Multimodal drugs and their future for Alzheimer's and Parkinson's disease

International Review of Neurobiology

Volumn 100, Issue , 2011, Pages 107-125

  Van der Schyf, Cornelis J ^a   Geldenhuys, Werner J ^a  

^a NORTHEAST OHIO MEDICAL UNIVERSITY   (United States)

Author keywords

Alzheimer's disease; Designed multiple ligands; HLA20 HLA20A; KW 6002; Ladostigil; Monoamine oxidase inhibitors; Multimodal drugs; Parkinson's disease; Pioglitazone; Rasagiline

Indexed keywords

4 [2 [7 AMINO 2 (2 FURYL) 1,2,4 TRIAZOLO[2,3 A][1,3,5]TRIAZIN 5 YLAMINO]ETHYL]PHENOL; ADENOSINE A2A RECEPTOR; AMINE OXIDASE (FLAVIN CONTAINING); AMYLOID BETA PROTEIN; CAFFEINE; CHOLINESTERASE INHIBITOR; CLIOQUINOL; COPPER ZINC SUPEROXIDE DISMUTASE; DIMEBON; GELATINASE B; GLIZONE; HLA 2OA; INDUCIBLE NITRIC OXIDE SYNTHASE; ISTRADEFYLLINE; LADOSTIGIL; LEVODOPA; MONOAMINE OXIDASE A INHIBITOR; P7C3; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; PIOGLITAZONE; PIOZ; RASAGILINE; RIVASTIGMINE; ROSIGLITAZONE; SEMAGACESTAT; SEROTONIN 6 ANTAGONIST; SEROTONIN 6 RECEPTOR; TROGLITAZONE; UNCLASSIFIED DRUG;

ADJUVANT THERAPY; ALZHEIMER DISEASE; BOOK; BRAIN ISCHEMIA; CELL SURVIVAL; DEMENTIA; DISEASE COURSE; DRUG DESIGN; DRUG ISOLATION; DRUG RESEARCH; DRUG TARGETING; ENZYME ACTIVITY; ENZYME INHIBITION; HIGH THROUGHPUT SCREENING; HUMAN; INCIDENCE; INFLAMMATION; LIPID PEROXIDATION; LIVER DISEASE; NERVOUS SYSTEM DEVELOPMENT; NEUROPROTECTION; NEUROTOXICITY; NEUROTRANSMISSION; NONHUMAN; PARKINSON DISEASE; PATHOPHYSIOLOGY; PREVALENCE; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN TARGETING; STRUCTURE ACTIVITY RELATION; SUBSTANTIA NIGRA;

EID: 80053511144     PISSN: 00747742     EISSN: None     Source Type: Book Series    
DOI: 10.1016/B978-0-12-386467-3.00006-6     Document Type: Chapter

References (99)

1. Amenta F., Tayebati S.K. Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction. Curr. Med. Chem. 2008, 15:488-498.
2. Bachurin S., Bukatina E., Lermontova N., Tkachenko S., Afanasiev A., Grigoriev V., Grigorieva I., Ivanov Y., Sablin S., Zefirov N. Antihistamine agent Dimebon as a novel neuroprotector and a cognition enhancer. Ann. N. Y. Acad. Sci. 2001, 939:425-435.
3. Barbiero J.K., Santiago R.M., Lima M.M., Ariza D., Morais L.H., Andreatini R., Vital M.A. Acute but not chronic administration of pioglitazone promoted behavioral and neurochemical protective effects in the MPTP model of Parkinson's disease. Behav. Brain Res 2011, 216:186-192.
4. Bezprozvanny I. The rise and fall of Dimebon. Drug News Perspect. 2010, 23:518-523.
5. Bordet R., Ouk T., Petrault O., Gele P., Gautier S., Laprais M., Deplanque D., Duriez P., Staels B., Fruchart J.C., Bastide M. PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases. Biochem. Soc. Trans. 2006, 34:1341-1346.
6. Breidert T., Callebert J., Heneka M.T., Landreth G., Launay J.M., Hirsch E.C. Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson's disease. J. Neurochem. 2002, 82:615-624.
7. Butterfield D.A., Kanski J. Brain oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins. Mech. Ageing Dev. 2001, 122:945-962.
8. Chen J.F., Xu K., Petzer J.P., Staal R., Xu Y.H., Beilstein M., Sonsalla P.K., Castagnoli K., Castagnoli N., Schwarzschild M.A. Neuroprotection by caffeine and A(2A) adenosine receptor inactivation in a model of Parkinson's disease. J. Neurosci. 2001, 21:RC143.
9. Chen J.J., Swope D.M., Dashtipour K. Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson's disease. Clin. Ther. 2007, 29:1825-1849.
10. Chen Y.F., Kao C.H., Kirby R., Tsai T.F. Cisd2 mediates mitochondrial integrity and life span in mammals. Autophagy 2009, 5:1043-1045.
11. Chimenti F., Bolasco A., Manna F., Secci D., Chimenti P., Granese A., Befani O., Turini P., Cirilli R., La Torre F., Alcaro S., Ortuso F., et al. Synthesis, biological evaluation and 3D-QSAR of 1,3,5-trisubstituted-4,5-dihydro-(1H)-pyrazole derivatives as potent and highly selective monoamine oxidase A inhibitors. Curr. Med. Chem. 2006, 13:1411-1428.
12. Choi J.S., Braymer J.J., Nanga R.P., Ramamoorthy A., Lim M.H. Design of small molecules that target metal-Aβ species and regulate metal-induced Aβ aggregation and neurotoxicity. Proc. Natl. Acad. Sci. USA 2010, 107:21990-21995.
13. Colca J.R., McDonald W.G., Waldon D.J., Leone J.W., Lull J.M., Bannow C.A., Lund E.T., Mathews W.R. Identification of a novel mitochondrial protein (" mitoNEET" ) cross-linked specifically by a thiazolidinedione photoprobe. Am. J. Physiol. Endocrinol. Metab. 2004, 286:E252-E260.
14. Collino M., Aragno M., Mastrocola R., Gallicchio M., Rosa A.C., Dianzani C., Danni O., Thiemermann C., Fantozzi R. Modulation of the oxidative stress and inflammatory response by PPAR-gamma agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion. Eur. J. Pharmacol. 2006, 530:70-80.
15. Combs C.K., Johnson D.E., Karlo J.C., Cannady S.B., Landreth G.E. Inflammatory mechanisms in Alzheimer's disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J. Neurosci. 2000, 20:558-567.
16. Culman J., Zhao Y., Gohlke P., Herdegen T. PPAR-gamma: therapeutic target for ischemic stroke. Trends Pharmacol. Sci. 2007, 28:244-249.
17. Dall'Igna O.P., Porciuncula L.O., Souza D.O., Cunha R.A., Lara D.R. Neuroprotection by caffeine and adenosine A2A receptor blockade of beta-amyloid neurotoxicity. Br. J. Pharmacol. 2003, 138:1207-1209.
18. Dall'Igna O.P., Souza D.O., Lara D.R. Caffeine as a neuroprotective adenosine receptor antagonist. Ann. Pharmacother. 2004, 38:717-718.
19. Di Monte D.A. The environment and Parkinson's disease: is the nigrostriatal system preferentially targeted by neurotoxins?. Lancet Neurol. 2003, 2:531-538.
20. Fahn S., Cohen G. The oxidant stress hypothesis in Parkinson's disease: evidence supporting it. Ann. Neurol. 1992, 32:804-812.
21. Fernandez H.H., Greeley D.R., Zweig R.M., Wojcieszek J., Mori A., Sussman N.M. Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat. Disord 2009, 16:16-20.
22. Foley A.G., Hirst W.D., Gallagher H.C., Barry C., Hagan J.J., Upton N., Walsh F.S., Hunter A.J., Regan C.M. The selective 5-HT6 receptor antagonists SB-271046 and SB-399885 potentiate NCAM PSA immunolabeling of dentate granule cells, but not neurogenesis, in the hippocampal formation of mature Wistar rats. Neuropharmacology 2008, 54:1166-1174.
23. Fowler C.J., Wiberg A., Oreland L., Marcusson J., Winblad B. The effect of age on the activity and molecular properties of human brain monoamine oxidase. J. Neural Transm. 1980, 49:1-20.
24. Fowler J.S., Volkow N.D., Wang G.J., Logan J., Pappas N., Shea C., MacGregor R. Age-related increases in brain monoamine oxidase B in living healthy human subjects. Neurobiol. Aging 1997, 18:431-435.
25. Gaeta A., Hider R.C. The crucial role of metal ions in neurodegeneration: the basis for a promising therapeutic strategy. Br. J. Pharmacol. 2005, 146:1041-1059.
26. Gautier S., Petrault O., Gele P., Laprais M., Bastide M., Bauters A., Deplanque D., Jude B., Caron J., Bordet R. Involvement of thrombolysis in recombinant tissue plasminogen activator-induced cerebral hemorrhages and effect on infarct volume and postischemic endothelial function. Stroke 2003, 34:2975-2979.
27. Geldenhuys W.J., Darvesh A.S., Funk M.O., Van der Schyf C.J., Carroll R.T. Identification of novel monoamine oxidase B inhibitors by structure-based virtual screening. Bioorg. Med. Chem. Lett. 2010, 20:5295-5298.
28. Geldenhuys W.J., Funk M.O., Barnes K.F., Carroll R.T. Structure-based design of a thiazolidinedione which targets the mitochondrial protein mitoNEET. Bioorg. Med. Chem. Lett. 2010, 20:819-823.
29. Glennon R.A., Siripurapu U., Roth B.L., Kolanos R., Bondarev M.L., Sikazwe D., Lee M., Dukat M. The medicinal chemistry of 5-HT6 receptor ligands with a focus on arylsulfonyltryptamine analogs. Curr. Top. Med. Chem. 2010, 10:579-595.
30. Hauptmann N., Grimsby J., Shih J.C., Cadenas E. The metabolism of tyramine by monoamine oxidase A/B causes oxidative damage to mitochondrial DNA. Arch. Biochem. Biophys. 1996, 335:295-304.
31. Hauser R.A., Shulman L.M., Trugman J.M., Roberts J.W., Mori A., Ballerini R., Sussman N.M. Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations. Mov. Disord. 2008, 23:2177-2185.
32. Haycox A., Armand C., Murteira S., Cochran J., Francois C. Cost effectiveness of rasagiline and pramipexole as treatment strategies in early Parkinson's disease in the UK setting: an economic Markov model evaluation. Drugs Aging 2009, 26:791-801.
33. Heneka M.T., Sastre M., Dumitrescu-Ozimek L., Hanke A., Dewachter I., Kuiperi C., O'Banion K., Klockgether T., Van Leuven F., Landreth G.E. Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice. Brain 2005, 128:1442-1453.
34. Herrine S.K., Choudhary C. Severe hepatotoxicity associated with troglitazone. Ann. Intern. Med. 1999, 130:163-164.
35. Hindo S.S., Mancino A.M., Braymer J.J., Liu Y., Vivekanandan S., Ramamoorthy A., Lim M.H. Small molecule modulators of copper-induced Abeta aggregation. J. Am. Chem. Soc. 2009, 131:16663-16665.
36. Honda T., Kaikita K., Tsujita K., Hayasaki T., Matsukawa M., Fuchigami S., Sugiyama S., Sakashita N., Ogawa H., Takeya M. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, attenuates myocardial ischemia-reperfusion injury in mice with metabolic disorders. J. Mol. Cell. Cardiol. 2008, 44:915-926.
37. Jacobson K.A., Gao Z.G. Adenosine receptors as therapeutic targets. Nat. Rev. Drug Discov. 2006, 5:247-264.
38. Jenner P., Mori A., Hauser R., Morelli M., Fredholm B.B., Chen J.F. Adenosine, adenosine A 2A antagonists, and Parkinson's disease. Parkinsonism Relat. Disord. 2009, 15:406-413.
39. Ji S., Kronenberg G., Balkaya M., Farber K., Gertz K., Kettenmann H., Endres M. Acute neuroprotection by pioglitazone after mild brain ischemia without effect on long-term outcome. Exp. Neurol. 2009, 216:321-328.
40. Joghataie M.T., Roghani M., Negahdar F., Hashemi L. Protective effect of caffeine against neurodegeneration in a model of Parkinson's disease in rat: behavioral and histochemical evidence. Parkinsonism Relat. Disord. 2004, 10:465-468.
41. Kaundal R.K., Iyer S., Kumar A., Sharma S.S. Protective effects of pioglitazone against global cerebral ischemic-reperfusion injury in gerbils. J. Pharmacol. Sci. 2009, 109:361-367.
42. 6 serotonin receptor. J. Neurochem. 1996, 66:47-56.
43. Kummer M.P., Heneka M.T. PPARs in Alzheimer's disease. PPAR Res. 2008, 2008:403896.
44. Langston J.W., Ballard P.A. Parkinson's disease in a chemist working with 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. N. Engl. J. Med. 1983, 309:310.
45. Lee S.R., Kim H.Y., Hong J.S., Baek W.K., Park J.W. PPARgamma agonist pioglitazone reduces matrix metalloproteinase-9 activity and neuronal damage after focal cerebral ischemia. Biochem. Biophys. Res. Commun. 2009, 380:17-21.
46. Lermontova N.N., Lukoyanov N.V., Serkova T.P., Lukoyanova E.A., Bachurin S.O. Dimebon improves learning in animals with experimental Alzheimer's disease. Bull. Exp. Biol. Med. 2000, 129:544-546.
47. LeWitt P.A., Guttman M., Tetrud J.W., Tuite P.J., Mori A., Chaikin P., Sussman N.M. Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005). Ann. Neurol. 2008, 63:295-302.
48. Li J., Lang M.J., Mao X.B., Tian L., Feng Y.B. Antiapoptosis and mitochondrial effect of pioglitazone preconditioning in the ischemic/reperfused heart of rat. Cardiovasc. Drugs Ther. 2008, 22:283-291.
49. Lin J., Zhou T., Ye K., Wang J. Crystal structure of human mitoNEET reveals distinct groups of iron sulfur proteins. Proc. Natl. Acad. Sci. USA 2007, 104:14640-14645.
50. Luna-Medina R., Cortes-Canteli M., Alonso M., Santos A., Martinez A., Perez-Castillo A. Regulation of inflammatory response in neural cells in vitro by thiadiazolidinones derivatives through peroxisome proliferator-activated receptor gamma activation. J. Biol. Chem. 2005, 280:21453-21462.
51. Maia L., de Mendonca A. Does caffeine intake protect from Alzheimer's disease?. Eur. J. Neurol. 2002, 9:377-382.
52. Mancino A.M., Hindo S.S., Kochi A., Lim M.H. Effects of clioquinol on metal-triggered amyloid-beta aggregation revisited. Inorg. Chem. 2009, 48:9596-9598.
53. Morelli M., Carta A.R., Jenner P. Adenosine A2A receptors and Parkinson's disease. Handb. Exp. Pharmacol. 2009, 193:589-615.
54. Morphy R., Rankovic Z. Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem. 2005, 48:6523-6543.
55. Morphy R., Kay C., Rankovic Z. From magic bullets to designed multiple ligands. Drug Discov. Today 2004, 9:641-651.
56. Navarro A., Boveris A. Brain mitochondrial dysfunction and oxidative damage in Parkinson's disease. J. Bioenerg. Biomembr. 2009, 41:517-521.
57. Nowakowska E., Kus K., Chodera A., Rybakowski J. Investigating potential anxiolytic, antidepressant and memory enhancing activity of deprenyl. J. Physiol. Pharmacol. 2001, 52:863-873.
58. Nunomura A., Perry G., Aliev G., Hirai K., Takeda A., Balraj E.K., Jones P.K., Ghanbari H., Wataya T., Shimohama S., Chiba S., Atwood C.S., et al. Oxidative damage is the earliest event in Alzheimer disease. J. Neuropathol. Exp. Neurol. 2001, 60:759-767.
59. Olanow C.W., Rascol O., Hauser R., Feigin P.D., 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, 361:1268-1278.
60. Paddock M.L., Wiley S.E., Axelrod H.L., Cohen A.E., Roy M., Abresch E.C., Capraro D., Murphy A.N., Nechushtai R., Dixon J.E., Jennings P.A. MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone. Proc. Natl. Acad. Sci. USA 2007, 104:14342-14347.
61. Patzer A., Zhao Y., Stock I., Gohlke P., Herdegen T., Culman J. Peroxisome proliferator-activated receptorsgamma (PPARgamma) differently modulate the interleukin-6 expression in the peri-infarct cortical tissue in the acute and delayed phases of cerebral ischaemia. Eur. J. Neurosci. 2008, 28:1786-1794.
62. Pieper A.A., Xie S., Capota E., Estill S.J., Zhong J., Long J.M., Becker G.L., Huntington P., Goldman S.E., Shen C.H., Capota M., Britt J.K., et al. Discovery of a proneurogenic, neuroprotective chemical. Cell 2010, 142:39-51.
63. Prediger R.D., Batista L.C., Takahashi R.N. Caffeine reverses age-related deficits in olfactory discrimination and social recognition memory in rats. Involvement of adenosine A1 and A2A receptors. Neurobiol. Aging 2005, 26:957-964.
64. Prediger R.D., Pamplona F.A., Fernandes D., Takahashi R.N. Caffeine improves spatial learning deficits in an animal model of attention deficit hyperactivity disorder (ADHD)-the spontaneously hypertensive rat (SHR). Int. J. Neuropsychopharmacol. 2005, 8:583-594.
65. Quinn L.P., Crook B., Hows M.E., Vidgeon-Hart M., Chapman H., Upton N., Medhurst A.D., Virley D.J. The PPARgamma agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase B. Br. J. Pharmacol. 2008, 154:226-233.
66. Reinikainen K.J., Soininen H., Riekkinen P.J. Neurotransmitter changes in Alzheimer's disease: implications to diagnostics and therapy. J. Neurosci. Res. 1990, 27:576-586.
67. Rennings A.J., Meijer P., van Uden D.J., Tack C.J., Smits P., Boerman O.C., Oyen W.J., Rongen G.A. Rosiglitazone reduces ischaemia-reperfusion injury in patients with the metabolic syndrome. Eur. Heart J. 2010, 31:983.
68. Sagi Y., Weinstock M., Youdim M.B. Attenuation of MPTP-induced dopaminergic neurotoxicity by TV3326, a cholinesterase-monoamine oxidase inhibitor. J. Neurochem. 2003, 86:290-297.
69. Sano M., Ernesto C., Thomas R.G., Klauber M.R., Schafer K., Grundman M., Woodbury P., Growdon J., Cotman C.W., Pfeiffer E., Schneider L.S., Thal L.J. A controlled trial of selegiline, α-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N. Engl. J. Med. 1997, 336:1216-1222.
70. Saura J., Luque J.M., Cesura A.M., Da Prada M., Chan-Palay V., Huber G., Loffler J., Richards J.G. Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience 1994, 62:15-30.
71. Sayre L.M., Perry G., Smith M.A. Oxidative stress and neurotoxicity. Chem. Res. Toxicol. 2008, 21:172-188.
72. Schapira A.H., Olanow C.W. Drug selection and timing of initiation of treatment in early Parkinson's disease. Ann. Neurol. 2008, 64(Suppl. 2):S47-S55.
73. Shadrina M.I., Slominsky P.A., Limborska S.A. Molecular mechanisms of pathogenesis of Parkinson's disease. Int. Rev. Cell Mol. Biol. 2010, 281:229-266.
74. Shastry B.S. Neurodegenerative disorders of protein aggregation. Neurochem. Int. 2003, 43:1-7.
75. Shimazu T., Inoue I., Araki N., Asano Y., Sawada M., Furuya D., Nagoya H., Greenberg J.H. A peroxisome proliferator-activated receptor-gamma agonist reduces infarct size in transient but not in permanent ischemia. Stroke 2005, 36:353-359.
76. Soong N.W., Hinton D.R., Cortopassi G., Arnheim N. Mosaicism for a specific somatic mitochondrial DNA mutation in adult human brain. Nat. Genet. 1992, 2:318-323.
77. Strolin Benedetti M., Dostert P. Monoamine oxidase, brain ageing and degenerative diseases. Biochem. Pharmacol. 1989, 38:555-561.
78. Terry R.D., DeTeresa R., Hansen L.A. Neocortical cell counts in normal human adult aging. Ann. Neurol. 1987, 21:530-539.
79. Tsunekawa H., Noda Y., Mouri A., Yoneda F., Nabeshima T. Synergistic effects of selegiline and donepezil on cognitive impairment induced by amyloid beta (25-35). Behav. Brain Res. 2008, 190:224-232.
80. Van der Schyf C.J., Mandel S., Geldenhuys W.J., Amit T., Avramovich Y., Zheng H., Fridkin M., Gal S., Weinreb O., Bar Am O., Sagi Y., Youdim M.B. Novel multifunctional anti-Alzheimer drugs with various CNS neurotransmitter targets and neuroprotective moieties. Curr. Alzheimer Res. 2007, 4:522-536.
81. Weinreb O., Amit T., Bar-Am O., Yogev-Falach M., Youdim M.B. The neuroprotective mechanism of action of the multimodal drug ladostigil. Front. Biosci. 2008, 13:5131-5137.
82. Weinreb O., Bar-Am O., Amit T., Drigues N., Sagi Y., Youdim M.B. The neuroprotective effect of ladostigil against hydrogen peroxide-mediated cytotoxicity. Chem. Biol. Interact. 2008, 175:318-326.
83. Weinreb O., Mandel S., Bar-Am O., Yogev-Falach M., Avramovich-Tirosh Y., Amit T., Youdim M.B. Multifunctional neuroprotective derivatives of rasagiline as anti-Alzheimer's disease drugs. Neurotherapeutics 2009, 6:163-174.
84. Weinstock M., Luques L., Poltyrev T., Bejar C., Shoham S. Ladostigil prevents age-related glial activation and spatial memory deficits in rats. Neurobiol. Aging 2011, 32:1069-1078.
85. Wiley S.E., Murphy A.N., Ross S.A., van der Geer P., Dixon J.E. MitoNEET is an iron-containing outer mitochondrial membrane protein that regulates oxidative capacity. Proc. Natl. Acad. Sci. USA 2007, 104:5318-5323.
86. Wiley S.E., Paddock M.L., Abresch E.C., Gross L., van der Geer P., Nechushtai R., Murphy A.N., Jennings P.A., Dixon J.E. The outer mitochondrial membrane protein mitoNEET contains a novel redox-active 2Fe-2S cluster. J. Biol. Chem. 2007, 282:23745-23749.
87. Wu J.S., Cheung W.M., Tsai Y.S., Chen Y.T., Fong W.H., Tsai H.D., Chen Y.C., Liou J.Y., Shyue S.K., Chen J.J., Chen Y.E., Maeda N., et al. Ligand-activated peroxisome proliferator-activated receptor-gamma protects against ischemic cerebral infarction and neuronal apoptosis by 14-3-3 epsilon upregulation. Circulation 2009, 119:1124-1134.
88. Yan Q., Zhang J., Liu H., Babu-Khan S., Vassar R., Biere A.L., Citron M., Landreth G. Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease. J. Neurosci. 2003, 23:7504-7509.
89. Yi J.H., Park S.W., Brooks N., Lang B.T., Vemuganti R. PPARgamma agonist rosiglitazone is neuroprotective after traumatic brain injury via anti-inflammatory and anti-oxidative mechanisms. Brain Res. 2008, 1244:164-172.
90. Yogev-Falach M., Amit T., Bar-Am O., Weinstock M., Youdim M.B. Involvement of MAP kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline. FASEB J. 2002, 16:1674-1676.
91. Youdim M.B., Buccafusco J.J. CNS Targets for multi-functional drugs in the treatment of Alzheimer's and Parkinson's diseases. J. Neural Transm. 2005, 112:519-537.
92. Youdim M.B., Buccafusco J.J. Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol. Sci. 2005, 26:27-35.
93. Youdim M.B., Van der Schyf C.J. Magic bullets or novel multimodal drugs with various targets for Parkinson's Disease?. Nat. Rev. Drug Discov. 2007, 6:iii-vi.
94. Youdim M.B., Edmondson D., Tipton K.F. The therapeutic potential of monoamine oxidase inhibitors. Nat. Rev. Neurosci. 2006, 7:295-309.
95. Yu H.C., Feng S.F., Chao P.L., Lin A.M. Anti-inflammatory effects of pioglitazone on iron-induced oxidative injury in the nigrostriatal dopaminergic system. Neuropathol. Appl. Neurobiol. 2010, 36:612-622.
96. Zheng H., Youdim M.B., Fridkin M. Site-Activated Multifunctional Chelator with Acetylcholinesterase and Neuroprotective-Neurorestorative Moieties for Alzheimer's Therapy. J. Med. Chem 2009, 52:4095-4098.
97. Zheng H., Youdim M.B.H., Fridkin M. New selective acetylcholinesterase inhibitor with site-activated chelating, neurorescuing and anti-amyloid activities for Alzheimer's therapy. ACS Chem. Neurosci 2010, 1:737-746.
98. Zheng H., Youdim M.B.H., Fridkin M. Site-activated chelators targeting acetylcholinesterase and monoamine oxidase for Alzheimer's therapy. ACS Chem. Biol. 2010, 5:603-610.
99. Zimmermann G.R., Lehar J., Keith C.T. Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov. Today 2007, 12:34-42.