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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

Role of Flavonoids in Management of Various Biological Targets in Alzheimer’s Disease: Evidence from Preclinical to Clinical Studies

Author(s): Khalid Saad Alharbi, Mohammad Arshad Javed Shaikh, Syed Sarim Imam, Sultan Alshehri, Mohammed M. Ghoneim, Waleed Hassan Almalki, Sachin Kumar Singh, Deepak Kumar, Avvaru Praveen Kumar, Kamal Dua, Dinesh Kumar Chellappan, Keshav Raj Paudel and Gaurav Gupta*

Volume 30, Issue 18, 2023

Published on: 29 December, 2022

Page: [2061 - 2074] Pages: 14

DOI: 10.2174/0929867330666221122115212

Price: $65


More than 10 million people worldwide have Alzheimer's disease (AD), a degenerative neurological illness and the most prevalent form of dementia. AD's progression in memory loss, cognitive deterioration, and behavioral changes are all symptoms. Amyloid-beta 42 (Aβ42), the hyperphosphorylated forms of microtubule-associated tau protein, and other cellular and systemic alterations are all factors that contribute to cognitive decline in AD. Rather than delivering a possible cure, present therapy strategies focus on reducing disease symptoms. It has long been suggested that various naturally occurring small molecules (plant extract products and microbiological isolates, for example) could be beneficial in preventing or treating disease. Small compounds, such as flavonoids, have attracted much interest recently due to their potential to alleviate cellular stress. Flavonoids have been proven helpful in various ways, including antioxidants, anti-inflammatory agents, and anti-apoptotic agents, but their mechanism remains unknown. The flavonoid therapy of Alzheimer's disease focuses on this review, which includes a comprehensive literature analysis.

Keywords: Flavonoids, Alzheimer's disease, antioxidant, amyloid-beta 42, cognitive deficits, anti-apoptotic.

Griciuc, A.; Tanzi, R.E. The role of innate immune genes in Alzheimer’s disease. Curr. Opin. Neurol., 2021, 34(2), 228-236.
[] [PMID: 33560670]
Levey, A.I. Progress with Treatments for Alzheimer’s Disease. N. Engl. J. Med., 2021, 384(18), 1762-1763.
[] [PMID: 33951366]
Gupta, G.; Kazmi, I.; Afzal, M.; Rahman, M.; Saleem, S.; Ashraf, M.S.; Khusroo, M.J.; Nazeer, K.; Ahmed, S.; Mujeeb, M.; Ahmed, Z.; Anwar, F. Sedative, antiepileptic and antipsychotic effects of Viscum album L. (Loranthaceae) in mice and rats. J. Ethnopharmacol., 2012, 141(3), 810-816.
[] [PMID: 22449438]
Gupta, G.; Dua, K.; Kazmi, I.; Anwar, F. Anticonvulsant activity of Morusin isolated from Morus alba: Modulation of GABA receptor. Biomed. Aging Pathol., 2014, 4(1), 29-32.
Jha, N.K.; Sharma, A.; Jha, S.K.; Ojha, S.; Chellappan, D.K.; Gupta, G.; Kesari, K.K.; Bhardwaj, S.; Shukla, S.D.; Tambuwala, M.M.; Ruokolainen, J.; Dua, K.; Singh, S.K. Alzheimer’s disease-like perturbations in HIV-mediated neuronal dysfunctions: Understanding mechanisms and developing therapeutic strategies. Open Biol., 2020, 10(12), 200286.
[] [PMID: 33352062]
Gupta, G.; Dahiya, R.; Dua, K.; Chellappan, D.K.; Tiwari, J.; Narayan Sharma, G.; Kumar Singh, S.; Mishra, A.; Kumar Sharma, R.; Agrawal, M. Anticonvulsant effect of liraglutide, GLP-1 agonist by averting a change in GABA and brain glutathione level on picrotoxin-induced seizures. EXCLI J., 2017, 16, 752-754.
[PMID: 28827991]
Gupta, G.; Singh, R.; David, S.R.; Verma, R.K. Effect of rosiglitazone, a PPAR-γ ligand on haloperidol-induced catalepsy. CNS Neurosci. Ther., 2013, 19(9), 724-725.
[] [PMID: 23786164]
Kazmi, I.; Afzal, M.; Gupta, G.; Anwar, F. Antiepileptic potential of ursolic acid stearoyl glucoside by GABA receptor stimulation. CNS Neurosci. Ther., 2012, 18(9), 799-800.
[] [PMID: 22943148]
Krishna, K.V.; Dubey, S.K.; Singhvi, G.; Gupta, G.; Kesharwani, P. MAPK pathway: Potential role in glioblastoma multiforme. Interdiscip. Neurosurg., 2021, 23, 100901.
Kumar, P.; Deb, P.K. Frontiers in Pharmacology of Neurotransmitters; Springer: Singapore, 2020.
Madhu, A.; Gupta, G.; Arali, B.; Chellappan, D.K.; Dua, K. Anti-psychotic activity of aqueous root extract of Hemidesmus indicus: A time bound study in rats. Recent Pat. Drug Deliv. Formul., 2017, 11(1), 36-41.
[PMID: 27993107]
Pathak, S.; Gupta, G.; Thangavelu, L.; Singh, S.K.; Dua, K.; Chellappan, D.K.; Gilhotra, R.M. Recent update on barbiturate in relation to brain disorder. Excli J., 2021, 20, 1028-1032.
[PMID: 34267614]
Singh, Y.; Gupta, G.; Shrivastava, B.; Dahiya, R.; Tiwari, J.; Ashwathanarayana, M.; Sharma, R.K.; Agrawal, M.; Mishra, A.; Dua, K. Calcitonin gene-related peptide (CGRP): A novel target for Alzheimer’s disease. CNS Neurosci. Ther., 2017, 23(6), 457-461.
[] [PMID: 28417590]
Qin, Q.; Teng, Z.; Liu, C.; Li, Q.; Yin, Y.; Tang, Y. TREM2, microglia, and Alzheimer’s disease. Mech. Ageing Dev., 2021, 195, 111438.
[] [PMID: 33516818]
Scheltens, P.; De Strooper, B.; Kivipelto, M.; Holstege, H.; Chételat, G.; Teunissen, C.E.; Cummings, J.; van der Flier, W.M. Alzheimer’s disease. Lancet, 2021, 397(10284), 1577-1590.
[] [PMID: 33667416]
Selkoe, D.J. Treatments for Alzheimer’s disease emerge. Science, 2021, 373(6555), 624-626.
[] [PMID: 34353940]
Srivastava, S.; Ahmad, R.; Khare, S.K. Alzheimer’s disease and its treatment by different approaches: A review. Eur. J. Med. Chem., 2021, 216, 113320.
[] [PMID: 33652356]
Thummayot, S.; Tocharus, C.; Suksamrarn, A.; Tocharus, J. Neuroprotective effects of cyanidin against Aβ-induced oxidative and ER stress in SK-N-SH cells. Neurochem. Int., 2016, 101, 15-21.
[] [PMID: 27697517]
Song, N.; Zhang, L.; Chen, W.; Zhu, H.; Deng, W.; Han, Y.; Guo, J.; Qin, C. Cyanidin 3-O-β-glucopyranoside activates peroxisome proliferator-activated receptor-γ and alleviates cognitive impairment in the APP swe /PS1 ΔE9 mouse model. Biochim. Biophys. Acta Mol. Basis Dis., 2016, 1862(9), 1786-1800.
[] [PMID: 27240542]
Heysieattalab, S.; Sadeghi, L. Effects of delphinidin on pathophysiological signs of nucleus basalis of meynert lesioned rats as animal model of Alzheimer disease. Neurochem. Res., 2020, 45(7), 1636-1646.
[] [PMID: 32297026]
Hung, T.C.; Chang, T.T.; Fan, M.J.; Lee, C.C.; Chen, Y.C. In silico insight into potent of anthocyanin regulation of FKBP52 to prevent Alzheimer's disease. Evid.-based Complement. Altern. Med., 2014, 2014, 450592.
Sohanaki, H.; Baluchnejadmojarad, T.; Nikbakht, F.; Roghani, M. Pelargonidin improves memory deficit in amyloid β25-35 rat model of Alzheimer’s disease by inhibition of glial activation, cholinesterase, and oxidative stress. Biomed. Pharmacother., 2016, 83, 85-91.
Wei, J.; Yang, F.; Gong, C.; Shi, X.; Wang, G. Protective effect of daidzein against streptozotocin induced Alzheimer’s disease via improving cognitive dysfunction and oxidative stress in rat model. J. Biochem. Mol. Toxicol., 2019, 33(6), e22319.
[] [PMID: 30897277]
Ahuja, A.; Tyagi, P.K.; Tyagi, S.; Kumar, A.; Kumar, M.; Sharifi-Rad, J. Potential of Pueraria tuberosa (Willd.) DC. to rescue cognitive decline associated with BACE1 protein of Alzheimer’s disease on Drosophila model: An integrated molecular modeling and in vivo approach. Int. J. Biol. Macromol., 2021, 179, 586-600.
[] [PMID: 33705837]
Ma, W.; Yuan, L.; Yu, H.; Ding, B.; Xi, Y.; Feng, J.; Xiao, R. Genistein as a neuroprotective antioxidant attenuates redox imbalance induced by β-amyloid peptides 25–35 in PC12 cells. Int. J. Dev. Neurosci., 2010, 28(4), 289-295.
[] [PMID: 20362658]
Bagheri, M.; Roghani, M.; Joghataei, M.T.; Mohseni, S. Genistein inhibits aggregation of exogenous amyloid-beta1–40 and alleviates astrogliosis in the hippocampus of rats. Brain Res., 2012, 1429, 145-154.
[] [PMID: 22079317]
Tsai, M.C.; Lin, S.H.; Hidayah, K.; Lin, C.I. Equol pretreatment protection of SH-SY5Y cells against Aβ (25–35)-induced cytotoxicity and cell-cycle reentry via sustaining estrogen receptor alpha expression. Nutrients, 2019, 11(10), 2356.
[] [PMID: 31623342]
Beg, T.; Jyoti, S.; Naz, F.; Rahul; Ali, F.; Ali, S.K.; Reyad, A.M.; Siddique, Y.H. Protective effect of kaempferol on the transgenic drosophila model of Alzheimer’s disease. CNS Neurol. Disord. Drug Targets, 2018, 17(6), 421-429.
[] [PMID: 29745345]
Carmona, V.; Martín-Aragón, S.; Goldberg, J.; Schubert, D.; Bermejo-Bescós, P. Several targets involved in Alzheimer’s disease amyloidogenesis are affected by morin and isoquercitrin. Nutr. Neurosci., 2020, 23(8), 575-590.
[] [PMID: 30326823]
Zeng, H.; Huang, P.; Wang, X.; Wu, J.; Wu, M.; Huang, J. Galangin-induced down-regulation of BACE1 by epigenetic mechanisms in SH-SY5Y cells. Neuroscience, 2015, 294, 172-181.
[] [PMID: 25779965]
Currais, A.; Farrokhi, C.; Dargusch, R.; Armando, A.; Quehenberger, O.; Schubert, D.; Maher, P. Fisetin reduces the impact of aging on behavior and physiology in the rapidly aging SAMP8 mouse. J. Gerontol. A Biol. Sci. Med. Sci., 2018, 73(3), 299-307.
[] [PMID: 28575152]
Pan, R.Y.; Ma, J.; Kong, X.X.; Wang, X.F.; Li, S.S.; Qi, X.L.; Yan, Y.H.; Cheng, J.; Liu, Q.; Jin, W.; Tan, C.H.; Yuan, Z. Sodium rutin ameliorates Alzheimer’s disease–like pathology by enhancing microglial amyloid-β clearance. Sci. Adv., 2019, 5(2), eaau6328.
[] [PMID: 30820451]
Zaplatic, E.; Bule, M.; Shah, S.Z.A.; Uddin, M.S.; Niaz, K. Molecular mechanisms underlying protective role of quercetin in attenuating Alzheimer’s disease. Life Sci., 2019, 224, 109-119.
[] [PMID: 30914316]
Saito, S.; Yamamoto, Y.; Maki, T.; Hattori, Y.; Ito, H.; Mizuno, K.; Harada-Shiba, M.; Kalaria, R.N.; Fukushima, M.; Takahashi, R.; Ihara, M. Taxifolin inhibits amyloid-β oligomer formation and fully restores vascular integrity and memory in cerebral amyloid angiopathy. Acta Neuropathol. Commun., 2017, 5(1), 26.
[] [PMID: 28376923]
Zhang, S.Q.; Obregon, D.; Ehrhart, J.; Deng, J.; Tian, J.; Hou, H.; Giunta, B.; Sawmiller, D.; Tan, J. Baicalein reduces β amyloid and promotes nonamyloidogenic amyloid precursor protein processing in an Alzheimer’s disease transgenic mouse model. J. Neurosci. Res., 2013, 91(9), 1239-1246.
[] [PMID: 23686791]
Zhao, L.; Wang, J.; Wang, Y.; Fa, X. Apigenin attenuates copper-mediated β-amyloid neurotoxicity through antioxidation, mitochondrion protection and MAPK signal inactivation in an AD cell model. Brain Res., 2013, 1492, 33-45.
[] [PMID: 23178511]
Cheng, H.Y.; Hsieh, M.T.; Tsai, F.S.; Wu, C.R.; Chiu, C.S.; Lee, M.M.; Xu, H.X.; Zhao, Z.Z.; Peng, W.H. Neuroprotective effect of luteolin on amyloid β protein (25-35)-induced toxicity in cultured rat cortical neurons. Phytother. Res., 2010, 24(S1), S102-S108.
[] [PMID: 19610032]
Kimura, J.; Shimizu, K.; Kajima, K.; Yokosuka, A.; Mimaki, Y.; Oku, N.; Ohizumi, Y. Nobiletin reduces intracellular and extracellular β-amyloid in ips cell-derived Alzheimer’s disease model neurons. Biol. Pharm. Bull., 2018, 41(4), 451-457.
[] [PMID: 29607920]
Merlo, S.; Basile, L.; Giuffrida, M.L.; Sortino, M.A.; Guccione, S.; Copani, A. Identification of 5-methoxyflavone as a novel DNA polymerase-beta inhibitor and neuroprotective agent against beta-amyloid toxicity. J. Nat. Prod., 2015, 78(11), 2704-2711.
[] [PMID: 26517378]
Ikram, M.; Muhammad, T.; Rehman, S.U.; Khan, A.; Jo, M.G.; Ali, T.; Kim, M.O. Hesperetin confers neuroprotection by regulating Nrf2/TLR4/NF-κB signaling in an Aβ mouse model. Mol. Neurobiol., 2019, 56(9), 6293-6309.
[] [PMID: 30756299]
Jing, X.; Shi, H.; Zhu, X.; Wei, X.; Ren, M.; Han, M.; Ren, D.; Lou, H. Eriodictyol attenuates β-amyloid 25–35 peptide-induced oxidative cell death in primary cultured neurons by activation of Nrf2. Neurochem. Res., 2015, 40(7), 1463-1471.
[] [PMID: 25994859]
Md, S.; Gan, S.Y.; Haw, Y.H.; Ho, C.L.; Wong, S.; Choudhury, H. In vitro neuroprotective effects of naringenin nanoemulsion against β-amyloid toxicity through the regulation of amyloidogenesis and tau phosphorylation. Int. J. Biol. Macromol., 2018, 118(Pt A), 1211-1219.
[] [PMID: 30001606]
Justin Thenmozhi, A.; William Raja, T.R.; Manivasagam, T.; Janakiraman, U.; Essa, M.M. Hesperidin ameliorates cognitive dysfunction, oxidative stress and apoptosis against aluminium chloride induced rat model of Alzheimer’s disease. Nutr. Neurosci., 2017, 20(6), 360-368.
[] [PMID: 26878879]
Jahanshahi, M.; Khalili, M.; Margedari, A. Naringin chelates excessive iron and prevents the formation of amyloid-beta plaques in the hippocampus of iron-overloaded mice. Front. Pharmacol., 2021, 12, 651156-651156.
[] [PMID: 34276359]
Cao, Y.; Xu, W.; Huang, Y.; Zeng, X. Licochalcone B, a chalcone derivative from Glycyrrhiza inflata, as a multifunctional agent for the treatment of Alzheimer’s disease. Nat. Prod. Res., 2020, 34(5), 736-739.
[] [PMID: 30345819]
Ghumatkar, P.; Peshattiwar, V.; Patil, S.; Muke, S.; Whitfield, D.; Howlett, D.; Francis, P.; Sathaye, S. The effect of phloretin on synaptic proteins and adult hippocampal neurogenesis in Aβ (1-42)-injected male Wistar rats. J. Pharm. Pharmacol., 2018, 70(8), 1022-1030.
[] [PMID: 29682750]
Ghumatkar, P.J.; Patil, S.P.; Jain, P.D.; Tambe, R.M.; Sathaye, S. Nootropic, neuroprotective and neurotrophic effects of phloretin in scopolamine induced amnesia in mice. Pharmacol. Biochem. Behav., 2015, 135, 182-191.
[] [PMID: 26071678]
Gleason, C.E.; Fischer, B.L.; Dowling, N.M.; Setchell, K.D.R.; Atwood, C.S.; Carlsson, C.M.; Asthana, S. Cognitive effects of soy isoflavones in patients with Alzheimer’s disease. J. Alzheimers Dis., 2015, 47(4), 1009-1019.
[] [PMID: 26401779]
Mastroiacovo, D.; Kwik-Uribe, C.; Grassi, D.; Necozione, S.; Raffaele, A.; Pistacchio, L.; Righetti, R.; Bocale, R.; Lechiara, M.C.; Marini, C.; Ferri, C.; Desideri, G. Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: The cocoa, cognition, and aging (cocoa) study—a randomized controlled trial. Am. J. Clin. Nutr., 2015, 101(3), 538-548.
[] [PMID: 25733639]
Wilkins, H.M.; Mahnken, J.D.; Welch, P.; Bothwell, R.; Koppel, S.; Jackson, R.L.; Burns, J.M.; Swerdlow, R.H. A mitochondrial biomarker-based study of s-equol in Alzheimer’s disease subjects: Results of a single-arm, pilot trial. J. Alzheimers Dis., 2017, 59(1), 291-300.
[] [PMID: 28598847]
Sekikawa, A.; Higashiyama, A.; Lopresti, B.J.; Ihara, M.; Aizenstein, H.; Watanabe, M.; Chang, Y.; Kakuta, C.; Yu, Z.; Mathis, C.; Kokubo, Y.; Klunk, W.; Lopez, O.L.; Kuller, L.H.; Miyamoto, Y.; Cui, C. Associations of equol producing status with white matter lesion and amyloid β deposition in cognitively normal elderly Japanese. Alzheimers Dement., 2020, 6(1), e12089.
[] [PMID: 33117881]

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