Progress in drug development for Alzheimer's disease: An overview in relation to mitochondrial energy metabolism

European Journal of Medicinal Chemistry

Volumn 121, Issue , 2016, Pages 774-784

  Hroudová, Jana ^a   Singh, Namrata ^a   Fišar, Zdeněk ^a   Ghosh, Kallol K ^b  

^a CHARLES UNIVERSITY   (Czech Republic)

^b PT RAVISHANKAR SHUKLA UNIVERSITY   (India)

Author keywords

Alzheimer's disease; Amyloid beta binding alcohol dehydrogenase modulators; Cholinesterase inhibitors; Monoamine oxidase (MAO) inhibitors

Indexed keywords

1,2,3,6 TETRAHYDRO 1 METHYL 4 PHENYLPYRIDINE; 8 QUINOLINOL; ALCOHOL DEHYDROGENASE; ALPHA SYNUCLEIN; AMINE OXIDASE (FLAVIN CONTAINING) ISOENZYME A; AMINE OXIDASE (FLAVIN CONTAINING) ISOENZYME B; AMYLOID BETA PROTEIN; ANTIOXIDANT; BIOLOGICAL MARKER; CHOLINESTERASE INHIBITOR; CYCLOPHILIN D; CYTOCHROME C OXIDASE; DONEPEZIL; GALANTAMINE; HUPERZINE A; LADOSTIGIL; MEMANTINE; MITOCHONDRIAL DNA; MITOCHONDRIAL ENZYME; MITOCHONDRIAL PERMEABILITY TRANSITION PORE; MITOCHONDRIAL PROTEIN; MONOAMINE OXIDASE B INHIBITOR; RASAGILINE; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE DEHYDROGENASE (UBIQUINONE); RIVASTIGMINE; TACRINE; TACRINE DERIVATIVE; TAU PROTEIN; MONOAMINE OXIDASE INHIBITOR;

ALZHEIMER DISEASE; CALCIUM HOMEOSTASIS; CALCIUM SIGNALING; CITRIC ACID CYCLE; DRUG SYNTHESIS; ELECTRON TRANSPORT; ENERGY METABOLISM; HUMAN; HYBRID; MITOCHONDRIAL BIOGENESIS; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOCHONDRIAL RESPIRATION; MITOCHONDRION SWELLING; NONHUMAN; OXIDATIVE PHOSPHORYLATION; PATHOPHYSIOLOGY; RESPIRATORY CHAIN; REVIEW; ANIMAL; CHEMISTRY; DRUG DEVELOPMENT; DRUG EFFECTS; METABOLISM; MITOCHONDRION; PATHOLOGY; PROCEDURES;

ALZHEIMER DISEASE; ANIMALS; DRUG DISCOVERY; ENERGY METABOLISM; HUMANS; MITOCHONDRIA; MONOAMINE OXIDASE INHIBITORS;

EID: 84963657194     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2016.03.084     Document Type: Review

References (123)

1. [1] Hardy, J.A., Higgins, G.A., Alzheimer's disease: the amyloid cascade hypothesis. Sci. (New York, N.Y.) 256 (1992), 184–185.
2. [2] Mohandas, E., Rajmohan, V., Raghunath, B., Neurobiology of Alzheimer's disease. Indian J. Psychiatry 51 (2009), 55–61.
3. [3] Swerdlow, R.H., Burns, J.M., Khan, S.M., The Alzheimer's disease mitochondrial cascade hypothesis. J. Alzheimer's Dis. JAD 20:Suppl. 2 (2010), S265–S279.
4. [4] Hardy, J., Selkoe, D.J., The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Sci. (New York, N.Y.) 297 (2002), 353–356.
5. [5] Walsh, D.M., Selkoe, D.J., A beta oligomers - a decade of discovery. J. Neurochem. 101 (2007), 1172–1184.
6. [6] Maccioni, R.B., Farias, G., Morales, I., Navarrete, L., The revitalized tau hypothesis on Alzheimer's disease. Arch. Med. Res. 41 (2010), 226–231.
7. [7] Markesbery, W.R., Oxidative stress hypothesis in Alzheimer's disease. Free Radic. Biol. Med. 23 (1997), 134–147.
8. [8] Zotova, E., Nicoll, J.A., Kalaria, R., Holmes, C., Boche, D., Inflammation in Alzheimer's disease: relevance to pathogenesis and therapy. Alzheimer's Res. Ther., 2, 2010, 1.
9. [9] de la Torre, J.C., The vascular hypothesis of Alzheimer's disease: bench to bedside and beyond. Neuro-degenerative Dis. 7 (2010), 116–121.
10. [10] Wood, W.G., Li, L., Muller, W.E., Eckert, G.P., Cholesterol as a causative factor in Alzheimer's disease: a debatable hypothesis. J. Neurochem. 129 (2014), 559–572.
11. [11] Bush, A.I., Tanzi, R.E., Therapeutics for Alzheimer's disease based on the metal hypothesis. Neurother. J. Am. Soc. Exp. Neurother. 5 (2008), 421–432.
12. [12] Neve, R.L., McPhie, D.L., The cell cycle as a therapeutic target for Alzheimer's disease. Pharmacol. Ther. 111 (2006), 99–113.
13. [13] Lane, R.M., Potkin, S.G., Enz, A., Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int. J. Neuropsychopharmacol./Off. Sci. J. Coll. Int. Neuropsychopharmacol. (CINP) 9 (2006), 101–124.
14. [14] Ballard, C.G., Greig, N.H., Guillozet-Bongaarts, A.L., Enz, A., Darvesh, S., Cholinesterases: roles in the brain during health and disease. Curr. Alzheimer Res. 2 (2005), 307–318.
15. [15] Atack, J.R., Perry, E.K., Bonham, J.R., Candy, J.M., Perry, R.H., Molecular forms of acetylcholinesterase and butyrylcholinesterase in the aged human central nervous system. J. Neurochem. 47 (1986), 263–277.
16. [16] Mesulam, M., Guillozet, A., Shaw, P., Quinn, B., Widely spread butyrylcholinesterase can hydrolyze acetylcholine in the normal and Alzheimer brain. Neurobiol. Dis. 9 (2002), 88–93.
17. [17] Anand, P., Singh, B., A review on cholinesterase inhibitors for Alzheimer's disease,. Arch. Pharmacal Res. 36 (2013), 375–399.
18. [18] Arendt, T., Bruckner, M.K., Lange, M., Bigl, V., Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease resemble embryonic development–a study of molecular forms. Neurochem. Int. 21 (1992), 381–396.
19. [19] Greig, N.H., Lahiri, D.K., Sambamurti, K., Butyrylcholinesterase: an important new target in Alzheimer's disease therapy. Int. Psychogeriatr. 14:Suppl. 1 (2002), 77–91.
20. [20] Cavalli, A., Bolognesi, M.L., Minarini, A., Rosini, M., Tumiatti, V., Recanatini, M., Melchiorre, C., Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem. 51 (2008), 347–372.
21. [21] Mishra, N., Sasmal, D., Singh, K.K., Attenuating Abeta1-42-induced toxicity by a novel acetylcholinesterase inhibitor. Neuroscience 250 (2013), 309–319.
22. [22] Hashimoto, M., Rockenstein, E., Crews, L., Masliah, E., Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases. Neuromolecular Med. 4 (2003), 21–36.
23. [23] Devi, L., Prabhu, B.M., Galati, D.F., Avadhani, N.G., Anandatheerthavarada, H.K., Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction. J. Neurosci. 26 (2006), 9057–9068.
24. [24] Lustbader, J.W., Cirilli, M., Lin, C., Xu, H.W., Takuma, K., Wang, N., Caspersen, C., Chen, X., Pollak, S., Chaney, M., Trinchese, F., Liu, S., Gunn-Moore, F., Lue, L.F., Walker, D.G., Kuppusamy, P., Zewier, Z.L., Arancio, O., Stern, D., Yan, S.S., Wu, H., ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Sci. (New York, N.Y.) 304 (2004), 448–452.
25. [25] Camilleri, A., Zarb, C., Caruana, M., Ostermeier, U., Ghio, S., Hogen, T., Schmidt, F., Giese, A., Vassallo, N., Mitochondrial membrane permeabilisation by amyloid aggregates and protection by polyphenols. Biochimica et Biophysica Acta 1828 (2013), 2532–2543.
26. [26] Takuma, K., Yao, J., Huang, J., Xu, H., Chen, X., Luddy, J., Trillat, A.C., Stern, D.M., Arancio, O., Yan, S.S., ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 19 (2005), 597–598.
27. [27] Tillement, L., Lecanu, L., Papadopoulos, V., Alzheimer's disease: effects of beta-amyloid on mitochondria. Mitochondrion 11 (2011), 13–21.
28. [28] Chaturvedi, R.K., Flint Beal, M., Mitochondrial diseases of the brain. Free Radic. Biol. Med. 63 (2013), 1–29.
29. [29] Shi, Y., Apoptosome assembly. Methods Enzym. 442 (2008), 141–156.
30. [30] Sherif, F., Gottfries, C.G., Alafuzoff, I., Oreland, L., Brain gamma-aminobutyrate aminotransferase (GABA-T) and monoamine oxidase (MAO) in patients with Alzheimer's disease. J. neural Transm. Parkinson's Dis. Dementia Sect. 4 (1992), 227–240.
31. [31] Cai, Z., Monoamine oxidase inhibitors: promising therapeutic agents for Alzheimer's disease (Review). Mol. Med. Rep. 9 (2014), 1533–1541.
32. [32] Naoi, M., Maruyama, W., Akao, Y., Yi, H., Yamaoka, Y., Involvement of type A monoamine oxidase in neurodegeneration: regulation of mitochondrial signaling leading to cell death or neuroprotection. J. Neural Transm. Suppl., 2006, 67–77.
33. [33] Youdim, M.B., Edmondson, D., Tipton, K.F., The therapeutic potential of monoamine oxidase inhibitors. Nat. Rev. Neurosci. 7 (2006), 295–309.
34. [34] Fisar, Z., Hroudova, J., Raboch, J., Inhibition of monoamine oxidase activity by antidepressants and mood stabilizers. Neuro Endocrinol. Lett. 31 (2010), 645–656.
35. [35] Bosetti, F., Brizzi, F., Barogi, S., Mancuso, M., Siciliano, G., Tendi, E.A., Murri, L., Rapoport, S.I., Solaini, G., Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer's disease. Neurobiol. Aging 23 (2002), 371–376.
36. [36] Cardoso, S.M., Proenca, M.T., Santos, S., Santana, I., Oliveira, C.R., Cytochrome c oxidase is decreased in Alzheimer's disease platelets. Neurobiol. Aging 25 (2004), 105–110.
37. [37] Gibson, G.E., Sheu, K.F., Blass, J.P., Abnormalities of mitochondrial enzymes in Alzheimer disease. J. Neural Transm. (Vienna, Austria 1996) 105 (1998), 855–870.
38. [38] Chandrasekaran, K., Hatanpaa, K., Brady, D.R., Rapoport, S.I., Evidence for physiological down-regulation of brain oxidative phosphorylation in Alzheimer's disease. Exp. Neurol. 142 (1996), 80–88.
39. [39] Parker, W.D. Jr., Parks, J., Filley, C.M., Kleinschmidt-DeMasters, B.K., Electron transport chain defects in Alzheimer's disease brain. Neurol. 44 (1994), 1090–1096.
40. [40]] J.L. Cummings, Biomarkers in Alzheimer's disease drug development, in: Alzheimer's & dementia : The Journal of the Alzheimer's Association, Copyright (C) 2011 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved., United States, 2011, pp. e13–44.
41. [41] Kristofikova, Z., Ripova, D., Hegnerova, K., Sirova, J., Homola, J., Protein tau-mediated effects on rat hippocampal choline transporters CHT1 and tau-amyloid beta interactions. Neurochem. Res. 38 (2013), 1949–1959.
42. [42] Munguia, M.E., Govezensky, T., Martinez, R., Manoutcharian, K., Gevorkian, G., Identification of amyloid-beta 1-42 binding protein fragments by screening of a human brain cDNA library. Neuroscience Letters, Ireland, 2006, 79–82.
43. [43] Parker, W.D. Jr., Filley, C.M., Parks, J.K., Cytochrome oxidase deficiency in Alzheimer's disease. Neurol. 40 (1990), 1302–1303.
44. [44] Karbowski, M., Neutzner, A., Neurodegeneration as a consequence of failed mitochondrial maintenance. Acta Neuropathol. 123 (2012), 157–171.
45. [45] Starkov, A.A., The role of mitochondria in reactive oxygen species metabolism and signaling. Ann. N. Y. Acad. Sci. 1147 (2008), 37–52.
46. [46] Maes, M., Fisar, Z., Medina, M., Scapagnini, G., Nowak, G., Berk, M., New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates–Nrf2 activators and GSK-3 inhibitors. Inflammopharmacol. 20 (2012), 127–150.
47. [47] Goure, W.F., Krafft, G.A., Jerecic, J., Hefti, F., Targeting the proper amyloid-beta neuronal toxins: a path forward for Alzheimer's disease immunotherapeutics. Alzheimer's Res. Ther., 6, 2014, 42.
48. [48] Ye, C.Y., Lei, Y., Tang, X.C., Zhang, H.Y., Donepezil attenuates Abeta-associated mitochondrial dysfunction and reduces mitochondrial Abeta accumulation in vivo and in vitro. Neuropharmacol. 95 (2015), 29–36.
49. [49] Hroudova, J., Singh, N., Fisar, Z., Mitochondrial dysfunctions in neurodegenerative diseases: relevance to Alzheimer's disease. BioMed Res. Int., 2014, 2014, 175062.
50. [50] Kamat, P.K., Tota, S., Shukla, R., Ali, S., Najmi, A.K., Nath, C., Mitochondrial dysfunction: a crucial event in okadaic acid (ICV) induced memory impairment and apoptotic cell death in rat brain. Pharmacology, Biochemistry, and Behavior, 2011, 2011, Elsevier B.V, United States, 311–319.
51. [51] Arias, E., Gallego-Sandin, S., Villarroya, M., Garcia, A.G., Lopez, M.G., Unequal neuroprotection afforded by the acetylcholinesterase inhibitors galantamine, donepezil, and rivastigmine in SH-SY5Y neuroblastoma cells: role of nicotinic receptors. J. Pharmacol. Exp. Ther. 315 (2005), 1346–1353.
52. [52] Noh, M.Y., Koh, S.H., Kim, Y., Kim, H.Y., Cho, G.W., Kim, S.H., Neuroprotective effects of donepezil through inhibition of GSK-3 activity in amyloid-beta-induced neuronal cell death. J. Neurochem. 108 (2009), 1116–1125.
53. [53] Takada, Y., Yonezawa, A., Kume, T., Katsuki, H., Kaneko, S., Sugimoto, H., Akaike, A., Nicotinic acetylcholine receptor-mediated neuroprotection by donepezil against glutamate neurotoxicity in rat cortical neurons. J. Pharmacol. Exp. Ther. 306 (2003), 772–777.
54. [54] Ki, Y.S., Park, E.Y., Lee, H.W., Oh, M.S., Cho, Y.W., Kwon, Y.K., Moon, J.H., Lee, K.T., Donepezil, a potent acetylcholinesterase inhibitor, induces caspase-dependent apoptosis in human promyelocytic leukemia HL-60 cells. Biol. Pharm. Bull. 33 (2010), 1054–1059.
55. [55] Ellis, J.M., Cholinesterase inhibitors in the treatment of dementia. J. Am. Osteopath. Assoc. 105 (2005), 145–158.
56. [56] Jann, M.W., Rivastigmine, a new-generation cholinesterase inhibitor for the treatment of Alzheimer's disease. Pharmacother. 20 (2000), 1–12.
57. [57] Parnetti, L., Amici, S., Lanari, A., Romani, C., Antognelli, C., Andreasen, N., Minthon, L., Davidsson, P., Pottel, H., Blennow, K., Gallai, V., Cerebrospinal fluid levels of biomarkers and activity of acetylcholinesterase (AChE) and butyrylcholinesterase in AD patients before and after treatment with different AChE inhibitors. Neurol. Sci. 23:Suppl. 2 (2002), S95–S96.
58. [58] Amici, S., Lanari, A., Romani, R., Antognelli, C., Gallai, V., Parnetti, L., Cerebrospinal fluid acetylcholinesterase activity after long-term treatment with donepezil and rivastigmina. Mech. Ageing Dev. 122 (2001), 2057–2062.
59. [59] Hellstrom-Lindahl, E., Moore, H., Nordberg, A., Increased levels of tau protein in SH-SY5Y cells after treatment with cholinesterase inhibitors and nicotinic agonists. J. Neurochem. 74 (2000), 777–784.
60. [60] Polinsky, R.J., Clinical pharmacology of rivastigmine: a new-generation acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. Clin. Ther. 20 (1998), 634–647.
61. [61] Bartorelli, L., Giraldi, C., Saccardo, M., Cammarata, S., Bottini, G., Fasanaro, A.M., Trequattrini, A., Effects of switching from an AChE inhibitor to a dual AChE-BuChE inhibitor in patients with Alzheimer's disease. Curr. Med. Res. Opin. 21 (2005), 1809–1818.
62. [62] Auriacombe, S., Pere, J.J., Loria-Kanza, Y., Vellas, B., Efficacy and safety of rivastigmine in patients with Alzheimer's disease who failed to benefit from treatment with donepezil. Curr. Med. Res. Opin. 18 (2002), 129–138.
63. [63] Ballard, C.G., Advances in the treatment of Alzheimer's disease: benefits of dual cholinesterase inhibition. Eur. Neurol. 47 (2002), 64–70.
64. [64] Bailey, J.A., Ray, B., Greig, N.H., Lahiri, D.K., Rivastigmine lowers Abeta and increases sAPPalpha levels, which parallel elevated synaptic markers and metabolic activity in degenerating primary rat neurons. PloS one, 6, 2011, e21954.
65. [65] Kumar, P., Kumar, A., Protective effect of rivastigmine against 3-nitropropionic acid-induced Huntington's disease like symptoms: possible behavioural, biochemical and cellular alterations. Eur. J. Pharmacol. 615 (2009), 91–101.
66. [66] Casademont, J., Miro, O., Rodriguez-Santiago, B., Viedma, P., Blesa, R., Cardellach, F., Cholinesterase inhibitor rivastigmine enhance the mitochondrial electron transport chain in lymphocytes of patients with Alzheimer's disease. J. neurological Sci. Neth., 2003, 23–26.
67. [67] Rogawski, M.A., What is the rationale for new treatment strategies in Alzheimer's disease?. CNS spectrums 9 (2004), 6–12.
68. [68] Maelicke, A., Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer's disease. Dementia Geriatr. Cognit. Disord. 11:Suppl. 1 (2000), 11–18.
69. [69] Arias, E., Ales, E., Gabilan, N.H., Cano-Abad, M.F., Villarroya, M., Garcia, A.G., Lopez, M.G., Galantamine prevents apoptosis induced by beta-amyloid and thapsigargin: involvement of nicotinic acetylcholine receptors. Neuropharmacol. 46 (2004), 103–114.
70. [70] Liu, X., Xu, K., Yan, M., Wang, Y., Zheng, X., Protective effects of galantamine against Abeta-induced PC12 cell apoptosis by preventing mitochondrial dysfunction and endoplasmic reticulum stress. Neurochem. Int. 57 (2010), 588–599.
71. [71] Ezoulin, M.J., Li, J., Wu, G., Dong, C.Z., Ombetta, J.E., Chen, H.Z., Massicot, F., Heymans, F., Differential effect of PMS777, a new type of acetylcholinesterase inhibitor, and galanthamine on oxidative injury induced in human neuroblastoma SK-N-SH cells. Neurosci. Lett. 389 (2005), 61–65.
72. [72] Kumar, A., Prakash, A., Pahwa, D., Galantamine potentiates the protective effect of rofecoxib and caffeic acid against intrahippocampal Kainic acid-induced cognitive dysfunction in rat. Brain Res. Bull. 85 (2011), 158–168.
73. [73] Lipton, S.A., Paradigm shift in NMDA receptor antagonist drug development: molecular mechanism of uncompetitive inhibition by memantine in the treatment of Alzheimer's disease and other neurologic disorders. J. Alzheimer's Dis. JAD 6 (2004), S61–S74.
74. [74] Lipton, S.A., The molecular basis of memantine action in Alzheimer's disease and other neurologic disorders: low-affinity, uncompetitive antagonism. Curr. Alzheimer Res. 2 (2005), 155–165.
75. [75] Kysenius, K., Brunello, C.A., Huttunen, H.J., Mitochondria and NMDA receptor-dependent toxicity of berberine sensitizes neurons to glutamate and rotenone injury. PloS one, U. S., 2014, e107129.
76. [76] Tozzi, A., Costa, C., Di Filippo, M., Tantucci, M., Siliquini, S., Belcastro, V., Parnetti, L., Picconi, B., Calabresi, P., Memantine reduces neuronal dysfunctions triggered by in vitro ischemia and 3-nitropropionic acid. Exp. Neurol. 207 (2007), 218–226.
77. [77] Alley, G.M., Bailey, J.A., Chen, D., Ray, B., Puli, L.K., Tanila, H., Banerjee, P.K., Lahiri, D.K., Memantine lowers amyloid-beta peptide levels in neuronal cultures and in APP/PS1 transgenic mice. J. Neurosci. Res. 88 (2010), 143–154.
78. [78] Picco, A., Polidori, M.C., Ferrara, M., Cecchetti, R., Arnaldi, D., Baglioni, M., Morbelli, S., Bastiani, P., Bossert, I., Fiorucci, G., Brugnolo, A., Dottorini, M.E., Nobili, F., Mecocci, P., Plasma antioxidants and brain glucose metabolism in elderly subjects with cognitive complaints. Eur. J. Nucl. Med. Mol. Imaging 41 (2014), 764–775.
79. [79] Ahmed, M.M., Hoshino, H., Chikuma, T., Yamada, M., Kato, T., Effect of memantine on the levels of glial cells, neuropeptides, and peptide-degrading enzymes in rat brain regions of ibotenic acid-treated alzheimer's disease model. Neurosci. 126 (2004), 639–649.
80. [80] Arif, M., Chikuma, T., Ahmed, M.M., Nakazato, M., Smith, M.A., Kato, T., Effects of memantine on soluble Alphabeta(25-35)-induced changes in peptidergic and glial cells in Alzheimer's disease model rat brain regions. Neurosci. 164 (2009), 1199–1209.
81. [81] Miguel-Hidalgo, J.J., Alvarez, X.A., Cacabelos, R., Quack, G., Neuroprotection by memantine against neurodegeneration induced by beta-amyloid(1-40). Brain Res. 958 (2002), 210–221.
82. [82] Song, M.S., Rauw, G., Baker, G.B., Kar, S., Memantine protects rat cortical cultured neurons against beta-amyloid-induced toxicity by attenuating tau phosphorylation. Eur. J. Neurosci. 28 (2008), 1989–2002.
83. [83] Wang, Z.F., Tang, X.C., Huperzine A protects C6 rat glioma cells against oxygen-glucose deprivation-induced injury. FEBS Lett. 581 (2007), 596–602.
84. [84] Ashani, Y., Peggins, J.O. 3rd, Doctor, B.P., Mechanism of inhibition of cholinesterases by huperzine A. Biochemical and Biophysical Research Communications, United States, 1992, 719–726.
85. [85] Gordon, R.K., Nigam, S.V., Weitz, J.A., Dave, J.R., Doctor, B.P., Ved, H.S., The NMDA receptor ion channel: a site for binding of Huperzine A. J Appl Toxicol, 2001, 2001, John Wiley & Sons, Ltd., England, S47–S51.
86. [86] Zhang, H.Y., New insights into huperzine A for the treatment of Alzheimer's disease. Acta Pharmacol. Sin. 33 (2012), 1170–1175.
87. [87] Yang, L., Ye, C.Y., Huang, X.T., Tang, X.C., Zhang, H.Y., Decreased accumulation of subcellular amyloid-beta with improved mitochondrial function mediates the neuroprotective effect of huperzine A. J. Alzheimer's Dis. JAD, Neth., 2012, 131–142.
88. [88] Wang, C.Y., Zheng, W., Wang, T., Xie, J.W., Wang, S.L., Zhao, B.L., Teng, W.P., Wang, Z.Y., Huperzine A activates Wnt/beta-catenin signaling and enhances the nonamyloidogenic pathway in an Alzheimer transgenic mouse model, Neuropsychopharmacology. Off. Publ. Am. Coll. Neuropsychopharmacol. 36 (2011), 1073–1089.
89. [89] Wang, R., Yan, H., Tang, X.C., Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacol. Sin. 27 (2006), 1–26.
90. [90] Dragicevic, N., Mamcarz, M., Zhu, Y., Buzzeo, R., Tan, J., Arendash, G.W., Bradshaw, P.C., Mitochondrial amyloid-beta levels are associated with the extent of mitochondrial dysfunction in different brain regions and the degree of cognitive impairment in Alzheimer's transgenic mice. J. Alzheimer's Dis. JAD 20:Suppl. 2 (2010), S535–S550.
91. [91] Korabecny, J., Musilek, K., Holas, O., Binder, J., Zemek, F., Marek, J., Pohanka, M., Opletalova, V., Dohnal, V., Kuca, K., Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease. Bioorg. Med. Chem. Lett. 20 (2010), 6093–6095.
92. [92] Soukup, O., Jun, D., Zdarova-Karasova, J., Patocka, J., Musilek, K., Korabecny, J., Krusek, J., Kaniakova, M., Sepsova, V., Mandikova, J., Trejtnar, F., Pohanka, M., Drtinova, L., Pavlik, M., Tobin, G., Kuca, K., A resurrection of 7-MEOTA: a comparison with tacrine. Curr. Alzheimer Res. 10 (2013), 893–906.
93. [93] Hroudova, J., Fisar, Z., Korabecny, J., Kuca, K., In vitro effects of acetylcholinesterase inhibitors and reactivators on Complex I of electron transport chain. Neuro Endocrinol. Lett. 32 (2011), 259–263.
94. [94] Lan, J.S., Xie, S.S., Li, S.Y., Pan, L.F., Wang, X.B., Kong, L.Y., Design, synthesis and evaluation of novel tacrine-(beta-carboline) hybrids as multifunctional agents for the treatment of Alzheimer's disease. Bioorg. Med. Chem. 22 (2014), 6089–6104.
95. [95] Li, S.Y., Wang, X.B., Xie, S.S., Jiang, N., Wang, K.D., Yao, H.Q., Sun, H.B., Kong, L.Y., Multifunctional tacrine-flavonoid hybrids with cholinergic, beta-amyloid-reducing, and metal chelating properties for the treatment of Alzheimer's disease. Eur. J. Med. Chem. 69 (2013), 632–646.
96. [96] Mao, F., Li, J., Wei, H., Huang, L., Li, X., Tacrine-propargylamine derivatives with improved acetylcholinesterase inhibitory activity and lower hepatotoxicity as a potential lead compound for the treatment of Alzheimer's disease. J. Enzyme Inhib. Med. Chem., 2015, 1–7.
97. [97] Wang, Y., Wang, F., Yu, J.P., Jiang, F.C., Guan, X.L., Wang, C.M., Li, L., Cao, H., Li, M.X., Chen, J.G., Novel multipotent phenylthiazole-tacrine hybrids for the inhibition of cholinesterase activity, beta-amyloid aggregation and Ca(2)(+) overload. Bioorg. Med. Chem. 20 (2012), 6513–6522.
98. [98] Xie, S.S., Lan, J.S., Wang, X.B., Jiang, N., Dong, G., Li, Z.R., Wang, K.D., Guo, P.P., Kong, L.Y., Multifunctional tacrine-trolox hybrids for the treatment of Alzheimer's disease with cholinergic, antioxidant, neuroprotective and hepatoprotective properties. Eur. J. Med. Chem. 93 (2015), 42–50.
99. [99] Xie, S.S., Wang, X.B., Li, J.Y., Yang, L., Kong, L.Y., Design, synthesis and evaluation of novel tacrine-coumarin hybrids as multifunctional cholinesterase inhibitors against Alzheimer's disease. Eur. J. Med. Chem. 64 (2013), 540–553.
100. [100] Bautista-Aguilera, O.M., Esteban, G., Bolea, I., Nikolic, K., Agbaba, D., Moraleda, I., Iriepa, I., Samadi, A., Soriano, E., Unzeta, M., Marco-Contelles, J., Design, synthesis, pharmacological evaluation, QSAR analysis, molecular modeling and ADMET of novel donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer's disease. Eur. J. Med. Chem. 75 (2014), 82–95.
101. [101] Kitani, K., Minami, C., Isobe, K., Maehara, K., Kanai, S., Ivy, G.O., Carrillo, M.C., Why (–)deprenyl prolongs survivals of experimental animals: increase of anti-oxidant enzymes in brain and other body tissues as well as mobilization of various humoral factors may lead to systemic anti-aging effects. Mechanisms of Ageing and Development, Ireland, 2002, 1087–1100.
102. [102] Kiray, M., Bagriyanik, H.A., Pekcetin, C., Ergur, B.U., Uysal, N., Ozyurt, D., Buldan, Z., Deprenyl and the relationship between its effects on spatial memory, oxidant stress and hippocampal neurons in aged male rats. Physiological Research/Academia Scientiarum Bohemoslovaca, Czech Republic, 2006, 205–212.
103. [103] Sterling, J., Herzig, Y., Goren, T., Finkelstein, N., Lerner, D., Goldenberg, W., Miskolczi, I., Molnar, S., Rantal, F., Tamas, T., Toth, G., Zagyva, A., Zekany, A., Finberg, J., Lavian, G., Gross, A., Friedman, R., Razin, M., Huang, W., Krais, B., Chorev, M., Youdim, M.B., Weinstock, M., Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease. J. Med. Chem. U. S., 2002, 5260–5279.
104. [104] Bolea, I., Juarez-Jimenez, J., de Los Rios, C., Chioua, M., Pouplana, R., Luque, F.J., Unzeta, M., Marco-Contelles, J., Samadi, A., Synthesis, biological evaluation, and molecular modeling of donepezil and N-[(5-(benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine hybrids as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease. J. Med. Chem. 54 (2011), 8251–8270.
105. [105] Lu, C., Zhou, Q., Yan, J., Du, Z., Huang, L., Li, X., A novel series of tacrine-selegiline hybrids with cholinesterase and monoamine oxidase inhibition activities for the treatment of Alzheimer's disease. Eur. J. Med. Chem. 62 (2013), 745–753.
106. [106] Martinez, A., Castro, A., Novel cholinesterase inhibitors as future effective drugs for the treatment of Alzheimer's disease. Expert Opin. Investig. Drugs 15 (2006), 1–12.
107. [107] Maruyama, W., Weinstock, M., Youdim, M.B., Nagai, M., Naoi, M., Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor. Neurosci. Lett. 341 (2003), 233–236.
108. [108] Weinstock, M., Bejar, C., Wang, R.H., Poltyrev, T., Gross, A., Finberg, J.P., Youdim, M.B., TV3326, a novel neuroprotective drug with cholinesterase and monoamine oxidase inhibitory activities for the treatment of Alzheimer's disease. J. Neural Transm. Suppl., 2000, 157–169.
109. [109] Weinstock, M., Kirschbaum-Slager, N., Lazarovici, P., Bejar, C., Youdim, M.B., Shoham, S., Neuroprotective effects of novel cholinesterase inhibitors derived from rasagiline as potential anti-Alzheimer drugs. Ann. N. Y. Acad. Sci. 939 (2001), 148–161.
110. [110] Weinstock, M., Poltyrev, T., Bejar, C., Youdim, M.B., Effect of TV3326, a novel monoamine-oxidase cholinesterase inhibitor, in rat models of anxiety and depression. Psychopharmacol. 160 (2002), 318–324.
111. [111] Camps, P., Formosa, X., Galdeano, C., Gomez, T., Munoz-Torrero, D., Ramirez, L., Viayna, E., Gomez, E., Isambert, N., Lavilla, R., Badia, A., Clos, M.V., Bartolini, M., Mancini, F., Andrisano, V., Bidon-Chanal, A., Huertas, O., Dafni, T., Luque, F.J., Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates. Chemico-biological Interact. 187 (2010), 411–415.
112. [112] H, S., Kozurkova, M., Gazova, Z., Paulikova, H., Kristian, P., Neuroactive multifunctional tacrine congeners with cholinesterase, anti-amyloid aggregation and neuroprotective properties. Pharmaceuticals 4 (2011), 382–418.
113. [113] Wang, L., Esteban, G., Ojima, M., Bautista-Aguilera, O.M., Inokuchi, T., Moraleda, I., Iriepa, I., Samadi, A., Youdim, M.B., Romero, A., Soriano, E., Herrero, R., Fernandez Fernandez, A.P., Ricardo Martinez, M., Marco-Contelles, J., Unzeta, M., Donepezil + propargylamine + 8-hydroxyquinoline hybrids as new multifunctional metal-chelators, ChE and MAO inhibitors for the potential treatment of Alzheimer's disease. Eur. J. Med. Chem. 80 (2014), 543–561.
114. [114] Fang, F., Liu, G.T., Protective effects of compound FLZ, a novel synthetic analogue of squamosamide, on beta-amyloid-induced rat brain mitochondrial dysfunction in vitro. Acta Pharmacol. Sin. 30 (2009), 522–529.
115. [115] Ye, X., Tai, W., Bao, X., Chen, X., Zhang, D., FLZ inhibited gamma-secretase selectively and decreased Abeta mitochondrial production in APP-SH-SY5Y cells. Naunyn-Schmiedeberg's Arch. Pharmacol. 387 (2014), 75–85.
116. [116] Bao, X.Q., Li, N., Wang, T., Kong, X.C., Tai, W.J., Sun, H., Zhang, D., FLZ alleviates the memory deficits in transgenic mouse model of Alzheimer's disease via decreasing beta-amyloid production and tau hyperphosphorylation. PloS one, 8, 2013, e78033.
117. [117] Muirhead, K.E., Borger, E., Aitken, L., Conway, S.J., Gunn-Moore, F.J., The consequences of mitochondrial amyloid beta-peptide in Alzheimer's disease. Biochem. J. 426 (2010), 255–270.
118. [118] Valasani, K.R., Sun, Q., Hu, G., Li, J., Du, F., Guo, Y., Carlson, E.A., Gan, X., Yan, S.S., Identification of human ABAD inhibitors for rescuing Abeta-mediated mitochondrial dysfunction. Curr. Alzheimer Res. 11 (2014), 128–136.
119. [119] Lim, Y.A., Grimm, A., Giese, M., Mensah-Nyagan, A.G., Villafranca, J.E., Ittner, L.M., Eckert, A., Gotz, J., Inhibition of the mitochondrial enzyme ABAD restores the amyloid-beta-mediated deregulation of estradiol. PloS one, 6, 2011, e28887.
120. [120] Valasani, K.R., Hu, G., Chaney, M.O., Yan, S.S., Structure-based design and synthesis of benzothiazole phosphonate analogues with inhibitors of human ABAD-Abeta for treatment of Alzheimer's disease. Chem. Biol. Drug Des. 81 (2013), 238–249.
121. [121] Rao, V.K., Carlson, E.A., Yan, S.S., Mitochondrial permeability transition pore is a potential drug target for neurodegeneration. Biochimica et Biophysica Acta 1842 (2014), 1267–1272.
122. [122] Du, H., Guo, L., Fang, F., Chen, D., Sosunov, A.A., McKhann, G.M., Yan, Y., Wang, C., Zhang, H., Molkentin, J.D., Gunn-Moore, F.J., Vonsattel, J.P., Arancio, O., Chen, J.X., Yan, S.D., Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nat. Med. 14 (2008), 1097–1105.
123. [123] Elkamhawy, A., Lee, J., Park, B.G., Park, I., Pae, A.N., Roh, E.J., Novel quinazoline-urea analogues as modulators for Abeta-induced mitochondrial dysfunction: design, synthesis, and molecular docking study. Eur. J. Med. Chem. 84 (2014), 466–475.