Genistein and Galantamine Combinations Decrease β-Amyloid Peptide (1–42)–Induced Genotoxicity and Cell Death in SH-SY5Y Cell Line: an In Vitro and In Silico Approach for Mimic of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the primary dementia-causing disease worldwide, involving a multifactorial combination of environmental, genetic, and epigenetic factors, with essential participation of age and sex. Biochemically, AD is characterized by the presence of abnormal deposition of beta amyloid peptide (Aβ(1–42)), which in the brain is strongly correlated with oxidative stress, inflammation, DNA damage, and cholinergic impairment. The multiple mechanisms involved in its etiology create significant difficulty in producing an effective treatment. Neuroprotective properties of genistein and galantamine have been widely demonstrated through different mechanisms; however, it is unknown a possible synergistic neuroprotective effect against Aβ(1–42). In order to understand how genistein and galantamine combinations regulate the mechanisms of neuroprotection, we conducted a set of bioassays in vitro to evaluate cell viability, clonogenic survival, cell death, and anti-genotoxicity. Through molecular docking and therapeutic viability assays, we analyzed the inhibitory activity exerted by genistein on three major protein targets (AChE, BChE, and NMDA) involved in AD. The results showed that genistein and galantamine afforded significant protection at higher concentrations; however, combinations of sub-effective concentrations of both compounds provided marked neuroprotection when they were combined. In silico approaches showed that genistein has higher scores than the positive controls and low toxicity levels; nevertheless, the therapeutic viability indicated that unlike galantamine, genistein cannot undergo the action by P glycoprotein (PGP) and probably may be unable to cross the blood-brain barrier. In conclusion, our results show that genistein and galantamine exert neuroprotective by decreasing genotoxicity and cell death. In silico analysis, suggest that genistein modulates positively the expression of AChE, BChE, and NMDA. In this context, a combination of two or more drugs could inspire an attractive therapeutic strategy.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. Agholme L, Lindström T, Kågedal K, Marcusson J, Hallbeck M (2010) An in vitro model for neuroscience: differentiation of SH-SY5Y cells into cells with morphological and biochemical characteristics of mature neurons. J Alzheimers Dis 20(4):1069–1082

    CAS  PubMed  Google Scholar 

  2. Algazo M, Rahimi N, Amiri Gheshlaghi S, Alshaib H, Fahimi R, Dehpour AR (2019) Involvement of NMDA receptor and nitric oxide pathway in the anticonvulsant effect of genistein in ovariectomized mice. Journal of Iranian Medical Council 1(3):133–139

    Google Scholar 

  3. Anand R, Gill KD, Mahdi AA (2014) Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology 76:27–50

    CAS  PubMed  Google Scholar 

  4. Arias E, Ales E, Gabilan NH, Cano-Abad MF, Villarroya M, García AG, López MG (2004) Galantamine prevents apoptosis induced by β-amyloid and thapsigargin: involvement of nicotinic acetylcholine receptors. Neuropharmacology 46(1):103–114

    CAS  PubMed  Google Scholar 

  5. Bagheri M, Joghataei MT, Mohseni RM (2011) Genistein ameliorates learning and memory deficits in amyloid β (1–40) rat model of Alzheimer’s disease. Neurobiol Learn Mem 95(3):270–276

    CAS  PubMed  Google Scholar 

  6. Bagheri M, Roghani M, Joghataei MT, Mohseni S (2012) Genistein inhibits aggregation of exogenous amyloid-beta1–40 and alleviates astrogliosis in the hippocampus of rats. Brain Res 1429:145–154

    CAS  PubMed  Google Scholar 

  7. Banerjee P, Eckert AO, Schrey AK, Preissner R (2018) ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res 46(W1):W257–W263

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bang OY, Hong HS, Kim DH, Kim H, Boo JH, Huh K, Mook-Jung I (2004) Neuroprotective effect of genistein against beta amyloid-induced neurotoxicity. Neurobiol Dis 16(1):21–28

    CAS  PubMed  Google Scholar 

  9. Bartus RT, Dean RL, Pontecorvo MJ, Flicker C (1985) The cholinergic hypothesis: a historical overview, current perspective, and future directions. Ann N Y Acad Sci 444(1):332–358

    CAS  PubMed  Google Scholar 

  10. Behl C, Davis JB, Klier FG, Schubert D (1994) Amyloid β peptide induces necrosis rather than apoptosis. Brain Res 645(1–2):253–264

    CAS  PubMed  Google Scholar 

  11. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The protein data bank. Nucleic Acids Res 28(1):235–242

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Brookmeyer R, Abdalla N, Kawas CH, Corrada MM (2018) Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States. Alzheimers Dement 14(2):121–129

    PubMed  Google Scholar 

  13. Burns A, Bernabei R, Bullock R, Cruz Jentoft AJ, Frolich L, Hock C, Raivio M, Triau E, Vandewoude M, Wimo A, Came E, Van Baelen B, Hammond GL, Van Oene JC, Schwalen S (2009) Safety and efficacy of galantamine (Reminyl) in severe Alzheimer’s disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurol 8(1):39–47

    CAS  PubMed  Google Scholar 

  14. Butterfield DA, Castegna A, Lauderback CM, Drake J (2002) Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contribute to neuronal death. Neurobiol Aging 23(5):655–664

    PubMed  Google Scholar 

  15. Cardinale A, Racaniello M, Saladini S, De Chiara G, Mollinari C, de Stefano MC, Pocchiari M, Garaci E, Merlo D (2012) Sublethal doses of β-amyloid peptide abrogate DNA-dependent protein kinase activity. J Biol Chem 287(4):2618–2631

    CAS  PubMed  Google Scholar 

  16. Castillo WO, Aristizabal-Pachon AF (2017) Galantamine protects against beta amyloid peptide-induced DNA damage in a model for Alzheimer’s disease. Neural Regen Res 12(6):916–917

    PubMed  PubMed Central  Google Scholar 

  17. Castillo WO, Aristizabal-Pachon AF, de Lima Montaldi AP, Sakamoto-Hojo ET, Takahashi CS (2016) Galanthamine decreases genotoxicity and cell death induced by β-amyloid peptide in SH-SY5Y cell line. Neurotoxicology 57:291–297

    CAS  PubMed  Google Scholar 

  18. Castillo WO, Aristizabal-Pachon AF, Sakamoto-Hojo E, Gasca CA, Cabezas-Fajardo FA, Takahashi CS (2018) Caliphruria subedentata (Amaryllidaceae) decreases genotoxicity and cell death induced by β-amyloid peptide in sh-sy5y cell line. Mutation Research/Genetic Toxicology and Environmental Mutagenesis 836:54–61

    CAS  PubMed  Google Scholar 

  19. Castro AF, Altenberg GA (1997) Inhibition of drug transport by genistein in multidrug-resistant cells expressing P-glycoprotein. Biochem Pharmacol 53(1):89–93

    PubMed  Google Scholar 

  20. Chan KK, Siu MK, Jiang YX, Wang JJ, Leung TH, Ngan HY (2018) Estrogen receptor modulators genistein, daidzein and ERB-041 inhibit cell migration, invasion, proliferation and sphere formation via modulation of FAK and PI3K/AKT signaling in ovarian cancer. Cancer Cell Int 18(1):65

    PubMed  PubMed Central  Google Scholar 

  21. Chen X, Yan SD (2006) Mitochondrial Aβ a potential cause of metabolic dysfunction in Alzheimer’s disease. IUBMB Life 58(12):686–694

    CAS  PubMed  Google Scholar 

  22. Cheung J, Rudolph MJ, Burshteyn F, Cassidy MS, Gary EN, Love J, Franklin MC, Height JJ (2012) Structures of human acetylcholinesterase in complex with pharmacologically important ligands. J Med Chem 55(22):10282–10286

    CAS  PubMed  Google Scholar 

  23. Coccini T, Manzo L, Bellotti V, De Simone U (2014) Assessment of cellular responses after short-and long-term exposure to silver nanoparticles in human neuroblastoma (SH-SY5Y) and astrocytoma (D384) cells. Sci World J 2014:1–13

    Google Scholar 

  24. Collins A, Koppen G, Valdiglesias V, Dusinska M, Kruszewski M, Møller P, Rojas E, Dhawan A, Benzie I, Coskun E (2014) The comet assay as a tool for human biomonitoring studies: the ComNet project. Mutation Research/Reviews in Mutation Research 759:27–39

    CAS  PubMed  Google Scholar 

  25. Daina A, Zoete V (2016) A boiled-egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem 11(11):1117–1121

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 7:42717

    PubMed  PubMed Central  Google Scholar 

  27. Darvesh S (2016) Butyrylcholinesterase as a diagnostic and therapeutic target for Alzheimer’s disease. Curr Alzheimer Res 13(10):1173–1177

    CAS  PubMed  Google Scholar 

  28. De Bruin N, Prickaerts J, Lange J, Akkerman S, Andriambeloson E, de Haan M, Wijnen J, van Drimmelen M, Hissink E, Heijink L (2010) SLV330, a cannabinoid CB 1 receptor antagonist, ameliorates deficits in the T-maze, object recognition and social recognition tasks in rodents. Neurobiol Learn Mem 93(4):522–531

    PubMed  Google Scholar 

  29. Devi KP, Shanmuganathan B, Manayi A, Nabavi SF, Nabavi SM (2017) Molecular and therapeutic targets of genistein in Alzheimer’s disease. Mol Neurobiol 54(9):7028–7041

    CAS  PubMed  Google Scholar 

  30. Ding B, Yuan L, Yu H, Li L, Ma W, Bi Y, Feng J, Xiao R (2011) Genistein and folic acid prevent oxidative injury induced by β-amyloid peptide. Basic & clinical pharmacology & toxicology 108(5):333–340

    CAS  Google Scholar 

  31. Donzelli A, Braida D, Finardi A, Capurro V, Valsecchi AE, Colleoni M, Sala M (2010) Neuroprotective effects of genistein in Mongolian gerbils: estrogen receptor–β involvement. J Pharmacol Sci 114(2):158–167

    CAS  PubMed  Google Scholar 

  32. Dorn GW (2013) Molecular mechanisms that differentiate apoptosis from programmed necrosis. Toxicol Pathol 41(2):227–234

    CAS  PubMed  Google Scholar 

  33. Duarte RA, Mello ER, Araki C, da Silva BV, Silva DHS, Regasini LO, Silva TGA, de Morais MCC, Ximenes VF, Soares CP (2010) Alkaloids extracted from Pterogyne nitens induce apoptosis in malignant breast cell line. Tumor Biol 31(5):513–522

    CAS  Google Scholar 

  34. Eriksson AH, Rønsted N, Güler S, Jäger AK, Sendra JR, Brodin B (2012) In-vitro evaluation of the P-glycoprotein interactions of a series of potentially CNS-active Amaryllidaceae alkaloids. J Pharm Pharmacol 64(11):1667–1677

    CAS  PubMed  Google Scholar 

  35. Ezoulin MJ, Ombetta JE, Dutertre-Catella H, Warnet JM, Massicot F (2008) Antioxidative properties of galantamine on neuronal damage induced by hydrogen peroxide in SK–N–SH cells. Neurotoxicology 29(2):270–277

    CAS  PubMed  Google Scholar 

  36. Fonseca ACR, Moreira PI, Oliveira CR, Cardoso SM, Pinton P, Pereira CF (2015) Amyloid-beta disrupts calcium and redox homeostasis in brain endothelial cells. Mol Neurobiol 51(2):610–622

    CAS  PubMed  Google Scholar 

  37. Furukawa H, Gouaux E (2003) Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand-binding core. EMBO J 22(12):2873–2885

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Green PS, Gridley KE, de Fiebre NC (1997) Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer’s disease. Am J Med 103(3):19S–25S

    PubMed  Google Scholar 

  39. Gupta SK, Dongare S, Mathur R, Mohanty IR, Srivastava S, Mathur S, Nag TC (2015) Genistein ameliorates cardiac inflammation and oxidative stress in streptozotocin-induced diabetic cardiomyopathy in rats. Mol Cell Biochem 408(1–2):63–72

    CAS  PubMed  Google Scholar 

  40. Hampel H, Mesulam MM, Cuello AC, Khachaturian AS, Vergallo A, Farlow M, Snyder P, Giacobini E, Khachaturian Z, Group CSW (2017) Revisiting the cholinergic hypothesis in Alzheimer’s disease: emerging evidence from translational and clinical research. The journal of prevention of Alzheimer's disease:1–14

  41. Han HJ, Kim BC, Lee JY, Ryu SH, Na HR, Yoon SJ, Park HY, Shin JH, Cho SJ, Yi HA (2012) Response to rivastigmine transdermal patch or memantine plus rivastigmine patch is affected by apolipoprotein E genotype in Alzheimer patients. Dement Geriatr Cogn Disord 34(3–4):167–173

    CAS  PubMed  Google Scholar 

  42. Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11(10):682–696

    CAS  PubMed  PubMed Central  Google Scholar 

  43. He W, He P, Wang A, Xia T, Xu B, Chen X (2008) Effects of PBDE-47 on cytotoxicity and genotoxicity in human neuroblastoma cells in vitro. Mutation Research/Genetic Toxicology and Environmental Mutagenesis 649(1):62–70

    CAS  Google Scholar 

  44. Heinrich M, Lee Teoh H (2004) Galanthamine from snowdrop—the development of a modern drug against Alzheimer’s disease from local Caucasian knowledge. J Ethnopharmacol 92(2):147–162

    CAS  PubMed  Google Scholar 

  45. Hemmings BA, Restuccia DF (2012) Pi3k-pkb/akt pathway. Cold Spring Harb Perspect Biol 4(9):1–3

    Google Scholar 

  46. Hsieh HM, Wu WM, Hu ML (2009) Soy isoflavones attenuate oxidative stress and improve parameters related to aging and Alzheimer’s disease in C57BL/6J mice treated with D-galactose. Food Chem Toxicol 47(3):625–632

    CAS  PubMed  Google Scholar 

  47. Jiang S, Zhao Y, Zhang T, Lan J, Yang J, Yuan L, Zhang Q, Pan K, Zhang K (2018) Galantamine inhibits β-amyloid-induced cytostatic autophagy in PC 12 cells through decreasing ROS production. Cell proliferation, e12427

  48. Jin H, Zhu Y, Wang C, Meng Q, Wu J, Sun P, Ma X, Sun H, Huo X, Liu K (2020) Molecular pharmacokinetic mechanism of the drug-drug interaction between genistein and repaglinide mediated by P-gp. Biomed Pharmacother 125:110032

    CAS  PubMed  Google Scholar 

  49. Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267(3):727–748

    CAS  PubMed  Google Scholar 

  50. Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA (2015) PubChem substance and compound databases. Nucleic Acids Res 44(D1):D1202–D1213

    PubMed  PubMed Central  Google Scholar 

  51. Korostoff J, Wang JF, Kieba I, Miller M, Shenker BJ, Lally ET (1998) Actinobacillus actinomycetemcomitansleukotoxin induces apoptosis in HL-60 cells. Infect Immun 66(9):4474–4483

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Košak U, Brus B, Knez D, Šink R, Žakelj S, Trontelj J, Pišlar A, Šlenc J, Gobec M, Živin M (2016) Development of an in-vivo active reversible butyrylcholinesterase inhibitor. Sci Rep 6:39495

    PubMed  PubMed Central  Google Scholar 

  53. Kosmidis MH, Vlachos GS, Anastasiou CA, Yannakoulia M, Dardiotis E, Hadjigeorgiou G, Sakka P, Ntanasi E, Scarmeas N (2018) Dementia prevalence in Greece: the Hellenic longitudinal investigation of aging and diet (HELIAD). Alzheimer Dis Assoc Disord 32(3):232–239

    PubMed  Google Scholar 

  54. Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JAk (1997) Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology 138(3), 863–870

  55. Lee JY, Kim HS, Song YS (2012) Genistein as a potential anticancer agent against ovarian cancer. J Tradit Complement Med 2(2):96–104

    PubMed  PubMed Central  Google Scholar 

  56. Lee SL, Thomas P, Fenech M (2014) Extracellular amyloid beta 42 causes necrosis, inhibition of nuclear division, and mitotic disruption under both folate deficient and folate replete conditions as measured by the cytokinesis-block micronucleus cytome assay. Environ Mol Mutagen 55(1):1–14

    PubMed  Google Scholar 

  57. Li Q, Wu D, Zhang L, Zhang Y (2010) Effects of galantamine on β-amyloid release and beta-site cleaving enzyme 1 expression in differentiated human neuroblastoma SH-SY5Y cells. Exp Gerontol 45(11):842–847

    CAS  PubMed  Google Scholar 

  58. Liu Y, Nair MG (2010) An efficient and economical MTT assay for determining the antioxidant activity of plant natural product extracts and pure compounds. J Nat Prod 73(7):1193–1195

    CAS  PubMed  Google Scholar 

  59. Liu R, Barkhordarian H, Emadi S, Park CB, Sierks MR (2005) Trehalose differentially inhibits aggregation and neurotoxicity of beta-amyloid 40 and 42. Neurobiol Dis 20(1):74–81

    PubMed  Google Scholar 

  60. Liu X, Xu K, Yan M, Wang Y, Zheng X (2010) Protective effects of galantamine against Aβ-induced PC12 cell apoptosis by preventing mitochondrial dysfunction and endoplasmic reticulum stress. Neurochem Int 57(5):588–599

    CAS  PubMed  Google Scholar 

  61. Lorenzo Y, Azqueta A, Luna L, Bonilla F, Domínguez G, Collins AR (2009) The carotenoid β-cryptoxanthin stimulates the repair of DNA oxidation damage in addition to acting as an antioxidant in human cells. Carcinogenesis 30(2):308–314

    CAS  PubMed  Google Scholar 

  62. Lu Y, Lin D, Li W, Yang X (2017) Non-digestible stachyose promotes bioavailability of genistein through inhibiting intestinal degradation and first-pass metabolism of genistein in mice. Food Nutr Res 61(1):1369343

    PubMed  PubMed Central  Google Scholar 

  63. Luo S, Lan T, Liao W, Zhao M, Yang H (2012) Genistein inhibits Aβ 25–35–induced neurotoxicity in PC12 cells via PKC signaling pathway. Neurochem Res 37(12):2787–2794

    CAS  PubMed  Google Scholar 

  64. Ma W, Ding B, Yu H, Yuan L, Xi Y, Xiao R (2015) Genistein alleviates β-amyloid-induced inflammatory damage through regulating toll-like receptor 4/nuclear factor κ B. J Med Food 18(3):273–279

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79(5):727–747

    CAS  PubMed  Google Scholar 

  66. Mannens G, Snel C, Hendrickx J, Verhaeghe T, Le Jeune L, Bode W, Van Beijsterveldt L, Lavrijsen K, Leempoels J, Van Osselaer N (2002) The metabolism and excretion of galantamine in rats, dogs, and humans. Drug Metab Dispos 30(5):553–563

    CAS  PubMed  Google Scholar 

  67. Marcantoni A, Cerullo MS, Buxeda P, Tomagra G, Giustetto M, Chiantia G, Carabelli V, Carbone E (2020). Abeta42 oligomers up-regulate the excitatory synapses by potentiating presynaptic release while impairing postsynaptic NMDA receptors. The Journal of Physiology

  68. Menze ET, Esmat A, Tadros MG, Abdel-Naim AB, Khalifa AE (2015) Genistein improves 3-NPA-induced memory impairment in ovariectomized rats: impact of its antioxidant, anti-inflammatory and acetylcholinesterase modulatory properties. PLoS One 10(2):e0117223

    PubMed  PubMed Central  Google Scholar 

  69. Mossmann D, Vögtle FN, Taskin AA, Teixeira PF, Ring J, Burkhart JM, Burger N, Pinho CM, Tadic J, Loreth D (2014) Amyloid-β peptide induces mitochondrial dysfunction by inhibition of Preprotein maturation. Cell Metab 20(4):662–669

    CAS  PubMed  Google Scholar 

  70. Namanja HA, Emmert D, Pires MM, Hrycyna CA, Chmielewski J (2009) Inhibition of human P-glycoprotein transport and substrate binding using a galantamine dimer. Biochem Biophys Res Commun 388(4):672–676

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Narciso L, Parlanti E, Racaniello M, Simonelli V, Cardinale A, Merlo D, Dogliotti E (2016) The response to oxidative DNA damage in neurons: mechanisms and disease. Neural plasticity 2016:1–14

    Google Scholar 

  72. Ni R, Marutle A, Nordberg A (2013) Modulation of α7 nicotinic acetylcholine receptor and fibrillar amyloid-β interactions in Alzheimer’s disease brain. J Alzheimers Dis 33(3):841–851

    CAS  PubMed  Google Scholar 

  73. Odle B, Dennison N, Al-Nakkash L, Broderick TL, Plochocki JH (2017) Genistein treatment improves fracture resistance in obese diabetic mice. BMC Endocr Disord 17(1):1

    PubMed  PubMed Central  Google Scholar 

  74. Parsons MP, Raymond LA (2014) Extrasynaptic NMDA receptor involvement in central nervous system disorders. Neuron 82(2):279–293

    CAS  PubMed  Google Scholar 

  75. Petry FS, Coelho BP, Gaelzer MM, Kreutz F, Guma FTCR, Salbego CG, Trindade VMT (2020) Genistein protects against amyloid-beta-induced toxicity in SH-SY5Y cells by regulation of Akt and Tau phosphorylation. Phytother Res 34(4):796–807

    CAS  PubMed  Google Scholar 

  76. Pierzynowska K, Podlacha M, Gaffke L, Majkutewicz I, Mantej J, Węgrzyn A, Osiadły M, Myślińska D, Węgrzyn G (2019) Autophagy-dependent mechanism of genistein-mediated elimination of behavioral and biochemical defects in the rat model of sporadic Alzheimer’s disease. Neuropharmacology 148:332–346

    CAS  PubMed  Google Scholar 

  77. Purgatorio R, de Candia M, Catto M, Carrieri A, Pisani L, De Palma A, Toma M, Ivanova OA, Voskressensky LG, Altomare CD (2019) Investigating 1, 2, 3, 4, 5, 6-hexahydroazepino [4, 3-b] indole as scaffold of butyrylcholinesterase-selective inhibitors with additional neuroprotective activities for Alzheimer’s disease. Eur J Med Chem 177:414–424

    CAS  PubMed  Google Scholar 

  78. Rajput MS, Sarkar PD (2017) Modulation of neuro-inflammatory condition, acetylcholinesterase and antioxidant levels by genistein attenuates diabetes associated cognitive decline in mice. Chem Biol Interact 268:93–102

    CAS  PubMed  Google Scholar 

  79. Release S (2014): Maestro, version 9.9; Schrödinger, LLC: New York, NY, 2014

  80. Ren B, Liu Y, Zhang Y, Cai Y, Gong X, Chang Y, Xu L, Zheng J (2018) Genistein: a dual inhibitor of both amyloid β and human islet amylin peptides. ACS Chem Neurosci 9(5):1215–1224

    CAS  PubMed  Google Scholar 

  81. Romero A, Egea J, García AG, López MG (2010) Synergistic neuroprotective effect of combined low concentrations of galantamine and melatonin against oxidative stress in SH-SY5Y neuroblastoma cells. J Pineal Res 49(2):141–148

    CAS  PubMed  Google Scholar 

  82. Rosenblum WI (2014) Why Alzheimer trials fail: removing soluble oligomeric beta amyloid is essential, inconsistent, and difficult. Neurobiol Aging 35(5):969–974

    CAS  PubMed  Google Scholar 

  83. Rusdiah R, AH NA (2009) Induction of DNA damage and cell death by beta amyloid peptide and its modification by tocotrienol rich fraction (TRF). Medicine & Health 4(1), 8–15

  84. Russo M, Russo GL, Daglia M, Kasi PD, Ravi S, Nabavi SF, Nabavi SM (2016) Understanding genistein in cancer: the “good” and the “bad” effects: a review. Food Chem 196:589–600

    CAS  PubMed  Google Scholar 

  85. Sciú ML, Sebastián-Pérez V, Martinez-Gonzalez L, Benitez R, Perez DI, Pérez C, Campillo NE, Martinez A, Moyano EL (2019) Computer-aided molecular design of pyrazolotriazines targeting glycogen synthase kinase 3. Journal of enzyme inhibition and medicinal chemistry 34(1):87–96

    PubMed  Google Scholar 

  86. Seshadri S, Beiser A, Kelly-Hayes M, Kase CS, Au R, Kannel WB, Wolf PA (2006) The lifetime risk of stroke: estimates from the Framingham study. Stroke 37(2):345–350

    PubMed  Google Scholar 

  87. Singh NP, McCoy MT, Tice RR, Schneider EL (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175(1):184–191

    CAS  PubMed  Google Scholar 

  88. Soltani Z, Khaksari M, Jafari E, Iranpour M, Shahrokhi N (2015) Is genistein neuroprotective in traumatic brain injury? Physiol Behav 152:26–31

    CAS  PubMed  Google Scholar 

  89. Supko JG, Malspeis (1995) Plasma pharmacokinetics of genistein in mice. Int J Oncol 7(4), 847–854

  90. Suzuki K, Koike H, Matsui H, Ono Y, Hasumi M, Nakazato H, Okugi H, Sekine Y, Oki K, Ito K (2002) Genistein, a soy isoflavone, induces glutathione peroxidase in the human prostate cancer cell lines LNCaP and PC-3. Int J Cancer 99(6):846–852

    CAS  PubMed  Google Scholar 

  91. Takada-Takatori Y, Kume T, Sugimoto M, Katsuki H, Sugimoto H, Akaike A (2006) Acetylcholinesterase inhibitors used in treatment of Alzheimer’s disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology 51(3):474–486

    CAS  PubMed  Google Scholar 

  92. Tranah GJ, Yokoyama JS, Katzman SM, Nalls MA, Newman AB, Harris TB, Cesari M, Manini TM, Schork NJ, Cummings SR (2014) Mitochondrial DNA sequence associations with dementia and amyloid-β in elderly African Americans. Neurobiology of aging 35(2), 442. e441-442. e448

  93. Tsai TH (2005) Concurrent measurement of unbound genistein in the blood, brain and bile of anesthetized rats using microdialysis and its pharmacokinetic application. J Chromatogr A 1073(1–2):317–322

    CAS  PubMed  Google Scholar 

  94. Unver N (2007) New skeletons and new concepts in Amaryllidaceae alkaloids. Phytochem Rev 6(1):125–135

    CAS  Google Scholar 

  95. Vallés SL, Borrás C, Gambini J, Furriol J, Ortega A, Sastre J, Pallardó FV, Viña J (2008) Oestradiol or genistein rescues neurons from amyloid beta-induced cell death by inhibiting activation of p38. Aging Cell 7(1):112–118

    PubMed  Google Scholar 

  96. Valles SL, Dolz-Gaiton P, Gambini J, Borras C, LLoret A, Pallardo FV, Viña J (2010) Estradiol or genistein prevent Alzheimer's disease-associated inflammation correlating with an increase PPARγ expression in cultured astrocytes. Brain Res 1312:138–144

    CAS  PubMed  Google Scholar 

  97. Varadarajan S, Yatin S, Aksenova M, Butterfield DA (2000) Review: Alzheimer’s amyloid ß-peptide-associated free radical oxidative stress and neurotoxicity. J Struct Biol 130(2–3):184–208

    CAS  PubMed  Google Scholar 

  98. Wang Y, Cai B, Shao J, Wang TT, Cai RZ, Ma CJ, Han T, Du J (2016) Genistein suppresses the mitochondrial apoptotic pathway in hippocampal neurons in rats with Alzheimer’s disease. Neural Regen Res 11(7):1153–1158

    PubMed  PubMed Central  Google Scholar 

  99. Watcharasit P, Visitnonthachai D, Suntararuks S, Thiantanawat A, Satayavivad J (2012) Low arsenite concentrations induce cell proliferation via activation of VEGF signaling in human neuroblastoma SH-SY5Y cells. Environ Toxicol Pharmacol 33(1):53–59

    CAS  PubMed  Google Scholar 

  100. Watkins PB, Zimmerman HJ, Knapp MJ, Gracon SI, Lewis KW (1994) Hepatotoxic effects of tacrine administration in patients with Alzheimer's disease. Jama 271(13):992–998

    CAS  PubMed  Google Scholar 

  101. Wirth M, Bejanin A, La Joie R, Arenaza-Urquijo EM, Gonneaud J, Landeau B, Perrotin A, Mézenge F, de La Sayette V, Desgranges B (2018) Regional patterns of gray matter volume, hypometabolism, and beta-amyloid in groups at risk of Alzheimer’s disease. Neurobiol Aging 63:140–151

    CAS  PubMed  Google Scholar 

  102. Xi YD, Y, HL, Ma WW, Ding BJ, Ding J, Yuan LH, Feng JF, Xiao R (2011) Genistein inhibits mitochondrial-targeted oxidative damage induced by beta-amyloid peptide 25–35 in PC12 cells. J Bioenerg Biomembr 43(4), 399, 407

  103. Xicoy H, Wieringa B, Marten GJ (2017) The SH-SY5Y cell line in Parkinson’s disease research: a systematic review. Mol Neurodegener 12(1):10

    PubMed  PubMed Central  Google Scholar 

  104. Xie B, Wang H, Zou H, Liu Y, Kong ., Fang X (2016) Increased intestinal absorption of genistein by coadministering verapamil in rats. Eur J Drug Metab Pharmacokinet 41(5), 637–643

  105. Xu H, Li LX, Wang YX, Wang HG, An D, Heng B, Liu YQ (2019) Genistein inhibits Aβ25–35-induced SH-SY5Y cell damage by modulating the expression of apoptosis-related proteins and Ca2+ influx through ionotropic glutamate receptors. Phytother Res 33(2):431–441

    CAS  PubMed  Google Scholar 

  106. Yang LB, Lindholm K, Yan R, Citron M, Xia W, Yang XL, Beach T, Sue L, Wong P, Price D (2003) Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 9(1):3–4

    CAS  PubMed  Google Scholar 

  107. Ye S, Wang TT, Cai B, Wang Y, Li J, Zhan JX, Shen GM (2017) Genistein protects hippocampal neurons against injury by regulating calcium/calmodulin dependent protein kinase IV protein levels in Alzheimer’s disease model rats. Neural Regen Res 12(9):1479–1484

    PubMed  PubMed Central  Google Scholar 

  108. Youn K, Park JH, Lee S, Lee S, Lee J, Yun EY, Jeong WS, Jun M (2018) BACE1 inhibition by genistein: biological evaluation, kinetic analysis, and molecular docking simulation. J Med Food 21(4):416–420

    CAS  PubMed  Google Scholar 

  109. Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, Breitner JC, Investigators CCMS (2002) Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County study. Jama 288(17):2123–2129

    CAS  PubMed  Google Scholar 

  110. Zheng H, Fridkin M, Youdim M (2015) New approaches to treating Alzheimer’s disease. Perspectives in medicinal chemistry 7:1

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Willian Orlando Castillo.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Castillo, W.O., Palomino, N.V., Takahashi, C.S. et al. Genistein and Galantamine Combinations Decrease β-Amyloid Peptide (1–42)–Induced Genotoxicity and Cell Death in SH-SY5Y Cell Line: an In Vitro and In Silico Approach for Mimic of Alzheimer’s Disease. Neurotox Res (2020). https://doi.org/10.1007/s12640-020-00243-8

Download citation

Keywords

  • Alzheimer’s disease
  • Estrogen
  • Oxidative stress
  • Neurotoxicity
  • Synergistic
  • Molecular docking