Browse > Article
http://dx.doi.org/10.11620/IJOB.2020.45.2.33

Flavonoids as anti-inflammatory and neuroprotective agents  

Lee, Heesu (Department of Anatomy, College of Dentistry, Gangneung-Wonju National University)
Selvaraj, Baskar (Natural Product Research Center, Korea Institute of Science and Technology)
Yoo, Ki Yeon (Department of Anatomy, College of Dentistry, Gangneung-Wonju National University)
Ko, Seong-Hee (Department of Pharmacology, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University)
Publication Information
International Journal of Oral Biology / v.45, no.2, 2020 , pp. 33-41 More about this Journal
Abstract
Neuroinflammation is known as the main mechanism implicated in the advancement of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The main feature of neuroinflammation is associated with the activation of microglia. The activated microglia increase proinflammatory cytokine production and induce progressive neuronal cell death. Citrus flavonoids show neuroprotective effects that are associated with the anti-inflammatory action of flavonoids in neurodegenerative diseases. Among these citrus flavonoids, kaempferol, naringin, and nobiletin show inhibitory effects on nuclear factor-κB and mitogen-activated protein kinase signaling pathways that can modulate inflammatory conditions in microglial cells. In the present review, we present the anti-inflammatory activities of citrus flavonoids and therapeutic potential of flavonoids as neuroprotective agents.
Keywords
Flavonoid; Anti-inflammatory agents; Neuroprotection; Microglia;
Citations & Related Records
Times Cited By KSCI : 2  (Citation Analysis)
연도 인용수 순위
1 Spencer JP. Flavonoids: modulators of brain function? Br J Nutr 2008;99 E Suppl 1:ES60-77. doi: 10.1017/S0007114508965776.   DOI
2 Gao X, Cassidy A, Schwarzschild MA, Rimm EB, Ascherio A. Habitual intake of dietary flavonoids and risk of Parkinson disease. Neurology 2012;78:1138-45. doi: 10.1212/WNL.0b013e31824f7fc4.   DOI
3 Tressera-Rimbau A, Arranz S, Eder M, Vallverdu-Queralt A. Dietary polyphenols in the prevention of stroke. Oxid Med Cell Longev 2017;2017:7467962. doi: 10.1155/2017/7467962.
4 Devore EE, Kang JH, Breteler MM, Grodstein F. Dietary intakes of berries and flavonoids in relation to cognitive decline. Ann Neurol 2012;72:135-43. doi: 10.1002/ana.23594.   DOI
5 Bakoyiannis I, Daskalopoulou A, Pergialiotis V, Perrea D. Phytochemicals and cognitive health: are flavonoids doing the trick? Biomed Pharmacother 2019;109:1488-97. doi: 10.1016/j.biopha.2018.10.086.   DOI
6 Badshah H, Ali T, Kim MO. Osmotin attenuates LPS-induced neuroinflammation and memory impairments via the TLR4/ NF$\kappa$B signaling pathway. Sci Rep 2016;6:24493. doi: 10.1038/srep24493.   DOI
7 Supriady H, Kamarudin MNA, Chan CK, Goh BH, Kadir HA. SMEAF attenuates the production of pro-inflammatory mediators through the inactivation of Akt-dependent NF-$\kappa$B, p38 and ERK1/2 pathways in LPS-stimulated BV-2 microglial cells. J Funct Foods 2015;17:434-48. doi: 10.1016/j.jff.2015.05.042.   DOI
8 Levi F, Pasche C, La Vecchia C, Lucchini F, Franceschi S. Food groups and colorectal cancer risk. Br J Cancer 1999;79:1283-7. doi: 10.1038/sj.bjc.6690206.   DOI
9 Spencer SJ, Korosi A, Laye S, Shukitt-Hale B, Barrientos RM. Food for thought: how nutrition impacts cognition and emotion. NPJ Sci Food 2017;1:7. doi: 10.1038/s41538-017-0008-y.   DOI
10 Panickar KS, Jang S. Dietary and plant polyphenols exert neuroprotective effects and improve cognitive function in cerebral ischemia. Recent Pat Food Nutr Agric 2013;5:128-43. doi: 10.2174/1876142911305020003.   DOI
11 Chen H, Ward MH, Graubard BI, Heineman EF, Markin RM, Potischman NA, Russell RM, Weisenburger DD, Tucker KL. Dietary patterns and adenocarcinoma of the esophagus and distal stomach. Am J Clin Nutr 2002;75:137-44. doi: 10.1093/ajcn/75.1.137.   DOI
12 McCullough ML, Robertson AS, Jacobs EJ, Chao A, Calle EE, Thun MJ. A prospective study of diet and stomach cancer mortality in United States men and women. Cancer Epidemiol Biomarkers Prev 2001;10:1201-5.
13 Leus NG, Zwinderman MR, Dekker FJ. Histone deacetylase 3 (HDAC 3) as emerging drug target in NF-$\kappa$B-mediated inflammation. Curr Opin Chem Biol 2016;33:160-8. doi: 10.1016/j.cbpa.2016.06.019.   DOI
14 Lo JY, Kamarudin MN, Hamdi OA, Awang K, Kadir HA. Curcumenol isolated from Curcuma zedoaria suppresses Aktmediated NF-$\kappa$B activation and p38 MAPK signaling pathway in LPS-stimulated BV-2 microglial cells. Food Funct 2015;6:3550-9. doi: 10.1039/c5fo00607d.   DOI
15 Mishra V, Banga J, Silveyra P. Oxidative stress and cellular pathways of asthma and inflammation: therapeutic strategies and pharmacological targets. Pharmacol Ther 2018;181:169-82. doi: 10.1016/j.pharmthera.2017.08.011.   DOI
16 Sun SC. The non-canonical NF-$\kappa$B pathway in immunity and inflammation. Nat Rev Immunol 2017;17:545-58. doi: 10.1038/nri.2017.52.   DOI
17 Herrington FD, Carmody RJ, Goodyear CS. Modulation of NF-$\kappa$B signaling as a therapeutic target in autoimmunity. J Biomol Screen 2016;21:223-42. doi: 10.1177/1087057115617456.   DOI
18 Shabab T, Khanabdali R, Moghadamtousi SZ, Kadir HA, Mohan G. Neuroinflammation pathways: a general review. Int J Neurosci 2017;127:624-33. doi: 10.1080/00207454.2016.1212854.   DOI
19 Spagnuolo C, Moccia S, Russo GL. Anti-inflammatory effects of flavonoids in neurodegenerative disorders. Eur J Med Chem 2018;153:105-15. doi: 10.1016/j.ejmech.2017.09.001.   DOI
20 Youdim KA, Dobbie MS, Kuhnle G, Proteggente AR, Abbott NJ, Rice-Evans C. Interaction between flavonoids and the blood-brain barrier: in vitro studies. J Neurochem 2003;85:180-92. doi: 10.1046/j.1471-4159.2003.01652.x.   DOI
21 Shu Z, Yang B, Zhao H, Xu B, Jiao W, Wang Q, Wang Z, Kuang H. Tangeretin exerts anti-neuroinflammatory effects via NF-$\kappa$B modulation in lipopolysaccharide-stimulated microglial cells. Int Immunopharmacol 2014;19:275-82. doi: 10.1016/j.intimp.2014.01.011.   DOI
22 Lapchak PA. A series of novel neuroprotective blood brain barrier penetrating flavonoid drugs to treat acute ischemic stroke. Curr Pharm Des 2012;18:3694-703. doi: 10.2174/138161212802002652.   DOI
23 Thilakarathna SH, Rupasinghe HP. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 2013;5:3367-87. doi: 10.3390/nu5093367.   DOI
24 Gonzales GB, Smagghe G, Grootaert C, Zotti M, Raes K, Van Camp J. Flavonoid interactions during digestion, absorption, distribution and metabolism: a sequential structure-activity/property relationship-based approach in the study of bioavailability and bioactivity. Drug Metab Rev 2015;47:175-90. doi: 10.3109/03602532.2014.1003649.   DOI
25 Qi G, Mi Y, Fan R, Li R, Liu Z, Liu X. Nobiletin protects against systemic inflammation-stimulated memory impairment via MAPK and NF-$\kappa$B signaling pathways. J Agric Food Chem 2019;67:5122-34. doi: 10.1021/acs.jafc.9b00133.   DOI
26 Okuyama S, Miyoshi K, Tsumura Y, Amakura Y, Yoshimura M, Yoshida T, Nakajima M, Furukawa Y. 3,5,6,7,8,3',4'-heptamethoxyflavone, a citrus polymethoxylated flavone, attenuates inflammation in the mouse hippocampus. Brain Sci 2015;5:118-29. doi: 10.3390/brainsci5020118.   DOI
27 Betteridge DJ. What is oxidative stress? Metabolism 2000;49(2 Suppl 1):3-8. doi: 10.1016/s0026-0495(00)80077-3.   DOI
28 Niedzielska E, Smaga I, Gawlik M, Moniczewski A, Stankowicz P, Pera J, Filip M. Oxidative stress in neurodegenerative diseases. Mol Neurobiol 2016;53:4094-125. doi: 10.1007/s12035-015-9337-5.   DOI
29 Fortes C, Forastiere F, Farchi S, Rapiti E, Pastori G, Perucci CA. Diet and overall survival in a cohort of very elderly people. Epidemiology 2000;11:440-5. doi: 10.1097/00001648-200007000-00013.   DOI
30 Feldman EB. Fruits and vegetables and the risk of stroke. Nutr Rev 2001;59(1 Pt 1):24-7. doi: 10.1111/j.1753-4887.2001.tb01902.x.   DOI
31 Aherne SA, O'Brien NM. Dietary flavonols: chemistry, food content, and metabolism. Nutrition 2002;18:75-81. doi: 10.1016/s0899-9007(01)00695-5.   DOI
32 Tapiero H, Tew KD, Ba GN, Mathe G. Polyphenols: do they play a role in the prevention of human pathologies? Biomed Pharmacother 2002;56:200-7. doi: 10.1016/s0753-3322(02)00178-6.   DOI
33 Veitch NC, Grayer RJ. Flavonoids and their glycosides, including anthocyanins. Nat Prod Rep 2008;25:555-611. doi: 10.1039/b718040n.   DOI
34 Nekooki-Machida Y, Kurosawa M, Nukina N, Ito K, Oda T, Tanaka M. Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity. Proc Natl Acad Sci U S A 2009;106:9679-84. doi: 10.1073/pnas.0812083106.   DOI
35 Li J, O W, Li W, Jiang ZG, Ghanbari HA. Oxidative stress and neurodegenerative disorders. Int J Mol Sci 2013;14:24438-75. doi: 10.3390/ijms141224438.   DOI
36 Perez M, Cuadros R, Smith MA, Perry G, Avila J. Phosphorylated, but not native, tau protein assembles following reaction with the lipid peroxidation product, 4-hydroxy-2-nonenal. FEBS Lett 2000;486:270-4. doi: 10.1016/s0014-5793(00)02323-1.   DOI
37 Xiang W, Schlachetzki JC, Helling S, Bussmann JC, Berlinghof M, Schäffer TE, Marcus K, Winkler J, Klucken J, Becker CM. Oxidative stress-induced posttranslational modifications of alpha-synuclein: specific modification of alphasynuclein by 4-hydroxy-2-nonenal increases dopaminergic toxicity. Mol Cell Neurosci 2013;54:71-83. doi: 10.1016/j.mcn.2013.01.004.   DOI
38 Cohen TJ, Hwang AW, Unger T, Trojanowski JQ, Lee VM. Redox signalling directly regulates TDP-43 via cysteine oxidation and disulphide cross-linking. EMBO J 2012;31:1241-52. doi: 10.1038/emboj.2011.471.   DOI
39 Pietta PG. Flavonoids as antioxidants. J Nat Prod 2000;63:1035-42. doi: 10.1021/np9904509.   DOI
40 Lin CM, Chen CT, Lee HH, Lin JK. Prevention of cellular ROS damage by isovitexin and related flavonoids. Planta Med 2002;68:365-7. doi: 10.1055/s-2002-26753.   DOI
41 Miyake Y, Sakurai C, Usuda M, Fukumoto S, Hiramitsu M, Sakaida K, Osawa T, Kondo K. Difference in plasma metabolite concentration after ingestion of lemon flavonoids and their aglycones in humans. J Nutr Sci Vitaminol (Tokyo) 2006;52:54-60. doi: 10.3177/jnsv.52.54.   DOI
42 Cui J, Wang G, Kandhare AD, Mukherjee-Kandhare AA, Bodhankar SL. Neuroprotective effect of naringin, a flavone glycoside in quinolinic acid-induced neurotoxicity: possible role of PPAR-$\gamma$, Bax/Bcl-2, and caspase-3. Food Chem Toxicol 2018;121:95-108. doi: 10.1016/j.fct.2018.08.028.   DOI
43 Miean KH, Mohamed S. Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. J Agric Food Chem 2001;49:3106-12. doi: 10.1021/jf000892m.   DOI
44 Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols. J Nutr 2000;130(8S Suppl):2073S-85S. doi: 10.1093/jn/130.8.2073S.   DOI
45 Prochazkova D, Boušova I, Wilhelmova N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia 2011;82:513-23. doi: 10.1016/j.fitote.2011.01.018.   DOI
46 Haghmorad D, Mahmoudi MB, Salehipour Z, Jalayer Z, Momtazi Brojeni AA, Rastin M, Kokhaei P, Mahmoudi M. Hesperidin ameliorates immunological outcome and reduces neuroinflammation in the mouse model of multiple sclerosis. J Neuroimmunol 2017;302:23-33. doi: 10.1016/j.jneuroim.2016.11.009.   DOI
47 Sawmiller D, Habib A, Li S, Darlington D, Hou H, Tian J, Shytle RD, Smith A, Giunta B, Mori T, Tan J. Diosmin reduces cerebral $A\beta$ levels, tau hyperphosphorylation, neuroinflammation, and cognitive impairment in the 3xTg-AD mice. J Neuroimmunol 2016;299:98-106. doi: 10.1016/j.jneuroim.2016.08.018.   DOI
48 Zhang Y, Jiang Y, Lu D. Diosmetin suppresses neuronal apoptosis and inflammation by modulating the phosphoinositide 3-kinase (PI3K)/AKT/nuclear factor-$\kappa$B (NF-$\kappa$B) signaling pathway in a rat model of pneumococcal meningitis. Med Sci Monit 2019;25:2238-45. doi: 10.12659/MSM.911860.   DOI
49 Jang S, Kelley KW, Johnson RW. Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci U S A 2008;105:7534-9. doi: 10.1073/pnas.0802865105.   DOI
50 Yao ZH, Yao XL, Zhang Y, Zhang SF, Hu JC. Luteolin could improve cognitive dysfunction by inhibiting neuroinflammation. Neurochem Res 2018;43:806-20. doi: 10.1007/s11064-018-2482-2.   DOI
51 Li WH, Cheng X, Yang YL, Liu M, Zhang SS, Wang YH, Du GH. Kaempferol attenuates neuroinflammation and blood brain barrier dysfunction to improve neurological deficits in cerebral ischemia/reperfusion rats. Brain Res 2019;1722:146361. doi: 10.1016/j.brainres.2019.146361.   DOI
52 Siracusa R, Paterniti I, Impellizzeri D, Cordaro M, Crupi R, Navarra M, Cuzzocrea S, Esposito E. The association of palmitoylethanolamide with luteolin decreases neuroinflammation and stimulates autophagy in Parkinson's disease model. CNS Neurol Disord Drug Targets 2015;14:1350-65. doi: 10.2174/1871527314666150821102823.   DOI
53 Park SE, Sapkota K, Kim S, Kim H, Kim SJ. Kaempferol acts through mitogen-activated protein kinases and protein kinase B/AKT to elicit protection in a model of neuroinflammation in BV2 microglial cells. Br J Pharmacol 2011;164:1008-25. doi: 10.1111/j.1476-5381.2011.01389.x.   DOI
54 Kouhestani S, Jafari A, Babaei P. Kaempferol attenuates cognitive deficit via regulating oxidative stress and neuroinflammation in an ovariectomized rat model of sporadic dementia. Neural Regen Res 2018;13:1827-32. doi: 10.4103/1673-5374.238714.   DOI
55 Jung UJ, Kim SR. Beneficial effects of flavonoids against Parkinson's disease. J Med Food 2018;21:421-32. doi: 10.1089/jmf.2017.4078.   DOI
56 Mattson MP. Pathways towards and away from Alzheimer's disease. Nature 2004;430:631-9. doi: 10.1038/nature02621.   DOI
57 Hoglund K, Salter H. Molecular biomarkers of neurodegeneration. Expert Rev Mol Diagn 2013;13:845-61. doi: 10.1586/14737159.2013.850033.   DOI
58 Halliwell B. Reactive oxygen species and the central nervous system. J Neurochem 1992;59:1609-23. doi: 10.1111/j.1471-4159.1992.tb10990.x.   DOI
59 Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med 2004;36:838-49. doi: 10.1016/j.freeradbiomed.2004.01.001.   DOI
60 Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K, Walter CA, Richardson A. Does oxidative damage to DNA increase with age? Proc Natl Acad Sci U S A 2001;98:10469-74. doi: 10.1073/pnas.171202698.   DOI
61 Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 2012;24:981-90. doi: 10.1016/j.cellsig.2012.01.008.   DOI
62 Kong AN, Yu R, Chen C, Mandlekar S, Primiano T. Signal transduction events elicited by natural products: role of MAPK and caspase pathways in homeostatic response and induction of apoptosis. Arch Pharm Res 2000;23:1-16. doi: 10.1007/BF02976458.   DOI
63 Choi JH, Choi AY, Yoon H, Choe W, Yoon KS, Ha J, Yeo EJ, Kang I. Baicalein protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis through inhibition of reactive oxygen species production and CHOP induction. Exp Mol Med 2010;42:811-22. doi:10.3858/emm.2010.42.12.084.   DOI
64 Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, Cobb MH. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 2001;22:153-83. doi: 10.1210/edrv.22.2.0428.   DOI
65 Tibbles LA, Woodgett JR. The stress-activated protein kinase pathways. Cell Mol Life Sci 1999;55:1230-54. doi: 10.1007/s000180050369.   DOI
66 Peterson JJ, Dwyer JT, Beecher GR, Bhagwat SA, Gebhardt SE, Haytowitz DB, Holden JM. Flavanones in oranges, tangerines (mandarins), tangors, and tangelos: a compilation and review of the data from the analytical literature. J Food Compos Anal 2006;19(Suppl):S66-73. doi: 10.1016/j.jfca.2005.12.006.   DOI
67 Panche AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci 2016;5:e47. doi: 10.1017/jns.2016.41.   DOI
68 Hwang SL, Shih PH, Yen GC. Neuroprotective effects of citrus flavonoids. J Agric Food Chem 2012;60:877-85. doi: 10.1021/jf204452y.   DOI
69 Spencer JP, Vafeiadou K, Williams RJ, Vauzour D. Neuroinflammation: modulation by flavonoids and mechanisms of action. Mol Aspects Med 2012;33:83-97. doi: 10.1016/j.mam.2011.10.016.   DOI
70 Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell 2010;140:918-34. doi: 10.1016/j.cell.2010.02.016.   DOI