Amyloid-β Aggregation Inhibitory and Neuroprotective Effects of Xanthohumol and its Derivatives for Alzheimer’s Diseases

Author(s): Xueli Wang, See-Lok Ho, Chung-Yan Poon, Ting Yan, Hung-Wing Li*, Man Shing Wong*

Journal Name: Current Alzheimer Research

Volume 16 , Issue 9 , 2019

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Abstract:

Background: Xanthohumol has been reported to have cytoprotection through activation of Nrf2−ARE signaling pathway and; it has capability of scavenging free radicals, suggesting its potential for the prevention of neurodegeneration. However, the bio-incompatibility and blood-brain barrier impermeability of xanthohumol hindered its in vivo efficacy potential for treating Alzheimer’s disease (AD).

Objective: We designed and prepared a series of xanthohumol derivatives to enhance the desirable physical, biological and pharmacological properties in particular the blood-brain barrier permeability for intervention of AD.

Methods: We designed and synthesized a novel series of 9 xanthohumol derivatives. Their inhibitory effect on amyloid-β (1-42), Aβ1-42, oligomerization and fibrillation as well as neuroprotection against amyloid-β induced toxicities, were explored.

Results: Among the 9 xanthohumol derivatives, some of them exhibited a moderate to high inhibitory effect on Aβ1-42 oligomerization and fibrillation. They were biocompatible and neuroprotective to the SH-SY5Y cells by reducing the ROS generation and calcium uploading that were induced by the amyloid- β. Importantly, two of the derivatives were found to be blood-brain barrier permeable showing promising potential for AD treatment.

Conclusion: Two derivatives have been identified to be biocompatible, non-toxic, neuroprotective against Aβ-induced toxicities and blood-brain barrier permeable highlighting their promising potential as AD drug candidates for future clinical use.

Keywords: Derivatives of xanthohumol, neuroprotective, amyloid aggregation inhibition, blood-brain barrier permeable.

[1]
Alzheimers A. 2015 Alzheimer’s disease facts and figures. Alzheimers Dement 11(3): 332-84. (2015).
[http://dx.doi.org/10.1016/j.jalz.2015.02.003] [PMID: 25984581]
[2]
Scheltens P, Blennow K, Breteler MMB, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer’s disease. Lancet 388(10043): 505-17. (2016).
[http://dx.doi.org/10.1016/S0140-6736(15)01124-1] [PMID: 26921134]
[3]
Muñoz-Torrero D. Acetylcholinesterase inhibitors as disease-modifying therapies for Alzheimer’s disease. Curr Med Chem 15(24): 2433-55. (2008).
[http://dx.doi.org/10.2174/092986708785909067] [PMID: 18855672]
[4]
Shi X, Lin X, Hu R, Sun N, Hao J, Gao C. Toxicological differences between nmda receptor antagonists and cholinesterase inhibitors. Am J Alzheimers Dis Other Demen 31(5): 405-12. (2016).
[http://dx.doi.org/10.1177/1533317515622283] [PMID: 26769920]
[5]
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580): 353-6. (2002).
[http://dx.doi.org/10.1126/science.1072994] [PMID: 12130773]
[6]
Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 274(5284): 99-102. (1996).
[http://dx.doi.org/10.1126/science.274.5284.99] [PMID: 8810256]
[7]
Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416(6880): 535-9. (2002).
[http://dx.doi.org/10.1038/416535a] [PMID: 11932745]
[8]
Benilova I, Karran E, De Strooper B. The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci 15(3): 349-57. (2012).
[http://dx.doi.org/10.1038/nn.3028] [PMID: 22286176]
[9]
Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300(5618): 486-9. (2003).
[http://dx.doi.org/10.1126/science.1079469] [PMID: 12702875]
[10]
Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, et al. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 27(4): 796-807. (2007).
[http://dx.doi.org/10.1523/JNEUROSCI.3501-06.2007] [PMID: 17251419]
[11]
De Felice FG, Wu D, Lambert MP, Fernandez SJ, Velasco PT, Lacor PN, et al. Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by A beta oligomers. Neurobiol Aging 29(9): 1334-47. (2008).
[http://dx.doi.org/10.1016/j.neurobiolaging.2007.02.029] [PMID: 17403556]
[12]
Lesné SE, Sherman MA, Grant M, Kuskowski M, Schneider JA, Bennett DA, et al. Brain amyloid-β oligomers in ageing and Alzheimer’s disease. Brain 136(Pt 5): 1383-98. (2013).
[http://dx.doi.org/10.1093/brain/awt062] [PMID: 23576130]
[13]
Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ, et al. Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci 29(28): 9078-89. (2009).
[http://dx.doi.org/10.1523/JNEUROSCI.1071-09.2009] [PMID: 19605645]
[14]
Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, et al. A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci 30(14): 4845-56. (2010).
[http://dx.doi.org/10.1523/JNEUROSCI.5825-09.2010] [PMID: 20371804]
[15]
Gerhäuser C. Beer constituents as potential cancer chemopreventive agents. Eur J Cancer 41(13): 1941-54. (2005).
[http://dx.doi.org/10.1016/j.ejca.2005.04.012] [PMID: 15953717]
[16]
Miranda CL, Stevens JF, Ivanov V, McCall M, Frei B, Deinzer ML, et al. Antioxidant and prooxidant actions of prenylated and nonprenylated chalcones and flavanones in vitro. J Agric Food Chem 48(9): 3876-84. (2000).
[http://dx.doi.org/10.1021/jf0002995] [PMID: 10995285]
[17]
Stevens JF, Page JE. Xanthohumol and related prenylflavonoids from hops and beer: to your good health! Phytochemistry 65(10): 1317-30. (2004).
[http://dx.doi.org/10.1016/j.phytochem.2004.04.025] [PMID: 15231405]
[18]
Lee IS, Lim J, Gal J, Kang JC, Kim HJ, Kang BY, et al. Anti-inflammatory activity of xanthohumol involves heme oxygenase-1 induction via NRF2-ARE signaling in microglial BV2 cells. Neurochem Int 58(2): 153-60. (2011).
[http://dx.doi.org/10.1016/j.neuint.2010.11.008] [PMID: 21093515]
[19]
Ban JY, Jeon S-Y, Nguyen TTH, Bae K, Song K-S, Seong YH. Neuroprotective effect of oxyresveratrol from smilacis chinae rhizome on amyloid Beta protein (25-35)-induced neurotoxicity in cultured rat cortical neurons. Biol Pharm Bull 29(12): 2419-24. (2006).
[http://dx.doi.org/10.1248/bpb.29.2419] [PMID: 17142975]


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Article Details

VOLUME: 16
ISSUE: 9
Year: 2019
Page: [836 - 842]
Pages: 7
DOI: 10.2174/1567205016666190827123222
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