Neurochemical Research

, Volume 36, Issue 10, pp 1776–1784 | Cite as

Hesperidin, a Flavone Glycoside, as Mediator of Neuronal Survival

  • Jader Nones
  • Tania Cristina Leite de Sampaio e Spohr
  • Flávia Carvalho Alcantara Gomes
Original Paper


Flavonoids comprise the most common group of plant polyphenols and provide much of the flavor and color to fruits and vegetables. More than 5,000 different flavonoids have been described. The biological activities of flavonoids cover a very broad spectrum, from anticancer and antibacterial activities to inhibition of bone reabsorption and neuroprotection effect. Although emerging evidence suggests that flavonoids have an important role on brain development, little is known about their mechanisms of action. In the present work, we performed a screening of flavonoid actions by analyzing the effects of these substances (hesperidin and rutin) on neural progenitors and neuronal morphogenesis in vitro. We demonstrated that treatment of neural progenitors with the flavonoid hesperidin enhanced neuronal population as revealed by an 80% increase in the number of β-tubulin III cells. This effect was mainly due to modulation of neuronal progenitor survival. Pools of astrocyte and oligodendrocyte progenitors were not affected by hesperidin whereas rutin had no effect on neuronal population. We also demonstrated that the flavonoid hesperidin modulates neuronal cell death by activating MAPK and PI3K pathways. This opens the possibility of using flavonoids for potential new therapeutic strategies for neurodegenerative diseases.


Flavonoids Neurons Survival PI3 and MAP kinase pathways 



We thank Adiel Batista do Nascimento, Marcelo Meloni and Severino Gomes for technical assistance. We are also indebted to David M. Kahn for the English revision of the manuscript. This study was supported by grants from the Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).


  1. 1.
    Beecher GR (2003) Overview of dietary flavonoids: nomenclature, occurrence and intake. J Nutr 133:3248–3254Google Scholar
  2. 2.
    Nones J, Stipursky J, Costa LC et al (2010) Flavonoids and astrocytes crosstalking: implications for brain development and pathology. Neurochem Res 35:955–966PubMedCrossRefGoogle Scholar
  3. 3.
    Rice-Evans CA, Miller NJ, Paganga G (1996) Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20:933–956PubMedCrossRefGoogle Scholar
  4. 4.
    Rice-Evans C (2001) Flavonoid antioxidants. Curr Med Chem 8:797–807PubMedGoogle Scholar
  5. 5.
    Gaur V, Kumar A (2010) Hesperidin pre-treatment attenuates NO-mediated cerebral ischemic reperfusion injury and memory dysfunction. Pharmacol Rep 62:635–648PubMedGoogle Scholar
  6. 6.
    Manach C, Mazur A, Scalbert A (2005) Polyphenols and prevention of cardiovascular diseases. Curr Opin Lipidol 16:77–84PubMedCrossRefGoogle Scholar
  7. 7.
    Amado NG, Cerqueira DM, Menezes FS (2009) Isoquercitrin isolated from hyptis fasciculata reduces glioblastoma cell proliferation and changes beta-catenin cellular localization. Anticancer Drugs 20:543–552PubMedCrossRefGoogle Scholar
  8. 8.
    Garg A, Garg S, Zaneveld LJD et al (2001) Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phytother Res 15:655–669PubMedCrossRefGoogle Scholar
  9. 9.
    Galleano M, Pechanova O, Fraga CG (2010) Hypertension, nitric oxide, oxidants, and dietary plant polyphenols. Curr Pharm Biotechnol 11:837–848PubMedCrossRefGoogle Scholar
  10. 10.
    Marder M, Viola H, Wasowski C et al (2003) 6-Methylapigenin and hesperidin: new valeriana flavonoids with activity on the CNS. Pharmacol Biochem Behav 75:537–745PubMedCrossRefGoogle Scholar
  11. 11.
    Costa BL, Fawcett R, Li GY et al (2008) Orally administered epigallocatechin gallate attenuates light-induced photoreceptor damage. Brain Res Bull 76:412–423PubMedCrossRefGoogle Scholar
  12. 12.
    Gottlieb M, Leal-Campanario R, Campos-Esparza MR et al (2006) Neuroprotection by two polyphenols following excitotoxicity and experimental ischemia. Neurobiol Dis 23:374–386PubMedCrossRefGoogle Scholar
  13. 13.
    Vauzour D, Vafeiadou K, Rice-Evans C et al (2007) Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons. J Neurochem 103:1355–1367PubMedCrossRefGoogle Scholar
  14. 14.
    Maher P (2008) Proteasome inhibitors prevent oxidative stress-induced nerve cell death by a novel mechanism. Biochem Pharmacol 75:1994–2006PubMedCrossRefGoogle Scholar
  15. 15.
    Mercer LD, Kelly BL, Horne MK et al (2005) Dietary polyphenols protect dopamine neurons from oxidative insults and apoptosis: investigations in primary rat mesencephalic cultures. Biochem Pharmacol 69:339–345PubMedCrossRefGoogle Scholar
  16. 16.
    Rainey-Smith S, Schroetke LW, Bahia P et al (2008) Neuroprotective effects of hesperetin in mouse primary neurones are independent of CREB activation. Neurosci Lett 438:29–33PubMedCrossRefGoogle Scholar
  17. 17.
    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 476:145–151PubMedCrossRefGoogle Scholar
  18. 18.
    Bastianetto S, Yao ZX, Papadopoulos V et al (2006) Neuroprotective effects of green and black teas and their catechin gallate esters against beta-amyloid-induced toxicity. Eur J Neurosci 23:55–64PubMedCrossRefGoogle Scholar
  19. 19.
    Obregon DF, Rezai-Zadeh K, Bai Y et al (2006) ADAM10 activation is required for green tea (-)-epigallocatechin-3-gallate-induced α-secretase cleavage of amyloid precursor protein. J Biol Chem 281:16419–16427PubMedCrossRefGoogle Scholar
  20. 20.
    Spohr TC, Stipursky J, Sasaki AC et al (2010) Effects of the flavonoid casticin from Brazilian Cróton betulaster in cerebral cortical progenitors in vitro: direct and indirect action through astrocytes. J Neurosci Res 15:530–541Google Scholar
  21. 21.
    Abou-Shoer M, Ma GE, Li XH et al (1993) Flavonoids from Koelreuteria henryi and other sources as protein-tyrosine kinase inhibitors. J Nat Prod 56:967–969PubMedCrossRefGoogle Scholar
  22. 22.
    Agullo G, Gamet-Payrastre L, Manenti S et al (1997) Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: a comparison with tyrosine kinase and protein kinase C inhibition. Biochem Pharmacol 53:1649–1657PubMedCrossRefGoogle Scholar
  23. 23.
    Hagiwara M, Inoue S, Tanaka T et al (1988) Differential effects of flavonoids as inhibitors of tyrosine protein kinases and serine/threonine protein kinases. Biochem Pharmacol 37:2987–2992PubMedCrossRefGoogle Scholar
  24. 24.
    Khan N, Afaq F, Saleem M et al (2006) Targeting multiple signaling pathways by green tea polyphenol (−)-epigallocatechin-3-gallate. Cancer Res 66:2500–25055PubMedCrossRefGoogle Scholar
  25. 25.
    Schroeter H, Boyd C, Spencer JP et al (2002) MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide. Neurobiol Aging 23:861–880PubMedCrossRefGoogle Scholar
  26. 26.
    Spencer JP (2008a) Flavonoids: modulators of brain function? Br J Nutr 99:60–77Google Scholar
  27. 27.
    Spencer JP (2008b) Food for thought: the role of dietary flavonoids in enhancing human memory, learning and neuro-cognitive performance. Proc Nutr Soc 67:238–252PubMedCrossRefGoogle Scholar
  28. 28.
    Almeida LMV, Pinheiro CC, Leite MC et al (2008) Protective effects of resveratrol. Toxicity in primary cortical astrocyte. Neurochem Res 33:8–15CrossRefGoogle Scholar
  29. 29.
    Lambert PJ, Shahrier AZ, Whitman AG et al (2007) Targeting the PI3K and MAPK pathways to treat Kaposi’s sarcoma-associated herpes virus infection and pathogenesis. Expert Opin Ther Targets 11:589–599PubMedCrossRefGoogle Scholar
  30. 30.
    Neuhaus T, Pabst S, Stier S et al (2004) Inhibition of the vascular-endothelial growth factor-induced intracellular signaling and mitogenesis of human endothelial cells by epigallocatechin-3 gallate. Eur J Pharmacol 483:223–227PubMedCrossRefGoogle Scholar
  31. 31.
    Sah JF, Balasubramanian S, Eckert RL et al (2004) Epigallocatechin-3-gallate inhibits epidermal growth factor receptor signaling pathway. Evidence for direct inhibition of ERK1/2 and AKT kinases. J Biol Chem 279:12755–12762PubMedCrossRefGoogle Scholar
  32. 32.
    Spencer JP, Rice-Evans C, Williams RJ (2003) Modulation of pro-survival Akt/protein kinase B and ERK1/2 signaling cascades by quercetin and its in vivo metabolites underlie their action on neuronal viability. J Biol Chem 278:34783–34793PubMedCrossRefGoogle Scholar
  33. 33.
    Silva AR, Pinheiro AM, Souza CS et al (2008) The flavonoid rutin induces astrocyte and microglia activation and regulates TNF-alpha and NO release in primary glial cell cultures. Cell Biol Toxicol 24:75–86PubMedCrossRefGoogle Scholar
  34. 34.
    Viola H, Marder M, Wasowski C et al (2000) 6, 3’-Dibromoflavone and 6-nitro-3’-bromoflavone: new additions to the 6, 3’-disubstituted flavone family of high-affinity ligands of the brain benzodiazepine binding site with agonistic properties. Biochem Biophys Res Commun 273:694–698PubMedCrossRefGoogle Scholar
  35. 35.
    Youdim KA, Dobbie MS, Kuhnle G et al (2003) Interaction between flavonoids and the blood-brain barrier: in vitro studies. J Neurochem 85:180–192PubMedCrossRefGoogle Scholar
  36. 36.
    Ishige K, Noguchi T (2000) Inorganic polyphosphate kinase and adenylate kinase participate in the polyphosphate:AMP phosphotransferase activity of Escherichia coli. Proc Natl Acad Sci USA 97:14168–14171PubMedCrossRefGoogle Scholar
  37. 37.
    Li M, Wang L, Peng Y et al (2010) Knockdown of the neuronal nitric oxide synthase gene retard the development of the cerebellar granule neurons in vitro. Dev Dyn 39:474–481CrossRefGoogle Scholar
  38. 38.
    Peña-Altamira E, Petazzi P, Contestabile A (2010) Nitric oxide control of proliferation in nerve cells and in tumor cells of nervous origin. Curr Pharm Des 16:440–450PubMedCrossRefGoogle Scholar
  39. 39.
    Marder M, Paladini AC (2002) GABA(A)-receptor ligands of flavonoid structure. Curr Top Med Chem 8:853–867CrossRefGoogle Scholar
  40. 40.
    Lau FC, Shukitt-Hale B, Joseph JA (2005) The beneficial effects of fruit polyphenols on brain aging. Neurobiol Aging 1:128–132CrossRefGoogle Scholar
  41. 41.
    Bodesheim U, Hölzl J (1997) Isolation and receptor binding properties of alkaloids and lignans from Valeriana officialis L. Pharmazie 52:386–391PubMedGoogle Scholar
  42. 42.
    Martínez MC, Fernandez SP, Loscalzo LM et al (2009) Hesperidin, a flavonoid glycoside with sedative effect, decreases brain pERK1/2 levels in mice. Pharmacol Biochem Behav 92:291–296PubMedCrossRefGoogle Scholar
  43. 43.
    Vaudry D, Stork PJ, Lazarovici P et al (2002) Signaling pathways for PC12 cell differentiation: making the right connections. Science 296:1648–1649PubMedCrossRefGoogle Scholar
  44. 44.
    Chen C, Yu R, Owuor ED et al (2000) Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death. Arch Pharm Res 6:605–612CrossRefGoogle Scholar
  45. 45.
    Owuor ED, Kong AN (2002) Antioxidants and oxidants regulated signal transduction pathways. Biochem Pharmacol 64:765–770PubMedCrossRefGoogle Scholar
  46. 46.
    Satoh T, Nakatsuka D, Watanabe Y et al (2000) Neuroprotection by MAPK/ERK kinase inhibition with U0126 against oxidative stress in a mouse neuronal cell line and rat primary cultured cortical neurons. Neurosci Lett 288:163–166PubMedCrossRefGoogle Scholar
  47. 47.
    Levites Y, Weinreb O, Maor GJ et al (2001) Green tea polyphenol (-)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced dopaminergic neurodegeneration. Neurochem 78:1073–1082CrossRefGoogle Scholar
  48. 48.
    Levites Y, Amit T, Youdim MB et al (2002) Involvement of protein kinase C activation and cell survival/cell cycle genes in green tea polyphenol (-)-epigallocatechin 3-gallate neuroprotective action. J Biol Chem 277:30574–30580PubMedCrossRefGoogle Scholar
  49. 49.
    Weinreb O, Mandel S, Amit T et al (2004) Neurological mechanisms of green tea polyphenols in Alzheimer’s and Parkinson’s diseases. J Nutr Biochem 15:506–516PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Jader Nones
    • 1
  • Tania Cristina Leite de Sampaio e Spohr
    • 1
  • Flávia Carvalho Alcantara Gomes
    • 1
  1. 1.Laboratório de Neurobiologia Celular, Instituto de Ciências BiomédicasUniversidade Federal do Rio de Janeiro, Centro de Ciências da SaúdeRio de JaneiroBrazil

Personalised recommendations