvarez A, Perez CA, Moreno RD, Vicente M, Linker C, Casanueva OI, Soto C, Garrido J. Acetylcholinesterase accelerates assembly of amyloid-beta-peptides into Alzheimer’s fibrils: possible role of the peripheral site of the enzyme. Neuron. 1996;16(4):881–91. S0896-6273(00)80108-7 [pii]CrossRefGoogle Scholar
  39. Ito K, Ahadieh S, Corrigan B, French J, Fullerton T, Tensfeldt T. Disease progression meta-analysis model in Alzheimer’s disease. Alzheimers Dement. 2010;6(1):39–53. S1552-5260(09)02013-5 [pii]CrossRefPubMedGoogle Scholar
  40. Jann MW. Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer’s disease. Pharmacotherapy. 2000;20(1):1–12.CrossRefGoogle Scholar
  41. 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(6):899–909. S0896627303001260 [pii]CrossRefGoogle Scholar
  42. Kayyali R, Pannala AS, Khodr H, Hider RC. Comparative radical scavenging ability of bidentate iron (III) chelators. Biochem Pharmacol. 1998;55(8):1327–32. S0006-2952(97)00602-3 [pii]CrossRefGoogle Scholar
  43. Kimura M, Akasofu S, Ogura H, Sawada K. Protective effect of donepezil against Abeta(1-40) neurotoxicity in rat septal neurons. Brain Res. 2005a;1047(1):72–84. S0006-8993(05)00516-0 [pii]. Scholar
  44. Kimura M, Komatsu H, Ogura H, Sawada K. Comparison of donepezil and memantine for protective effect against amyloid-beta(1-42) toxicity in rat septal neurons. Neurosci Lett. 2005b;391(1–2):17–21. S0304-3940(05)00961-4 [pii]. Scholar
  45. Kupershmidt L, Weinreb O, Amit T, Mandel S, Carri MT, Youdim MB. Neuroprotective and neuritogenic activities of novel multimodal iron-chelating drugs in motor-neuron-like NSC-34 cells and transgenic mouse model of amyotrophic lateral sclerosis. FASEB J. 2009;23(11):3766–79. fj.09-130047 [pii]CrossRefPubMedGoogle Scholar
  46. Kupershmidt L, Weinreb O, Amit T, Mandel S, Bar-Am O, Youdim MB. Novel molecular targets of the neuroprotective/neurorescue multimodal iron chelating drug M30 in the mouse brain. Neuroscience. 2011;189:345–58. S0306-4522(11)00322-8 [pii]CrossRefPubMedGoogle Scholar
  47. Lee HP, Zhu X, Casadesus G, Castellani RJ, Nunomura A, Smith MA, Lee HG, Perry G. Antioxidant approaches for the treatment of Alzheimer’s disease. Expert Rev Neurother. 2010;10(7):1201–8. Scholar
  48. Lin R, Chen X, Li W, Han Y, Liu P, Pi R. Exposure to metal ions regulates mRNA levels of APP and BACE1 in PC12 cells: blockage by curcumin. Neurosci Lett. 2008;440(3):344–7. S0304-3940(08)00733-7 [pii]CrossRefPubMedGoogle Scholar
  49. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1–3):3–26. S0169-409X(00)00129-0 [pii]CrossRefGoogle Scholar
  50. Luque FA, Jaffe SL. The molecular and cellular pathogenesis of dementia of the Alzheimer’s type an overview. Int Rev Neurobiol. 2009;84:151–65. S0074-7742(09)00408-5 [pii]CrossRefPubMedGoogle Scholar
  51. Mancini F, Naldi M, Cavrini V, Andrisano V. Multiwell fluorometric and colorimetric microassays for the evaluation of beta-secretase (BACE-1) inhibitors. Anal Bioanal Chem. 2007;388(5–6): 1175–83. Scholar
  52. Marrazzo A, Caraci F, Salinaro ET, Su TP, Copani A, Ronsisvalle G. Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity. Neuroreport. 2005;16(11): 1223–6. 00001756-200508010-00018 [pii]CrossRefGoogle Scholar
  53. Massoud F, Gauthier S. Update on the pharmacological treatment of Alzheimer’s disease. Curr Neuropharmacol. 2010;8(1):69–80. Scholar
  54. Mechlovich D, Amit T, Mandel SA, Bar-Am O, Bloch K, Vardi P, Youdim MB. The novel multifunctional, iron-chelating drugs M30 and HLA20 protect pancreatic beta-cell lines from oxidative stress damage. J Pharmacol Exp Ther. 2010;333(3):874–82. jpet.109.164269 [pii]CrossRefPubMedGoogle Scholar
  55. Meunier J, Ieni J, Maurice T. The anti-amnesic and neuroprotective effects of donepezil against amyloid beta25-35 peptide-induced toxicity in mice involve an interaction with the sigma1 receptor. Br J Pharmacol. 2006a;149(8):998–1012. 0706927 [pii]. Scholar
  56. Meunier J, Ieni J, Maurice T. Antiamnesic and neuroprotective effects of donepezil against learning impairments induced in mice by exposure to carbon monoxide gas. J Pharmacol Exp Ther. 2006b;317(3):1307–19. jpet.106.101527 [pii]. Scholar
  57. Morphy R. Selectively nonselective kinase inhibition: striking the right balance. J Med Chem. 2010;53(4):1413–37. Scholar
  58. Munoz-Torrero D. Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer’s disease. Curr Med Chem. 2008;15(24):2433–55.CrossRefGoogle Scholar
  59. Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, Langston W, Melamed E, Poewe W, Stocchi F, Tolosa E. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med. 2009;361(13):1268–78. 361/13/1268 [pii]CrossRefPubMedGoogle Scholar
  60. Patil S, Sheng L, Masserang A, Chan C. Palmitic acid-treated astrocytes induce BACE1 upregulation and accumulation of C-terminal fragment of APP in primary cortical neurons. Neurosci Lett. 2006;406(1–2):55–9. S0304-3940(06)00708-7 [pii]. Scholar
  61. Perez LR, Franz KJ. Minding metals: tailoring multifunctional chelating agents for neurodegenerative disease. Dalton Trans. 2010;39(9):2177–87. Scholar
  62. Piazzi L, Rampa A, Bisi A, Gobbi S, Belluti F, Cavalli A, Bartolini M, Andrisano V, Valenti P, Recanatini M. 3-(4-[[benzyl(methyl)amino]methyl]phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation: a dual function lead for Alzheimer’s disease therapy. J Med Chem. 2003;46(12): 2279–82. Scholar
  63. Querfurth HW, LaFerla FM. Alzheimer’s disease. N Engl J Med. 2010;362(4):329–44. 362/4/329 [pii]CrossRefPubMedGoogle Scholar
  64. Reinikainen KJ, Soininen H, Riekkinen PJ. Neurotransmitter changes in Alzheimer’s disease: implications to diagnostics and therapy. J Neurosci Res. 1990;27(4):576–86. Scholar
  65. Reznichenko L, Amit T, Zheng H, Avramovich-Tirosh Y, Youdim MB, Weinreb O, Mandel S. Reduction of iron-regulated amyloid precursor protein and beta-amyloid peptide by (−)-epigallocatechin-3-gallate in cell cultures: implications for iron chelation in Alzheimer’s disease. J Neurochem. 2006;97(2):527–36. JNC3770 [pii]. Scholar
  66. 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(47):45518–28. M207435200 [pii]CrossRefPubMedGoogle Scholar
  67. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease. The Alzheimer’s disease cooperative study. N Engl J Med. 1997;336(17):1216–22. Scholar
  68. Saura J, Luque JM, Cesura AM, Da Prada M, Chan-Palay V, Huber G, Loffler J, Richards JG. Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience. 1994;62(1):15–30.CrossRefGoogle Scholar
  69. Sayre LM, Perry G, Smith MA. Oxidative stress and neurotoxicity. Chem Res Toxicol. 2008;21(1):172–88. Scholar
  70. Schneider LS, Olin JT, Pawluczyk S. A double-blind crossover pilot study of l-deprenyl (selegiline) combined with cholinesterase inhibitor in Alzheimer’s disease. Am J Psychiatry. 1993;150(2): 321–3. Scholar
  71. Shachar DB, Kahana N, Kampel V, Warshawsky A, Youdim MB. Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats. Neuropharmacology. 2004;46(2):254–63. S002839080300354X [pii]CrossRefGoogle Scholar
  72. Silvestri L, Camaschella C. A potential pathogenetic role of iron in Alzheimer’s disease. J Cell Mol Med. 2008;12(5A):1548–50. JCMM356 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  73. Singh AT, Bhattacharyya RS, Radeff JM, Stern PH. Regulation of parathyroid hormone-stimulated phospholipase D in UMR-106 cells by calcium, MAP kinase, and small G proteins. J Bone Miner Res. 2003;18(8):1453–60. Scholar
  74. Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL, Siedlak SL, Tabaton M, Perry G. Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem. 1998;70(5):2212–5.CrossRefGoogle Scholar
  75. Soto C. Plaque busters: strategies to inhibit amyloid formation in Alzheimer’s disease. Mol Med Today. 1999;5(8):343–50. S1357-4310(99)01508-7 [pii]CrossRefGoogle Scholar
  76. Tamagno E, Bardini P, Obbili A, Vitali A, Borghi R, Zaccheo D, Pronzato MA, Danni O, Smith MA, Perry G, Tabaton M. Oxidative stress increases expression and activity of BACE in NT2 neurons. Neurobiol Dis. 2002;10(3):279–88. S0969996102905152 [pii]CrossRefGoogle Scholar
  77. Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, Santoro G, Davit A, Danni O, Smith MA, Perry G, Tabaton M. Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem. 2005;92(3):628–36. JNC2895 [pii]. Scholar
  78. van der Flier WM, Scheltens P. Epidemiology and risk factors of dementia. J Neurol Neurosurg Psychiatry. 2005;76(Suppl 5):v2–7. 76/suppl_5/v2 [pii]. Scholar
  79. Wang CY, Wang T, Zheng W, Zhao BL, Danscher G, Chen YH, Wang ZY. Zinc overload enhances APP cleavage and Abeta deposition in the Alzheimer mouse brain. PLoS One. 2010;5(12):e15349. Scholar
  80. Weinreb O, Amit T, Bar-Am O, Chillag-Talmor O, Youdim MB. Novel neuroprotective mechanism of action of rasagiline is associated with its propargyl moiety: interaction of Bcl-2 family members with PKC pathway. Ann N Y Acad Sci. 2005;1053:348–55. 1053/1/348 [pii]. Scholar
  81. Weinreb O, Amit T, Bar-Am O, Youdim MB. Induction of neurotrophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and ladostigil: new insights and implications for therapy. Ann N Y Acad Sci. 2007;1122:155–68. 1122/1/155 [pii]. Scholar
  82. Weinreb O, Amit T, Bar-Am O, Youdim MB. Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Prog Neurobiol. 2010;92(3): 330–44. S0301-0082(10)00120-6 [pii]CrossRefPubMedGoogle Scholar
  83. Weinreb O, Amit T, Bar-Am O, Youdim MB. A novel anti-Alzheimer’s disease drug, ladostigil neuroprotective, multimodal brain-selective monoamine oxidase and cholinesterase inhibitor. Int Rev Neurobiol. 2011;100:191–215. B978-0-12-386467-3.00010-8 [pii]CrossRefPubMedGoogle Scholar
  84. Wilkemeyer MF, Chen SY, Menkari CE, Brenneman DE, Sulik KK, Charness ME. Differential effects of ethanol antagonism and neuroprotection in peptide fragment NAPVSIPQ prevention of ethanol-induced developmental toxicity. Proc Natl Acad Sci U S A. 2003;100(14):8543–8. 1331636100 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  85. 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(5):1137–47. 1061 [pii]CrossRefGoogle Scholar
  86. Yatin SM, Varadarajan S, Link CD, Butterfield DA. In vitro and in vivo oxidative stress associated with Alzheimer’s amyloid beta-peptide (1-42). Neurobiol Aging. 1999;20(3):325–30. discussion 339-342. S0197458099000561 [pii]CrossRefGoogle Scholar
  87. Yogev-Falach M, Bar-Am O, Amit T, Weinreb O, Youdim MB. A multifunctional, neuroprotective drug, ladostigil (TV3326), regulates holo-APP translation and processing. FASEB J. 2006;20(12):2177–9. fj.05-4910fje [pii]. Scholar
  88. Zheng H, Gal S, Weiner LM, Bar-Am O, Warshawsky A, Fridkin M, Youdim MB. 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. 2005a;95(1):68–78. JNC3340 [pii]. Scholar
  89. 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. 2005b;13(3):773–83. S0968-0896(04)00839-9 [pii]. Scholar
  90. Zheng H, Blat D, Fridkin M. Novel neuroprotective neurotrophic NAP analogs targeting metal toxicity and oxidative stress: potential candidates for the control of neurodegenerative diseases. J Neural Transm Suppl. 2006;71:163–72.Google Scholar
  91. Zheng H, Youdim MB, Fridkin M. Site-activated multifunctional chelator with acetylcholinesterase and neuroprotective-neurorestorative moieties for Alzheimer’s therapy. J Med Chem. 2009;52(14):4095–8. Scholar
  92. Zheng H, Youdim MB, Fridkin M. Selective acetylcholinesterase inhibitor activated by acetylcholinesterase releases an active chelator with neurorescuing and anti-amyloid activities. ACS Chem Neurosci. 2010a;1(11):737–46. Scholar
  93. Zheng H, Youdim MB, Fridkin M. Site-activated chelators targeting acetylcholinesterase and monoamine oxidase for Alzheimer’s therapy. ACS Chem Biol. 2010b;5(6):603–10. Scholar

Authors and Affiliations

  1. 1.Department of Medicinal ChemistryIntra-cellular Therapies Inc.New YorkUSA
  2. 2.Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases and Department of PharmacologyTechnion-Rappaport Family Faculty of MedicineHaifaIsrael
  3. 3.Department of Organic ChemistryThe Weizmann Institute of ScienceRehovotIsrael
  4. 4.Department of BiologyYonsei World Central UniversitySeoulSouth Korea

Section editors and affiliations

  • Toshiharu Nagatsu
    • 1
    • 2
  • Akira Nakashima
    • 3
  1. 1.Fujita Health University School of MedicineToyoakeJapan
  2. 2.Institute of Environmental MedicineNagoya UniversityNagoyaJapan
  3. 3.Department of Physiological ChemistryFujita Health University School of MedicineToyoake, AichiJapan

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