Abstract
Developing therapies for neurodegenerative diseases are challenging because of the presence of blood–brain barrier and Alzheimer being one of the commonest and uprising neurodegenerative disorders possess the need for developing novel therapies. Alzheimer’s is attributed to be the sixth leading cause of death in the USA and the number of cases is estimated to be increased from 58 million in 2021 to 88 million by 2050. Natural drugs have benefits of being cost-effective, widely available, fewer side effects, and immuno-booster can be useful in managing Alzheimer. Flavonoids can slow the neuronal degeneration as they have shown activity in central nervous system and are able to cross the blood–brain barrier. These can be easily extracted from fruits, vegetable, and plants. In Alzheimer disease, flavonoids scavenges the reactive oxygen species and reduces the production of amyloid beta protein. Agents from sub-classes of flavonoids such as flavanones, flavanols, flavones, flavonols, anthocyanins, and isoflavones having pharmacological action in treating Alzheimer disease are discussed in this review.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Not applicable.
References
Acharya A, Stockmann J, Beyer L et al (2020) The effect of (-)-epigallocatechin-3-gallate on the amyloid-β secondary structure. Biophys J 119(2):349–359. https://doi.org/10.1016/j.bpj.2020.05.033
Acquaviva R, Russo A, Galvano F et al (2003) Cyanidin and cyanidin 3-O-beta-D-glucoside as DNA cleavage protectors and antioxidants. Cell BiolToxicol 19:243–252. https://doi.org/10.1023/b:cbto.0000003974.27349.4e
Agarwal P, Holland T, Wang Y et al (2020) Pelargonidin in strawberries may reduce alzheimer’s disease neuropathology: a community-based study. Curr Dev Nutr 4(Supplement_2):1186–1186. https://doi.org/10.1093/cdn/nzaa057_002
Ahmed ME, Khan MM, Javed H et al (2013) Amelioration of cognitive impairment and neurodegeneration by catechin hydrate in rat model of streptozotocin-induced experimental dementia of Alzheimer’s type. Neurochem Int 62(4):492–501. https://doi.org/10.1016/j.neuint.2013.02.006
Ahmed MM, Zaki NI (2009) Assessment the ameliorative effect of pomegranate and rutin on chlorpyrifos-ethyl-induced oxidative stress in rats. Nature and Science 7(10):49–61
Ahmed S, Khan H, Aschner M, et al (2019) Therapeutic potential of naringin in neurological disorders.Food Chem Toxicol 132:110646. https://doi.org/10.1016/j.fct.2019.110646
Airoldi C, La Ferla B, D’Orazio G et al (2018) Flavonoids in the treatment of Alzheimer’s and other neurodegenerative diseases. Curr Med Chem 25(27):3228–3246. https://doi.org/10.2174/0929867325666180209132125
Al-Dhabi NA, Arasu MV, Park CH et al (2015) An up-to-date review of rutin and its biological and pharmacological activities. EXCLI J 14:59–63. https://doi.org/10.17179/excli2014-663
Al-Enazi MM (2014) Protective effects of combined therapy of rutin with silymarin on experimentally-induced diabetic neuropathy in rats. Pharmacol Pharmacy 7:2014. https://doi.org/10.4236/pp.2014.59098
Alok S, Jain SK, Verma A et al (2014) Herbal antioxidant in clinical practice: a review. Asian Pac J Trop Biomed 4(1):78–84. https://doi.org/10.1016/S2221-1691(14)60213-6
Ansari MA, Abdul HM, Joshi G et al (2009) Protective effect of quercetin in primary neurons against Abeta(1–42): relevance to Alzheimer’s disease. J Nutr Biochem 20(4):269–275. https://doi.org/10.1016/j.jnutbio.2008.03.002
August PM, dos Santos BG Oxidative stress and dietary antioxidants in neurological diseases. Academic Press:Cambridge, Massachusetts, US, 2020; Chapter 20, pp.309–323, ISBN 978–0–12–817780–8
Ayaz M, Sadiq A, Junaid M et al (2019) Flavonoids as prospective neuroprotectants and their therapeutic propensity in aging associated neurological disorders. Front Aging Neurosci 11:155. https://doi.org/10.3389/fnagi.2019.00155
Bagheri M, Joghataei MT, Mohseni S et al (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. https://doi.org/10.1016/j.nlm.2010.12.001
Bagheri M, Rezakhani A, Nyström S et al (2013) Amyloid beta(1–40)-induced astrogliosis and the effect of genistein treatment in rat: a three-dimensional confocal morphometric and proteomic study. PLoS ONE 8(10):e76526. https://doi.org/10.1371/journal.pone.0076526
Bakhtiari M, Panahi Y, Ameli J et al (2017) Protective effects of flavonoids against Alzheimer’s disease-related neural dysfunctions. Biomed Pharmacother 93:218–229. https://doi.org/10.1016/j.biopha.2017.06.010
Balouchnejadmojarad T (2009) The effect of genistein on intracerebroventricular streptozotocin-induced cognitive deficits in male rat. Basic Clin Neurosci 1(1):17–21
Banerjee T, Van der Vliet A, Ziboh VA (2002) Downregulation of COX-2 and iNOS by amentoflavone and quercetin in A549 human lung adenocarcinoma cell line. Prostaglandins Leukot Essent Fatty Acids 66(5–6):485–492. https://doi.org/10.1054/plef.2002.0387
Bang OY, Hong HS, Kim DH et al (2004) Neuroprotective effect of genistein against beta amyloid-induced neurotoxicity. Neurobiol Dis 16(1):21–28. https://doi.org/10.1016/j.nbd.2003.12.017
Bhuiyan MI, Kim HB, Kim SY et al (2011) The neuroprotective potential of cyanidin-3-glucoside fraction extracted from mulberry following oxygen-glucose deprivation. Korean J Physiol Pharmacol: Official J Korean Physiol Soc Korean Soc Pharmacol 15(6):353–361. https://doi.org/10.4196/kjpp.2011.15.6.353
Bispo da Silva A, Cerqueira Coelho PL, Alves Oliveira Amparo J et al (2017) The flavonoid rutin modulates microglial/macrophage activation to a CD150/CD206 M2 phenotype. Chem Biol Interact 274:89–99. https://doi.org/10.1016/j.cbi.2017.07.004
Cano A, Ettcheto M, Chang JH et al (2019) Dual-drug loaded nanoparticles of epigallocatechin-3-gallate (EGCG)/ascorbic acid enhance therapeutic efficacy of EGCG in a APPswe/PS1dE9 Alzheimer’s disease mice model. J Control Release 301:62–75. https://doi.org/10.1016/j.jconrel.2019.03.010
Carrasco-Pozo C, Mizgier ML, Speisky H et al (2012) Differential protective effects of quercetin, resveratrol, rutin and epigallocatechin gallate against mitochondrial dysfunction induced by indomethacin in Caco-2 cells. Chemico-Biol Interact 195(3):199–205. https://doi.org/10.1016/j.cbi.2011.12.007
Chen G, Bower KA, Xu M et al (2009) Cyanidin-3-glucoside reverses ethanol-induced inhibition of neurite outgrowth: role of glycogen synthase kinase 3 Beta. Neurotoxic Res 15(4):321–331. https://doi.org/10.1007/s12640-009-9036-y
Chen J, Deng X, Liu N et al (2016) Quercetin attenuates tau hyperphosphorylation and improves cognitive disorder via suppression of ER stress in a manner dependent on AMPK pathway. J Funct Foods 22:463–476. https://doi.org/10.1016/j.jff.2016.01.036
Chen T, Yang Y, Zhu S et al (2020) Inhibition of Aβ aggregates in Alzheimer’s disease by epigallocatechin and epicatechin-3-gallate from green tea. Bioorg Chem 105:104382. https://doi.org/10.1016/j.bioorg.2020.104382
Cho RC, ZhuJT YAW et al (2013) Synergistic action of flavonoids, baicalein, and daidzein in estrogenic and neuroprotective effects: a development of potential health products and therapeutic drugs against Alzheimer’s disease. Evid Based Complement Alternat Med 2013:635694. https://doi.org/10.1155/2013/635694
Choi JS, Islam MN, Ali MY et al (2014) Effects of C-glycosylation on anti-diabetic, anti-Alzheimer’s disease and anti-inflammatory potential of apigenin. Food Chem Toxicol 64:27–33. https://doi.org/10.1016/j.fct.2013.11.020
Choi JY, Lee JM, Lee DG et al (2015) The n-butanol fraction and rutin from tartary buckwheat improve cognition and memory in an in vivo model of amyloid-β-induced alzheimer’s disease. J Med Food 18(6):631–641. https://doi.org/10.1089/jmf.2014.3292
Correia SC, Santos RX, Santos MS et al (2013) Mitochondrial abnormalities in a streptozotocin-induced rat model of sporadic Alzheimer’s disease. Curr Alzheimer Res 10(4):406–419. https://doi.org/10.2174/1567205011310040006
Cox CJ, Choudhry F, Peacey E et al (2015) Dietary (-)-epicatechin as a potent inhibitor of βγ-secretase amyloid precursor protein processing. Neurobiol Aging 36(1):178–187. https://doi.org/10.1016/j.neurobiolaging.2014.07.032
Cruz T, Gálvez J, Ocete MA et al (1998) Oral administration of rutoside can ameliorate inflammatory bowel disease in rats. Life Sci 62(7):687–695. https://doi.org/10.1016/s0024-3205(97)01164-8
D’Andrea G (2015) Quercetin: A flavonol with multifaceted therapeutic applications? Fitoterapia 106:256–271. https://doi.org/10.1016/j.fitote.2015.09.018
Dang ZC, Audinot V, Papapoulos SE et al (2003) Peroxisome proliferator-activated receptor gamma (PPARgamma ) as a molecular target for the soy phytoestrogen genistein. J Biol Chem 278(2):962–967. https://doi.org/10.1074/jbc.M209483200
David AV, Arulmoli R, Parasuraman S (2016) Overviews of biological importance of quercetin: a bioactive flavonoid. Pharmacogn Rev 10(20):84. https://doi.org/10.4103/0973-7847.194044
de Andrade Teles RB, Diniz TC, Costa Pinto TC, et al (2018) Flavonoids as therapeutic agents in Alzheimer’s and Parkinson’s diseases: a systematic review of preclinical evidences. Oxid Med Cell 7043213. https://doi.org/10.1155/2018/7043213
Desai AK, Grossberg GT (2005) Diagnosis and treatment of Alzheimer’s disease. Neurology 64(12 Suppl 3):S34–S39. https://doi.org/10.1212/wnl.64.12_suppl_3.s34
Despa F, Decarli C (2013) Amylin: what might be its role in Alzheimer’s disease and how could this affect therapy? Expert Rev Proteomics 10(5):403–405. https://doi.org/10.1586/14789450.2013.841549
Dey A, Bhattacharya R, Mukherjee A et al (2017) Natural products against Alzheimer’s disease: pharmaco-therapeutics and biotechnological interventions. Biotechnol Adv 35(2):178–216. https://doi.org/10.1016/j.biotechadv.2016.12.005
El-Horany HE, El-Latif RN, ElBatsh MM et al (2016) Ameliorative effect of quercetin on neurochemical and behavioral deficits in rotenone rat model of Parkinson’s disease: modulating autophagy (quercetin on experimental Parkinson’s disease). J Biochem Mol Toxicol 30(7):360–369. https://doi.org/10.1002/jbt.21821
Frandsen J, Narayanasamy P (2017) Flavonoid enhances the glyoxalase pathway in cerebellar neurons to retain cellular functions. Sci Rep 7(1):5126. https://doi.org/10.1038/s41598-017-05287-z
Frandsen JR, Narayanasamy P (2018) Neuroprotection through flavonoid: enhancement of the glyoxalase pathway. Redox Biol 14:465–473. https://doi.org/10.1016/j.redox.2017.10.015
Fukutake M, Takahashi M, Ishida K et al (1996) Quantification of genistein and genistin in soybeans and soybean products. Food Chem Toxicol : Int J Pub Brit Indust Biol Res Assoc 34(5):457–461. https://doi.org/10.1016/0278-6915(96)87355-8
Ganeshpurkar A, Saluja AK (2017) The pharmacological potential of rutin. Saudi Pharmaceut J : SPJ : Official Pub Saudi Pharmaceut Soc 25(2):149–164. https://doi.org/10.1016/j.jsps.2016.04.025
George J, Banik NL, Ray SK (2010) Genistein induces receptor and mitochondrial pathways and increases apoptosis during BCL-2 knockdown in human malignant neuroblastoma SK-N-DZ cells. J Neurosci Res 88(4):877–886. https://doi.org/10.1002/jnr.22244
Gliszczyńska-Swigło A, van der Woude H, de Haan L et al (2003) The role of quinone reductase (NQO1) and quinone chemistry in quercetin cytotoxicity. Toxicol Vitro : Int J Pub Assoc BIBRA 17(4):423–431. https://doi.org/10.1016/s0887-2333(03)00047-x
Gong EJ, Park HR, Kim ME et al (2011) Morin attenuates tau hyperphosphorylation by inhibiting GSK3β. Neurobiol Dis 44(2):223–230. https://doi.org/10.1016/j.nbd.2011.07.005
Grassi D, Ferri C, Desideri G (2016) Brain protection and cognitive function: cocoa flavonoids as nutraceuticals. Curr Pharm Des 22(2):145–151. https://doi.org/10.2174/1381612822666151112145730
Gupta A, Birhman K, Raheja I et al (2016) Quercetin: a wonder bioflavonoid with therapeutic potential in disease management. Asian Pacific J Trop Dis 6:248–252. https://doi.org/10.1016/S2222-1808(15)61024-6
Harborne JB (1986) Nature, distribution and function of plant flavonoids. Prog Clin Biol Res 213:15–24
Harrington CR (2012) The molecular pathology of Alzheimer’s disease. Neuroimaging Clin N Am 22(1):11–vii. https://doi.org/10.1016/j.nic.2011.11.003
He P, Yan S, Zheng J et al (2018) Eriodictyol attenuates LPS-induced neuroinflammation, amyloidogenesis, and cognitive impairments via the inhibition of NF-κB in male C57BL/6J mice and BV2 microglial cells. J Agric Food Chem 66(39):10205–10214. https://doi.org/10.1021/acs.jafc.8b03731
Hogervorst E, Sadjimim T, Yesufu A et al (2008) High tofu intake is associated with worse memory in elderly Indonesian men and women. Dement Geriatr Cogn Disord 26(1):50–57. https://doi.org/10.1159/000141484
Hole KL, Williams RJ (2021) Flavonoids as an Intervention for Alzheimer’s disease: progress and hurdles towards defining a mechanism of action. Brain Plasticity (Amsterdam, Netherlands) 6(2):167–192. https://doi.org/10.3233/BPL-200098
Huang DS, Yu YC, Wu CH et al (2017) Protective effects of wogonin against Alzheimer’s disease by inhibition of amyloidogenic pathway. Evidence-Based Complement Alternat Med : Ecam 2017:3545169. https://doi.org/10.1155/2017/3545169
Hui C, Bin Y, Xiaoping Y et al (2010) Anticancer activities of an anthocyanin-rich extract from black rice against breast cancer cells in vitro and in vivo. Nutr Cancer 62(8):1128–1136. https://doi.org/10.1080/01635581.2010.494821
Hussain G, Zhang L, Rasul A et al (2018) Role of plant-derived flavonoids and their mechanism in attenuation of Alzheimer’s and Parkinson’s diseases: an update of recent data. Molecules 23(4):814. https://doi.org/10.3390/molecules23040814
Ide K, Matsuoka N, Yamada H et al (2018) Effects of tea catechins on alzheimer’s disease: recent updates and perspectives. Molecules (Basel, Switzerland) 23(9):2357. https://doi.org/10.3390/molecules23092357
Jacome LF, Gautreaux C, Inagaki T et al (2010) Estradiol and ERβ agonists enhance recognition memory, and DPN, an ERβ agonist, alters brain monoamines. Neurobiol Learn Mem 94:488–498. https://doi.org/10.1016/j.nlm.2010.08.016
Javed H, Khan MM, Ahmad A et al (2012) Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. Neuroscience 210:340–352. https://doi.org/10.1016/j.neuroscience.2012.02.046
Ji Y, Han J, Lee N et al (2020) Neuroprotective effects of baicalein, wogonin, and oroxylin A on amyloid beta-induced toxicity via NF-κB/MAPK pathway modulation. Molecules 25(21):5087. https://doi.org/10.3390/molecules25215087
Jing X, Shi H, Zhu X et al (2015) Eriodictyol Attenuates β-amyloid 25–35 peptide-induced oxidative cell death in primary cultured neurons by activation of Nrf2. Neurochem Res 40(7):1463–1471. https://doi.org/10.1007/s11064-015-1616-z
Kandemir FM, Ozkaraca M, Yildirim BA et al (2015) Rutin attenuates gentamicin-induced renal damage by reducing oxidative stress, inflammation, apoptosis, and autophagy in rats. Ren Fail 37(3):518–525. https://doi.org/10.3109/0886022X.2015.1006100
Kang TH, Hur JY, Kim HB et al (2006) Neuroprotective effects of the cyanidin-3-O-beta-d-glucopyranoside isolated from mulberry fruit against cerebral ischemia. Neurosci Lett 391(3):122–126. https://doi.org/10.1016/j.neulet.2005.08.053
Kelsey N, Hulick W, Winter A et al (2011) Neuroprotective effects of anthocyanins on apoptosis induced by mitochondrial oxidative stress. NutrNeurosci 14:249–259. https://doi.org/10.1179/1476830511Y.0000000020
Khan MM, Raza SS, Javed H et al (2012) Rutin protects dopaminergic neurons from oxidative stress in an animal model of Parkinson’s disease. Neurotoxic Res 22(1):1–15. https://doi.org/10.1007/s12640-011-9295-2
Kim H, Peterson TG, Barnes S (1998) Mechanisms of action of the soy isoflavone genistein: emerging role for its effects via transforming growth factor beta signaling pathways. Am J Clin Nutr 68(6 Suppl):1418S-S1425. https://doi.org/10.1093/ajcn/68.6.1418S
King AE, Southam KA, Dittmann J et al (2013) Excitotoxin-induced caspase-3 activation and microtubule disintegration in axons is inhibited by taxol. Acta Neuropathol Commun 1:59. https://doi.org/10.1186/2051-5960-1-59
Kostić DA, Dimitrijević DS, Stojanović GS, et al (2015) Xanthine oxidase: isolation, assays of activity, and inhibition. J Chem 2015. https://doi.org/10.1155/2015/294858
Kreijkamp-Kaspers S, Kok L, Grobbee DE et al (2004) Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA 292(1):65–74. https://doi.org/10.1001/jama.292.1.65
Kumar A, Nisha CM, Silakari C et al (2016a) Current and novel therapeutic molecules and targets in Alzheimer’s disease. J Formos Med Assoc 115(1):3–10. https://doi.org/10.1016/j.jfma.2015.04.001
Kumar A, Prakash A, Dogra S (2010) Naringin alleviates cognitive impairment, mitochondrial dysfunction and oxidative stress induced by D-galactose in mice. Food Chem Toxicol 48:626–632. https://doi.org/10.1016/j.fct.2009.11.043
Kumar S, Sharma H, Yadav K (2016b) Quercetin and Metabolic Syndrome. EJPMR 3:701–709
Kuppusamy A, Arumugam M, George S (2017) Combining in silico and in vitro approaches to evaluate the acetylcholinesterase inhibitory profile of some commercially available flavonoids in the management of Alzheimer’s disease. Int J Biol Macromol 95:199–203. https://doi.org/10.1016/j.ijbiomac.2016.11.062
Kwon Y (2017) Luteolin as a potential preventive and therapeutic candidate for Alzheimer’s disease. Exp Gerontol 95:39–43. https://doi.org/10.1016/j.exger.2017.05.014
Lesjak M, Beara I, Simin N et al (2018) Antioxidant and anti-inflammatory activities of quercetin and its derivatives. J Funct Foods 40:68–75. https://doi.org/10.1016/j.jff.2017.10.047
Li Y, Yao J, Han C et al (2016) Quercetin, inflammation and immunity. Nutrients 8(3):167. https://doi.org/10.3390/nu8030167
Lim HJ, Shim SB, Jee SW et al (2013) Green tea catechin leads to global improvement among Alzheimer’s disease-related phenotypes in NSE/hAPP-C105 Tg mice. J Nutr Biochem 24(7):1302–1313. https://doi.org/10.1016/j.jnutbio.2012.10.005
Liu YW, Cheng YQ, Liu XL et al (2017) Mangiferin upregulates glyoxalase 1 through activation of Nrf2/ARE signaling in central neurons cultured with high glucose. Mol Neurobiol 54(6):4060–4070. https://doi.org/10.1007/s12035-016-9978-z\
Mangialasche F, Solomon A, Winblad B et al (2010) Alzheimer’s disease: clinical trials and drug development. The Lancet Neurol 9(7):702–716. https://doi.org/10.1016/S1474-4422(10)70119-8
Masilamani M, Wei J, Sampson HA (2012) Regulation of the immune response by soybean isoflavones. Immunol Res 54:95–110. https://doi.org/10.1007/s12026-012-8331-5
Masuda M, Suzuki N, Taniguchi S et al (2006) Small molecule inhibitors of alpha-synuclein filament assembly. Biochemistry 45(19):6085–6094. https://doi.org/10.1021/bi0600749
McGeer PL, Kawamata T, Walker DG et al (1993) Microglia in degenerative neurological disease. Glia 7(1):84–92. https://doi.org/10.1002/glia.440070114
Moghaddam AH, Zare M (2018) Neuroprotective effect of hesperetin and nano-hesperetin on recognition memory impairment and the elevated oxygen stress in rat model of Alzheimer’s disease. Biomed Pharmacother 97:1096–1101. https://doi.org/10.1016/j.biopha.2017.11.047
Morelli S, Piscioneri A, Curcio E, et al (2019) Membrane bioreactor for investigation of neurodegeneration. Mat Sci Eng C, Mat Biol Appl 103:109793. https://doi.org/10.1016/j.msec.2019.109793
Moreno L, Puerta E, Suárez-Santiago JE et al (2017) Effect of the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer’s disease. Int J Pharm 517(1–2):50–57. https://doi.org/10.1016/j.ijpharm.2016.11.061
Mori T, Koyama N, Tan J et al (2019) Combined treatment with the phenolics (-)-epigallocatechin-3-gallate and ferulic acid improves cognition and reduces Alzheimer-like pathology in mice. J Biol Chem 294(8):2714–2731. https://doi.org/10.1074/jbc.RA118.004280
Nabavi SF, Braidy N, Gortzi O et al (2015) Luteolin as an anti-inflammatory and neuroprotective agent: a brief review. Brain Res Bull 119:1–11. https://doi.org/10.1016/j.brainresbull.2015.09.002
Nabavi SF, Khan H, D’onofrio G et al (2018) Apigenin as neuroprotective agent: of mice and men. Pharmacol Res 128:359–365. https://doi.org/10.1016/j.phrs.2017.10.008
O’Brien RJ, Wong PC (2011) Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci 34:185–204. https://doi.org/10.1146/annurev-neuro-061010-113613
Pan M, Han H, Zhong C et al (2012) Effects of genistein and daidzein on hippocampus neuronal cell proliferation and BDNF expression in H19–7 neural cell line. J Nutr Health Aging 16(4):389–394. https://doi.org/10.1007/s12603-011-0140-3
Perk AA, Shatynska-Mytsyk I, Gerçek YC, Boztaş K, Yazgan M, Fayyaz S, Farooqi AA (2014) Rutin mediated targeting of signaling machinery in cancer cells. Cancer Cell Int 14(1):124. https://doi.org/10.1186/s12935-014-0124-6
Pyrzanowska J, Piechal A, Blecharz-Klin K et al (2012) Influence of long-term administration of rutin on spatial memory as well as the concentration of brain neurotransmitters in aged rats. Pharmacol Rep : PR 64(4):808–816. https://doi.org/10.1016/s1734-1140(12)70876-9
Ramalingayya GV, Nampoothiri M, Nayak PG et al (2016) Naringin and rutin alleviates episodic memory deficits in two differentially challenged object recognition tasks. Pharmacogn Mag 12(Suppl1):S63–S70. https://doi.org/10.4103/0973-1296.176104
RD, Tan J (2008) Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice. Brain Res 1214:177–187. https://doi.org/10.1016/j.brainres.2008.02.107
Richetti SK, Blank M, Capiotti KM et al (2011) Quercetin and rutin prevent scopolamine-induced memory impairment in zebrafish. Behav Brain Res 217(1):10–15. https://doi.org/10.1016/j.bbr.2010.09.027
Rishitha N, Muthuraman A (2018) Therapeutic evaluation of solid lipid nanoparticle of quercetin in pentylenetetrazole induced cognitive impairment of zebrafish. Life Sci 199:80–87. https://doi.org/10.1016/j.lfs.2018.03.010
Roghani M, Niknam A, Jalali-Nadoushan MR et al (2010) Oral pelargonidin exerts dose-dependent neuroprotection in 6-hydroxydopamine rat model of hemi-parkinsonism. Brain Res Bull 82(5–6):279–283. https://doi.org/10.1016/j.brainresbull.2010.06.004
Roohbakhsh A, Parhiz H, Soltani F et al (2014) Neuropharmacological properties and pharmacokinetics of the citrus flavonoids hesperidin and hesperetin—a mini-review. Life Sci 113(1–2):1–6. https://doi.org/10.1016/j.lfs.2014.07.029
Roy M, Sen S, Chakraborti AS (2008) Action of pelargonidin on hyperglycemia and oxidative damage in diabetic rats: implication for glycation-induced hemoglobin modification. Life Sci 82(21–22):1102–1110. https://doi.org/10.1016/j.lfs.2008.03.011
Sabogal-Guáqueta AM, Muñoz-Manco JI, Ramírez-Pineda JR et al (2015) The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice. Neuropharmacology 93:134–145. https://doi.org/10.1016/j.neuropharm.2015.01.027
Sang Z, Wang K, Shi J et al (2020) Apigenin-rivastigmine hybrids as multi-target-directed liagnds for the treatment of Alzheimer’s disease. Eur J Med Chem 187:111958. https://doi.org/10.1016/j.ejmech.2019.111958
Sastre M, Klockgether T, Heneka MT (2006) Contribution of inflammatory processes to Alzheimer’s disease: molecular mechanisms. Int J Dev Neurosci: Official J Int Soc Dev Neurosci 24(2–3):167–176. https://doi.org/10.1016/j.ijdevneu.2005.11.014
Sawmiller D, Habib A, Li S et al (2016) Diosmin reduces cerebral Aβ levels, tau hyperphosphorylation, neuroinflammation, and cognitive impairment in the 3xTg-AD mice. J Neuroimmunol 299:98–106. https://doi.org/10.1016/j.jneuroim.2016.08.018
Shabani S, Mirshekar MA (2018) Diosmin is neuroprotective in a rat model of scopolamine-induced cognitive impairment. Biomed Pharmacother 108:1376–1383. https://doi.org/10.1016/j.biopha.2018.09.127
Sharma D, Singh M, Kumar P et al (2017) Development and characterization of morin hydrate loaded microemulsion for the management of Alzheimer’s disease. Artif Cells, Nanomed Biotechnol 45(8):1620–1630. https://doi.org/10.1080/21691401.2016.1276919
Sharma D, Wani W, Sunkaria A et al (2016) Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus. Neuroscience 324:163–176. https://doi.org/10.1016/j.neuroscience.2016.02.055
Shih PH, Yeh CT, Yen GC (2007) Anthocyanins induce the activation of phase II enzymes through the antioxidant response element pathway against oxidative stress-induced apoptosis. J Agric Food Chem 55(23):9427–9435. https://doi.org/10.1021/jf071933i
Shukla R, Pandey V, Vadnere GP et al (2019) Bioactive food as dietary interventions for arthritis and related inflammatory diseases, 2nd edn. Academic Press, Cambridge, Massachusetts, pp 293–322
Singh M, Kaur M, Chadha N et al (2016) Hybrids: a new paradigm to treat Alzheimer’s disease. Mol Diversity 20(1):271–297. https://doi.org/10.1007/s11030-015-9628-9
Singh M, Kaur M, Kukreja H, et, (2013) Acetylcholinesterase inhibitors as Alzheimer therapy: from nerve toxins to neuroprotection. Eur J Med Chem 70:165–188. https://doi.org/10.1016/j.ejmech.2013.09.050
Skemiene K, Rakauskaite G, Trumbeckaite S et al (2013) Anthocyanins block ischemia-induced apoptosis in the perfused heart and support mitochondrial respiration potentially by reducing cytosolic cytochrome c. Int J Biochem Cell Biol 45(1):23–29. https://doi.org/10.1016/j.biocel.2012.07.022
Solanki I, Parihar P, Mansuri ML et al (2015) Flavonoid-based therapies in the early management of neurodegenerative diseases. Adv Nutr (Bethesda, Md) 6(1):64–72. https://doi.org/10.3945/an.114.007500
Sunphenon EGCg (Epigallocatechin-Gallate) in the early stage of Alzheimer´s disease (SUN-AK). https://clinicaltrials.gov/ct2/show/NCT00951834?term=NCT00951834&draw=2&rank=1. Accessed 24 April 2021
Taniguchi S, Suzuki N, Masuda M et al (2005) Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins. J Biol Chem 280(9):7614–7623. https://doi.org/10.1074/jbc.M408714200
Thummayot S, Tocharus C, Jumnongprakhon P et al (2018) Cyanidin attenuates Aβ25-35-induced neuroinflammation by suppressing NF-κB activity downstream of TLR4/NOX4 in human neuroblastoma cells. Acta pharmacologicaSinica 39(9):1439–1452. https://doi.org/10.1038/aps.2017.203
Thummayot S, Tocharus C, Pinkaew D et al (2014) Neuroprotective effect of purple rice extract and its constituent against amyloid beta-induced neuronal cell death in SK-N-SH cells. Neurotoxicology 45:149–158. https://doi.org/10.1016/j.neuro.2014.10.010
Turner PR, O’Connor K, Tate WP et al (2003) Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory. Prog Neurobiol 70(1):1–32. https://doi.org/10.1016/s0301-0082(03)00089-3
Uddin M, Kabir M, Niaz K et al (2020) Molecular insight into the therapeutic promise of flavonoids against Alzheimer’s disease. Molecules 25(6):1267. https://doi.org/10.3390/molecules25061267
Vaiserman A, Koliada A, Lushchak O (2020) Neuroinflammation in pathogenesis of Alzheimer’s disease: phytochemicals as potential therapeutics. Mech Ageing Dev 189:111259. https://doi.org/10.1016/j.mad.2020.111259
Valles SL, Dolz-Gaiton P, Gambini J et al (2010) Estradiol or genistein prevent Alzheimer’s disease-associated inflammation correlating with an increase PPAR gamma expression in cultured astrocytes. Brain Research 1312:138–144. https://doi.org/10.1016/j.brainres.2009.11.044
Vassar R, Kovacs DM, Yan R, Wong PC (2009) The β-secretase enzyme BACE in health and Alzheimer’s disease: regulation, cell biology, function, and therapeutic potential. J Neurosci 29(41):12787–12794. https://doi.org/10.1523/JNEUROSCI.3657-09.2009
Vauzour D, Ravaioli G, Vafeiadou K et al (2008) Peroxynitrite induced formation of the neurotoxins 5-S-cysteinyl-dopamine and DHBT-1: implications for Parkinson’s disease and protection by polyphenols. Arch Biochem Biophys 476(2):145–151. https://doi.org/10.1016/j.abb.2008.03.011
Viswanatha GL, Shylaja H, Moolemath Y (2017) The beneficial role of Naringin-a citrus bioflavonoid, against oxidative stress-induced neurobehavioral disorders and cognitive dysfunction in rodents: a systematic review and meta-analysis. Biomed Pharmacother 94:909–929. https://doi.org/10.1016/j.biopha.2017.07.072
Vitale DC, Piazza C, Melilli B et al (2013) Isoflavones: estrogenic activity, biological effect and bioavailability. Eur J Drug Metab Pharmacokinet 38(1):15–25. https://doi.org/10.1007/s13318-012-0112-y
Wang Q, Rowan MJ, Anwyl R (2004) Beta-amyloid-mediated inhibition of NMDA receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide. J Neurosci: Official J Soc Neurosci 24(27):6049–6056. https://doi.org/10.1523/JNEUROSCI.0233-04.2004
Wang SW, Wang YJ, Su YJ et al (2012) Rutin inhibits β-amyloid aggregation and cytotoxicity, attenuates oxidative stress, and decreases the production of nitric oxide and proinflammatory cytokines. Neurotoxicology 33(3):482–490. https://doi.org/10.1016/j.neuro.2012.03.003
Wang X, Wang W, Li L et al (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochem Biophys Acta 1842(8):1240–1247. https://doi.org/10.1016/j.bbadis.2013.10.015
Wang X, Wu J, Chiba H et al (2003) Puerariae radix prevents bone loss in ovariectomized mice. J Bone Miner Metab 21:268–275. https://doi.org/10.1007/s00774-003-0420-z
White LR, Petrovitch H, Ross GW et al (2000) Brain aging and midlife tofu consumption. J Am Coll Nutr 19(2):242–255. https://doi.org/10.1080/07315724.2000.10718923
Wong A, Lüth HJ, Deuther-Conrad W et al (2001) Advanced glycation end products co-localize with inducible nitric oxide synthase in Alzheimer’s disease. Brain research 920(1–2):32–40. https://doi.org/10.1016/s0006-8993(01)02872-4
WongKH LiGQ, Li KM et al (2011) Kudzu root: Traditional uses andpotential medicinal benefits in diabetes and cardiovascular diseases. J Ethnopharmacol 134:584–607. https://doi.org/10.1016/j.jep.2011.02.001
Wu M, Zhu X, Zhang Y et al (2021) Biological evaluation of 7-O-amide hesperetin derivatives as multitarget-directed ligands for the treatment of Alzheimer’s disease. Chem Biol Interact 334:109350. https://doi.org/10.1016/j.cbi.2020.109350
Xie X, Wang SS, Wong TC et al (2013) Genistein promotes cell death of ethanol-stressed HeLa cells through the continuation of apoptosis or secondary necrosis. Cancer Cell Int 13:63. https://doi.org/10.1186/1475-2867-13-63
Xu PX, Wang SW, Yu XL et al (2014) Rutin improves spatial memory in Alzheimer’s disease transgenic mice by reducing Aβ oligomer level and attenuating oxidative stress and neuroinflammation. Behav Brain Res 264:173–180. https://doi.org/10.1016/j.bbr.2014.02.002
YeJ MX, Yan C et al (2010) Effect of purple sweet potato anthocyanins on beta amyloid mediated PC-12 cells death by inhibition of oxidative stress. NeurochemRes 35:357–365. https://doi.org/10.1007/s11064-009-0063-0
Youdim KA, Qaiser MZ, Begley DJ et al (2004a) Flavonoid permeability across an in situ model of the blood–brain barrier. Free RadicBiol Med 36:592–604
Youdim KA, Shukitt-Hale B, Joseph JA (2004b) Flavonoids and the brain: interactions at the blood-brain barrier and their physiological effects on the central nervous system. Free Radical Biol Med 37(11):1683–1693. https://doi.org/10.1016/j.freeradbiomed.2004.08.002
Yu XL, Li YN, Zhang H et al (2015) Rutin inhibits amylin-induced neurocytotoxicity and oxidative stress. Food Funct 6(10):3296–3306. https://doi.org/10.1039/c5fo00500k
Yu Z, Fong WP, Cheng CH (2006) The dual actions of morin (3,5,7,2’,4’-pentahydroxyflavone) as a hypouricemic agent: uricosuric effect and xanthine oxidase inhibitory activity. J Pharmacol Exp Ther 316(1):169–175. https://doi.org/10.1124/jpet.105.092684
Yuan B, Wang L, Jin Y et al (2012) Role of metabolism in the effects of genistein and its phase II conjugates on the growth of human breast cell lines. AAPS J 14(2):329–344. https://doi.org/10.1208/s12248-012-9338-5
Zhang S, Zhu Q, Chen JY et al (2020) The pharmacological activity of epigallocatechin-3-gallate (EGCG) on Alzheimer’s disease animal model: a systematic review. Phytomedicine 79:153316. https://doi.org/10.1016/j.phymed.2020.153316
Zhang X, Hu J, Zhong L et al (2016) Quercetin stabilizes apolipoprotein E and reduces brain Aβ levels in amyloid model mice. Neuropharmacology 108:179–192. https://doi.org/10.1016/j.neuropharm.2016.04.032
Zhang YW, Thompson R, Zhang H et al (2011) APP processing in Alzheimer’s disease. Mol Brain 4:3. https://doi.org/10.1186/1756-6606-4-3
Zhao T, Ding KM, Zhang L et al (2013) Acetylcholinesterase and butyrylcholinesterase inhibitory activities of β-carboline and quinoline alkaloids derivatives from the plants of genus Peganum. J Chem 2013. https://doi.org/10.1155/2013/717232
Zhu GF, Guo HJ, Huang Y et al (2015) Eriodictyol, a plant flavonoid, attenuates LPS-induced acute lung injury through its antioxidative and anti-inflammatory activity. Exp Ther Med 10(6):2259–2266. https://doi.org/10.3892/etm.2015.2827
Zhu X, Cheng YQ, Lu Q et al (2018) Enhancement of glyoxalase 1, a polyfunctional defense enzyme, by quercetin in the brain in streptozotocin-induced diabetic rats. Naunyn-Schmiedeberg’s Arch Pharmacol 391(11):1237–1245. https://doi.org/10.1007/s00210-018-1543-z
Author information
Authors and Affiliations
Contributions
RK and TB: conceived the study; AS and DKL: wrote the first draft of the paper; SB and AAH: data compilation; TB and LA: proof Read.
Corresponding author
Ethics declarations
Ethical approval
Not applicable.
Consent to participate
Not applicable.
Consent to publish
All the authors have approved the manuscript for publication.
Competing interests
The authors declare no competing interests.
Additional information
Responsible Editor: Philippe Garrigues
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Kaur, R., Sood, A., Lang, D.K. et al. Potential of flavonoids as anti-Alzheimer’s agents: bench to bedside. Environ Sci Pollut Res 29, 26063–26077 (2022). https://doi.org/10.1007/s11356-021-18165-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-021-18165-z