Neuroprotective Effect of Flavonoids: A Systematic Review
- Flavonoids, neuro-inflammatory, neurodegeneration, Rutin, Apigenin, Hesperidin, Kaempferol, Naringenin, Anthocyanins, Naringin, Baicalein, Catechin
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease are underpinned by neuronal damage corollary to the cascade of events pitched in by neuron inflammatory processes. Increase in cases of neurodegenerative diseases and ageing population indicates the need for developing new strategies to prevent or treat brain dysfunction and associated cognitive decline. Flavonoids have been documented for various health promoting effects. They exert multiple neuroprotective actions within the brain, such as protection of neurons from neurotoxins, suppression of neuron-inflammation and thus improve memory, learning and cognitive function. Two processes appear to be the basis of these effects. Firstly, they promote neuronal survival and synaptic plasticity by inhibition of apopotosis triggered by neurotoxic species due to interaction with critical protein and lipid kinase signaling cascades. Secondly they induce beneficial effects on the vascular system leading to changes in cerebrovascular blood flow capable of causing angiogenesis, neurogenesis and neuronal morphology. Limiting neurodegeneration and prevention or reversal of age-dependent loss in cognitive performance is possible by consumption of flavonoids-rich food throughout life. Thus flavonoids are strong candidates of being an important precursor molecule in the development of new generation of brain enhancing drugs. The present review accentuates current information on neuroprotective effects of flavonoids.
2 Anand A. Zanwar, … Subhash L. Bodhankar(2014) Polyphenols in Chronic Diseases and their Mechanisms of Action in Polyphenols in Human Health and Disease
3 Allan Butterfield D. (2002). Amyloid β-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review. Free Rad Res. 36:1307-1313.
4 Baicalein inhibitor of protein tyrosine kinase in leukemia (CEM cells)https://focusbiomolecules.com/baicalein-inhibitor-of-protein-tyrosine-kinase-in-leukemia-cem-cells.
5 Bharti S., N. Rani, B. Krishnamurthy, and D. S. Arya (2014). “Preclinical evidence for the pharmacological actions of naringin: a review,” Planta Medica, vol. 80, no. 6, pp. 437–451.
6 Bastianetto S, Zheng WH, Quirion R (2000) The Ginkgo biloba extract (EGb 761) protects and rescues hippocampal cells against nitric oxide-induced toxicity: involvement of its flavonoids.
7 constituents and protein kinase C. J Neurochem 74:2268– 2277.
8 Chonodrohianni et al.(2010). Anti-aging and rejuvenating effects of quercitin. Exp Gerontol.5:763-771.
9 Costa BL, Fawcett R, Li GY et al (2008) Orally administered epigallocatechin gallate attenuates light-induced photoreceptor damage. Brain Res Bull 76:412–423.
10 Catechin https://www.researchgate.net/figure/Chemical-structures-of-catechin-and-four-major-green-tea-catechins_fig1_286523655.
11 Chen JC, Ho FM, Pei-Dawn LC et al (2005). Inhibition of iNOS gene expression by quercetin is mediated by the inhibition of IkappaB kinase, nuclear factor-kappa B and STAT1, and depends on heme oxygenase-1 induction in mouse BV-2 microglia. Eur J Pharmacol 521:9–20.
12 Chapter 46 – Naringenin and the Liver Author links open overlay panelE.Hernández AquinoP.Muriel.
13 Datla KP, Christidou M, Widmer WW et al (2001) Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of Parkinson’s disease. Neuroreport 12:3871–3875.
14 da Silva EL, Piskula MK, Yamamoto N et al (1998) Quercetin metabolites inhibit copper ion-induced lipid peroxidation in rat plasma. FEBS Lett 430:405–408.
15 El Mohsen MA, Marks J, Kuhnle G et al (2006). Absorption, tissue distribution and excretion of pelargonidin and its metabolites following oral administration to rats. Br J Nutr 95:51–58.
16 Evans C. R. (1995) Plant polyphenols: free radical scavengers or chain-breaking antioxidants? Biochem Soc Symp 61:103–116.
17 Esselen Melanie, Stephan W. Barth (2014) Food-Borne Topoisomerase Inhibitors in Advances in Molecular Toxicology.
18 Fariaa A Mateusb N. and Calhaua C.(2012). Flavonoid transport across blood-brain barrier: Implication for their direct neuroprotective actions Nutrition and Aging.1:89–97.
19 Fu W, Zhuang W, Zhou S, Wang X. (2015). Plant-derived neuroprotective agents in Parkinson’s disease. Am J Trans Res.7:1189-1195.
20 Floyd RA, Carney JM. (1992). Free radical damage to protein and DNA: mechanisms involved and relevant observations on brain undergoing oxidative stress. Annals of Neurology.32:S22-S27.
21 Æ Katerina Vafeiadou Æ Ana Rodriguez-Mateos Æ Catarina Rendeiro Æ Jeremy P. E. (2008) Intro- The neuroprotective potential of flavonoids: a multiplicity of effects David Vauzour Spencer Published online: 21 October 2008 Genes Nutr. 3:115–126.
22 Gaur V, Kumar A (2010) Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction. Pharmacol Rep 62:635–648.
23 Galleano M, Pechanova O, Fraga CG (2010) Hypertension, nitric oxide, oxidants, and dietary plant polyphenols. Curr Pharm Biotechnol 11:837–848.
24 Hesperidin Chemical Properties,Uses,Production https://www.chemicalbook.com/ChemicalProductProperty_EN_CB3234127.htm.
28 Inanami O, Watanabe Y, Syuto B et al (1998) Oral administration of (-)catechin protects against ischemia-reperfusioninduced neuronal death in the gerbil. Free Radic Res 29:359– 365.
29 Joseph JA, Shukitt-Hale B, Denisova NA et al (1999) Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, Strawberry dietary supplementation. J Neurosci 19:8114–8121.
30 Joseph JA, Shukitt-Hale B, Denisova NA et al (1998) Long-term dietary strawberry, spinach, or vitamin E supplementation etards the onset of age-related neuronal signal-transduction and cognitive behavioral deficits. J Neurosci 18:8047–8055.
31 Jeong K.H., U. J. Jung, and S. R. Kim (2015). “Naringin attenuates autophagic stress and neuroinflammation in kainic acidtreated hippocampus in vivo,” Evidence-based Complementary and Alternative Article ID 354326, 9 pages.
32 Kim H, Kim YS, Kim SY et al (2001) The plant flavonoids wogonin suppresses death of activated C6 rat glial cells by inhibiting nitric oxide production. Neurosci Lett 309:67–71.
33 Kandhare D., K. S. Raygude, P. Ghosh, A. E. Ghule, and S. L. Bodhankar (2012).“Neuroprotective effect of naringin by modulation of endogenous biomarkers in streptozotocin induced painful diabetic neuropathy,” Fitoterapia, vol. 83, no. 4, pp. 650–659.
34 Kroemer HK, Klotz U (1992) Glucuronidation of drugs. A reevaluation of the pharmacological significance of the conjugates and modulating factors. Clin Pharmacokinet 23:292–310.
35 Lin JH, Yamazaki M (2003) Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 42:59– 98.
36 Li Q., T. Wang, Z. Pei, B. Liu, and J. S. Hong(2005). “Inhibition of microglial activation by the herbal flavonoid baicalein 20 Oxidative Medicine and Cellular Longevity attenuates inflammation-mediated degeneration of dopaminergic neurons,” Journal of Neural Transmission, vol. 112, no. 3, pp. 331–347.
37 Luo Y, Smith JV, Paramasivam V et al (2002) Inhibition of amyloid-beta aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761. Proc Natl Acad Sci USA 99:12197–12202.
38 Lee, H. R. Park, S. T. Ji, Y. Lee, and J. Lee, “Baicalein attenuatesastroglial activation in the 1-methyl-4-phenyl-1,2,3,4- tetrahydropyridine-induced Parkinson’s disease model by downregulating the activations of nuclear factor-κB, ERK, and JNK,” Journal of Neuroscience Research, vol. 92, no. 1, pp. 130–139, 2014.
39 Miyake Y, Shimoi K, Kumazawa S et al (2000) Identification and antioxidant activity of flavonoid metabolites in plasma and urine of eriocitrin-treated rats. J Agric Food Chem 48:3217–3224.
40 M. E. Ahmed, M. M. Khan, H. Javed et al.,(2013) “Amelioration of cognitive impairment and neurodegeneration by catechin hydrate in rat model of streptozotocin-induced experimental dementia of Alzheimer’s type,” Neurochemistry International, vol. 62, no. 4, pp. 492–501.
41 M. L. F. Ferreyra, S. P. Rius, and P. Casati,(2012) “Flavonoids: biosynthesis, biological functions, and biotechnological applications,” Frontiers in Plant Science, vol. 3, p. 222.
42 M. J. Kim, S. U. Rehman, F. U. Amin, and M. O. Kim, “Enhanced neuroprotection of anthocyanin-loaded PEGgold nanoparticles against Aβ1-42-induced neuroinflammation and neurodegeneration via the NF-KB/JNK/GSK3β signaling pathway,” Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 13, no. 8, pp. 2533–2544, 2017.
43 Marder M, Viola H, Wasowski C et al (2003) 6-Methylapigenin and hesperidin: new valeriana flavonoids with activity on the CNS. Pharmacol Biochem Behav 75:537–745.
44 Mattson MP. (2004). Metal‐Catalyzed Disruption of Membrane Protein and Lipid Signaling in the Pathogenesis of Neurodegenerative Disorders. Annals of the New York Academy of Sciences.1012:37-50.
45 Marjan Nassiri-Asl a,⁎, Seyed-Reza Mortazavi a, Fatemeh Samiee-Rad b, Amir-Abdollah Zangivand c, Freshteh Safdari c, Sepideh Saroukhani c, Esmail Abbasi(2010) The effects of rutin on the development of pentylenetetrazole kindling and memory retrieval in rats Department of Pharmacology, Qazvin University of Medical Sciences, Qazvin, Iran Epilepsy and Behavior 18:50–53.
46 Obregon DF, Rezai-Zadeh K, Bai Y et al (2006) ADAM10 activation is required for green tea (-)-epigallocatechin-3-gallateinduced a-secretase cleavage of amyloid precursor protein. J Biol Chem 281:16419–16427.
47 Peng HW, Cheng FC, Huang YT et al (1998) Determination of naringenin and its glucuronide conjugate in rat plasma and brain tissue by high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 714:369–374.
48 Patel D1, Shukla S, Gupta S. Int J Oncol (2007) Apigenin and cancer chemoprevention: progress, potential and promise (review).n Jan;30(1):233-45.
49 Q. Hu, V. N. Uversky, M. Huang (2016).“Baicalein inhibits α-synuclein oligomer formation and prevents progression of α-synuclein accumulation in a rotenone mouse model of Parkinson’s disease,” Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, vol. 1862, no. 10, pp. 1883–1890.
50 Qin S., Q. Chen, H. Wu (2016), “Effects of naringin on learning and memory dysfunction induced by gp120 in rats,” Brain Research Bulletin, vol. 124, pp. 164–171.
51 R. Lim, C. J. Morwood, G. Barker, and M. Lappas, “Effect of silibinin in reducing inflammatory pathways in in vitro and in vivo models of infection-induced preterm birth,” PLoS One, vol. 9, no. 3, article e92505, 2014.
52 Rutin structure https://pubchem.ncbi.nlm.nih.gov/compound/rutin#section=Top
53 Rice-Evans CA, Miller NJ, Paganga G (1996) Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20:933–956.
54 Rehman S. U., S. A. Shah, T. Ali, J. I. Chung, and M. O. Kim (2017). “Anthocyanins reversed D-galactose-induced oxidative stress and neuroinflammation mediated cognitive impairment in adult rats,” Molecular Neurobiology, vol. 54, no. 1, pp. 255– 271.
55 Rodriguez-Mateos A, Vauzour D, Krueger CG, Shanmuganayagam D, Reed J, Calani L, Mena P, Del Rio D, Crozier A., (2014). Bioavailability, bioactivity and impact on health of dietary flavonoids and related compounds.10:1803-1853.
56 Ramalingayya V., M. Nampoothiri, P. G. Nayak (2016). “Naringin and Rutin alleviates episodic memory deficits in two differentially challenged object recognition tasks,” Pharmacognosy Magazine, vol. 12, no. 45, pp. 63–70.
57 Roriguez-Mateos C. Rendeiro _ J. Vauzour _ K. Vafeiadou _ A. (2014) P. E. Spencer Molecular Nutrition Group, School of Chemistry, Food and Pharmacy, University of Reading, Reading RG2 6AP, UK, School of Food Biosciences, University of Reading, 12263-008-009.
58 S. Y. Wang, C. T. Chen, W. Sciarappa, C. Y. Wang, and M. J.Camp (2008). “Fruit quality, antioxidant capacity, and flavonoids content of organically and conventionally grown blueberries,” Journal of Agricultural and Food Chemistry, vol. 56, no. 14, pp. 5788–5794.
59 Schroeter H, Spencer JP, Rice-Evans C et al (2001) Flavonoids protect neurons from oxidized low-density-lipoprotein-induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3. Biochem J 358:547–557.
60 Smith JV, Burdick AJ, Golik P et al (2002) Anti-apoptotic properties of Ginkgo biloba extract EGb 761 in differentiated PC12 cells. Cell Mol Biol (Noisy -le-grand) 48:699–707.
61 Spencer JPE, Schroeter H, Rechner AR et al (2001) Bioavailability of flavan-3-ols and procyanidins: gastrointestinal tract influences and their relevance to bioactive forms in vivo. Antioxid Redox Signal 3:1023–1039
62 Spencer JPE, Abd El Mohsen MM, Minihane AM et al (2007) Biomarkers of the intake of dietary polyphenols: strengths, limitations and application in nutrition research. Br J Nutr:1–11
63 Scheline RR (1999) Metabolism of Oxygen Heterocyclic Compounds. CRC Handbook of mammalian metabolism of plant compounds. CRC Press Inc., Boca Ranton, pp 243–95
64 Spencer JPE, Schroeter H, Crossthwaithe AJ et al (2001) Contrasting influences of glucuronidation and O-methylation of epicatechin on hydrogen peroxide-induced cell death in neurons and fibroblasts. Free Radic Biol Med 31:1139–1146
65 Shirai M, Moon JH, Tsushida T et al (2001) Inhibitory effect of a quercetin metabolite, quercetin 3-O-beta-D-glucuronide, on lipid peroxidation in liposomal membranes. J Agric Food Chem 49:5602–5608.
66 Sperker B, Backman JT, Kroemer HK (1997) The role of betaglucuronidase in drug disposition and drug targeting in humans. Clin Pharmacokinet 33:18–31
67 Suganuma M, Okabe S, Oniyama M et al (1998) Wide distribution of [H-3](-)-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue. Carcinogenesis 19:1771–1776
68 Suganuma M, Okabe S, Oniyama M et al (1998) Wide distribution of [H-3](-) epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue. Carcinogenesis 19:1771–1776
69 Song X., B. Zhou, L. Cui (2017).“Silibinin ameliorates Aβ25-35- induced memory deficits in rats by modulating autophagy and attenuating neuroinflammation as well as oxidative stress,” Neurochemical Research, vol. 42, no. 4, pp. 1073– 1083.
70 Švagera, N. Škottová, P. Váňa (2003).“Plasma lipoproteins in transport of silibinin, an antioxidant flavonolignan from Silybum marianum,” Phytotherapy Research, vol. 17, no. 5, pp. 524–530.
71 Sharma Manjulata.(2015). Neuronutrient efficiency of withania somnifera in again brain of mice .Department of zoology M.S.J. govt. collage ,Bharatpur J. of global biosc.4:1482-1487.
72 Saxena S, Caroni P. (2011). Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron.71:35-4.
73 Spagnuolo, S. Moccia, and G. L. Russo, “Anti-inflammatory effects of flavonoids in neurodegenerative disorders,” European Journal of Medicinal Chemistry, vol. 17, pp. 30683–30689, 2017.
74 Smeriglio, D. Barreca, E. Bellocco, and D. Trombetta, “Chemistry, pharmacology and health benefits of anthocyanins,” Phytotherapy Research, vol. 30, no. 8, pp. 1265–1286, 2016.
75 Spencer JPE, Chowrimootoo G, Choudhury R et al (1999) The small intestine can both absorb and glucuronidate luminal flavonoids. FEBS Lett 458:224–230.
76 Spencer JPE (2003) Metabolism of tea flavonoids in the gastrointestinal tract. J Nutr 133:3255S–3261S.
77 Talavera S, Felgines C, Texier O et al (2005) Anthocyanin metabolism in rats and their distribution to digestive area, kidney, and brain. J Agric Food Chem 53:3902–3908
78 The inhibition effect of Naringenin 12 May 2011 By Emma Shiells, Development Editor http://blogs.rsc.org/cc/2011/05/12/the-inhibition-effect-of-naringenin/
79 Terao J, Yamaguchi S, Shirai M et al (2001) Protection by quercetin and quercetin 3-O-beta-D-glucuronide of peroxynitrite- induced antioxidant consumption in human plasma lowdensity lipoprotein. Free Radic Res 35:925–931.
80 T. Makino, A. Hishida, Y. Goda, and H. Mizukami(2008). “Comparison of the major flavonoid content of S. Baicalensis, S. Lateriflora, and their commercial products,” Journal of Natural Medicines, vol. 62, no. 3, pp. 294–299.
81 Virmani A, Pinto L, Binienda Z, Ali S.(2013). Food, nutrigenomics, and neurodegeneration-neuroprotection by what you eat! Molecular neurobiology.48:353-362.
82 V. Gaur and A. Kumar (2010). “Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction,” Pharmacological Reports, vol. 62, no. 4, pp. 635–648.
83 V. M. Mani, S. Asha, and A. M. M. Sadiq (2014). “Pyrethroid deltamethrin-induced developmental neurodegenerative cerebral injury and ameliorating effect of dietary glycoside naringin in male wistar rats,” Biomedicine & Aging Pathology, vol. 4, no. 1, pp. 1–8.
84 W. F. Kum, S. S. Durairajan, Z. X. Bian et al., (2011)“Treatment of idiopathic Parkinson’s disase with traditional Chinese herbal medicine: a randomized placebo-controlled pilot clinical study,” Evidence-based Complementary and Alternative Medicine, vol. 2011, Article ID 724353, 8 pages,
85 W. Fu, W. Zhuang, S. Zhou, and X. Wang, (2015)“Plant-derived neuroprotective agents in Parkinson’s disease,” American Journal of Translational Research, vol. 7, no. 7, pp. 1189– 1202, 2015.
86 Winter N., E. K. Ross, H. M. Wilkins et al., “An anthocyanin-enriched extract from strawberries delays disease onset and extends survival in the hSOD1G93A mouse model of amyotrophic lateral sclerosis,” Nutritional Neuroscience, vol. 9, pp. 1–13, 2017.
87 Wang M., Y. J. Li, Y. Ding(2016). “Silibinin prevents autophagic cell death upon oxidative stress in cortical neurons and cerebral ischemia-reperfusion injury,” Molecular Neurobiology, vol. 53, no. 2, pp. 932–943.
88 X. Zhang, L. Du, W. Zhang, Y. Yang, Q. Zhou, and G. Du (2017). “Therapeutic effects of baicalein on rotenone-induced Parkinson’s disease through protecting mitochondrial function and biogenesis,” Scientific Reports, vol. 7, no. 1, article 9968.
89 Y. Su, Q. Wang, C. Wang, K. Chan, Y. Sun, and H. Kuang (2014). “The treatment of Alzheimer’s disease using Chinese medicinal plants: from disease models to potential clinical applications,” Journal of Ethnopharmacology, vol. 152, no. 3, pp. 403–423.
90 Yamamoto N, Moon JH, Tsushida T et al (1999) Inhibitory effect of quercetin metabolites and their related derivatives on copper ion-induced lipid peroxidation in human low-density lipoprotein. Arch Biochem Biophys 372:347–354.
91 Youdim KA, Qaiser MZ, Begley DJ et al (2004) Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic Biol Med 36:592–604.
92 Youdim KA, Dobbie MS, Kuhnle G et al (2003) Interaction between flavonoids and the blood-brain barrier: in vitro studies. J Neurochem 85:180–192.
93 Youdim KA, Joseph JA (2001) A possible emerging role of phytochemicals in improving age-related neurological dysfunctions: multiplicity of effects. Free Radic Biol Med 30:583–594
94 Y. Li, J. Yao, C. Han (2016). “Quercetin, inflammation and immunity,” Nutrients, vol. 8, no. 3, p. 167.