Skip to main content
    • Aa
    • Aa

Flavonoids: modulators of brain function?

  • Jeremy P. E. Spencer (a1)

Emerging evidence suggests that dietary phytochemicals, in particular flavonoids, may exert beneficial effects on the central nervous system by protecting neurons against stress-induced injury, by suppressing neuroinflammation and by improving cognitive function. It is likely that flavonoids exert such effects, through selective actions on different components of a number of protein kinase and lipid kinase signalling cascades, such as the phosphatidylinositol-3 kinase (PI3K)/Akt, protein kinase C and mitogen-activated protein kinase (MAPK) pathways. This review explores the potential inhibitory or stimulatory actions of flavonoids within these pathways, and describes how such interactions are likely to underlie neurological effects through their ability to affect the activation state of target molecules and/or by modulating gene expression. Future research directions are outlined in relation to the precise site(s) of action of flavonoids within signalling pathways and the sequence of events that allow them to regulate neuronal function.

  • View HTML
    • Send article to Kindle

      To send this article to your Kindle, first ensure is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle.

      Note you can select to send to either the or variations. ‘’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Flavonoids: modulators of brain function?
      Available formats
      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Dropbox account. Find out more about sending content to Dropbox.

      Flavonoids: modulators of brain function?
      Available formats
      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your Google Drive account. Find out more about sending content to Google Drive.

      Flavonoids: modulators of brain function?
      Available formats
Corresponding author
*Corresponding author: Dr J. P. E. Spencer, fax +44 118 931 0080, email
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

1KA Youdim & JA Joseph (2001) A possible emerging role of phytochemicals in improving age-related neurological dysfunctions: a multiplicity of effects. Free Radic Biol Med 30, 583594.

2KA Youdim , JP Spencer , H Schroeter & C Rice-Evans (2002) Dietary flavonoids as potential neuroprotectants. Biol Chem 383, 503519.

3RL Galli , B Shukitt-Hale , KA Youdim & JA Joseph (2002) Fruit polyphenolics and brain aging: nutritional interventions targeting age-related neuronal and behavioral deficits. Ann N Y Acad Sci 959, 128132.

4K Unno , F Takabayashi , T Kishido & N Oku (2004) Suppressive effect of green tea catechins on morphologic and functional regression of the brain in aged mice with accelerated senescence (SAMP10). Exp Gerontol 39, 10271034.

7Y Wang , L Wang , J Wu & J Cai (2006) The in vivo synaptic plasticity mechanism of EGb 761-induced enhancement of spatial learning and memory in aged rats. Br J Pharmacol 148, 147153.

8O Inanami , Y Watanabe , B Syuto , M Nakano , M Tsuji & M Kuwabara (1998) Oral administration of ( − )catechin protects against ischemia-reperfusion-induced neuronal death in the gerbil. Free Radic Res 29, 359365.

9Y Luo , JV Smith , V Paramasivam , A Burdick , KJ Curry , JP Buford , I Khan , WJ Netzer , H Xu & P Butko (2002) Inhibition of amyloid-beta aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761. Proc Natl Acad Sci U S A 99, 1219712202.

10S Bastianetto , WH Zheng & R Quirion (2000) The Ginkgo biloba extract (EGb 761) protects and rescues hippocampal cells against nitric oxide-induced toxicity: involvement of its flavonoid constituents and protein kinase C. J Neurochem 74, 22682277.

12KP Datla , M Christidou , WW Widmer , HK Rooprai & DT Dexter (2001) Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of Parkinson's disease. Neuroreport 12, 38713875.

13CA Rice-Evans , NJ Miller & G Paganga (1996) Structure–antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20, 933956.

14RJ Williams , JPE Spencer & C Rice-Evans (2004) Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med 36, 838849.

15JPE Spencer , C Rice-Evans & RJ Williams (2003) Modulation of pro-survival Akt/PKB and ERK1/2 signalling cascades by quercetin and its in vivo metabolites underlie their action on neuronal viability. J Biol Chem 278, 3478334793.

16H Schroeter , C Boyd , JPE Spencer , RJ Williams , E Cadenas & C Rice-Evans (2002) MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide. Neurobiol Aging 23, 861880.

18C Rice-Evans (2001) Flavonoid antioxidants. Curr Med Chem 8, 797807.

19C Rice-Evans (1995) Plant polyphenols: free radical scavengers or chain-breaking antioxidants? Biochem Soc Symp 61, 103116.

20JPE Spencer , H Schroeter , AR Rechner & C Rice-Evans (2001) Bioavailability of flavan-3-ols and procyanidins: gastrointestinal tract influences and their relevance to bioactive forms in vivo. Antioxid Redox Signal 3, 10231039.

25JPE Spencer , G Chowrimootoo , R Choudhury , ES Debnam , SK Srai & C Rice-Evans (1999) The small intestine can both absorb and glucuronidate luminal flavonoids. FEBS Lett 458, 224230.

27JPE Spencer , GG Kuhnle , RJ Williams & C Rice-Evans (2003) Intracellular metabolism and bioactivity of quercetin and its in vivo metabolites. Biochem J 372, 173181.

28JPE Spencer , H Schroeter , AJ Crossthwaithe , G Kuhnle , RJ Williams & C Rice-Evans (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, 11391146.

29Y Miyake , K Shimoi , S Kumazawa , K Yamamoto , N Kinae & T Osawa (2000) Identification and antioxidant activity of flavonoid metabolites in plasma and urine of eriocitrin-treated rats. J Agric Food Chem 48, 32173224.

30J Terao , S Yamaguchi , M Shirai , M Miyoshi , JH Moon , S Oshima , T Inakuma , T Tsushida & Y Kato (2001) Protection by quercetin and quercetin 3-O-beta-d-glucuronide of peroxynitrite-induced antioxidant consumption in human plasma low-density lipoprotein. Free Radic Res 35, 925931.

31M Shirai , JH Moon , T Tsushida & J Terao (2001) Inhibitory effect of a quercetin metabolite, quercetin 3-O-beta-d-glucuronide, on lipid peroxidation in liposomal membranes. J Agric Food Chem 49, 56025608.

32N Yamamoto , JH Moon , T Tsushida , A Nagao & J Terao (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, 347354.

33EL da Silva , MK Piskula , N Yamamoto , JH Moon & J Terao (1998) Quercetin metabolites inhibit copper ion-induced lipid peroxidation in rat plasma. FEBS Lett 430, 405408.

34NJ Abbott (2002) Astrocyte–endothelial interactions and blood–brain barrier permeability. J Anat 200, 629638.

35KA Youdim , MS Dobbie , G Kuhnle , AR Proteggente , NJ Abbott & C Rice-Evans (2003) Interaction between flavonoids and the blood–brain barrier: in vitro studies. J Neurochem 85, 180192.

36KA Youdim , B Shukitt-Hale & JA Joseph (2004) Flavonoids and the brain: interactions at the blood–brain barrier and their physiological effects on the central nervous system. Free Radic Biol Med 37, 16831693.

37KA Youdim , MZ Qaiser , DJ Begley , CA Rice-Evans & NJ Abbott (2004) Flavonoid permeability across an in situ model of the blood–brain barrier. Free Radic Biol Med 36, 592604.

39B Sperker , JT Backman & HK Kroemer (1997) The role of beta-glucuronidase in drug disposition and drug targeting in humans. Clin Pharmacokinet 33, 1831.

40HK Kroemer & U Klotz (1992) Glucuronidation of drugs. A re-evaluation of the pharmacological significance of the conjugates and modulating factors. Clin Pharmacokinet 23, 292310.

41JH Lin & M Yamazaki (2003) Role of P-glycoprotein in pharmacokinetics: clinical implications. Clin Pharmacokinet 42, 5998.

42M Suganuma , S Okabe , M Oniyama , Y Tada , H Ito & H Fujiki (1998) Wide distribution of [3H]( − )-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue. Carcinogenesis 19, 17711776.

43MM Abd El Mohsen , G Kuhnle , AR Rechner , H Schroeter , S Rose , P Jenner & CA Rice-Evans (2002) Uptake and metabolism of epicatechin and its access to the brain after oral ingestion. Free Radic Biol Med 33, 16931702.

44S Talavera , C Felgines , O Texier , C Besson , A Gil-Izquierdo , JL Lamaison & C Remesy (2005) Anthocyanin metabolism in rats and their distribution to digestive area, kidney, and brain. J Agric Food Chem 53, 39023908.

46C Andres-Lacueva , B Shukitt-Hale , RL Galli , O Jauregui , RM Lamuela-Raventos & JA Joseph (2005) Anthocyanins in aged blueberry-fed rats are found centrally and may enhance memory. Nutr Neurosci 8, 111120.

47B Halliwell , K Zhao & M Whiteman (2000) The gastrointestinal tract: a major site of antioxidant action? Free Radic Res 33, 819830.

50G Casadesus , B Shukitt-Hale , HM Stellwagen , X Zhu , HG Lee , MA Smith & JA Joseph (2004) Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats. Nutr Neurosci 7, 309316.

51B Shukitt-Hale , DE Smith , M Meydani & JA Joseph (1999) The effects of dietary antioxidants on psychomotor performance in aged mice. Exp Gerontol 34, 797808.

53P Goyarzu , DH Malin , FC Lau , (2004) Blueberry supplemented diet: effects on object recognition memory and nuclear factor-kappa B levels in aged rats. Nutr Neurosci 7, 7583.

54JA Joseph , NA Denisova , G Arendash , M Gordon , D Diamond , B Shukitt-Hale & D Morgan (2003) Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr Neurosci 6, 153162.

55MR Ramirez , I Izquierdo , RM do Carmo Bassols , JA Zuanazzi , D Barros & AT Henriques (2005) Effect of lyophilised Vaccinium berries on memory, anxiety and locomotion in adult rats. Pharmacol Res 52, 457462.

56H Schroeter , C Heiss , J Balzer , P Kleinbongard , CL Keen , NK Hollenberg , H Sies , C Kwik-Uribe , HH Schmitz & M Kelm (2006) ( − )-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci U S A 103, 10241029.

57ST Francis , K Head , PG Morris & IA Macdonald (2006) The effect of flavanol-rich cocoa on the fMRI response to a cognitive task in healthy young people. J Cardiovasc Pharmacol 47, Suppl. 2, S215S220.

58ND Fisher , FA Sorond & NK Hollenberg (2006) Cocoa flavanols and brain perfusion. J Cardiovasc Pharmacol 47, Suppl. 2, S210S214.

59FH Gage (2000) Mammalian neural stem cells. Science 287, 14331438.

60TD Palmer , AR Willhoite & FH Gage (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425, 479494.

61KM Harris & SB Kater (1994) Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Annu Rev Neurosci 17, 341371.

62TJ Carew (1996) Molecular enhancement of memory formation. Neuron 16, 58.

63KC Martin , M Barad & ER Kandel (2000) Local protein synthesis and its role in synapse-specific plasticity. Curr Opin Neurobiol 10, 587592.

64RJ Kelleher III, A Govindarajan & S Tonegawa (2004) Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron 44, 5973.

65S Impey , SR McCorkle , H Cha-Molstad , JM Dwyer , GS Yochum , JM Boss , S McWeeney , JJ Dunn , G Mandel & RH Goodman (2004) Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119, 10411054.

66A Barco , CH Bailey & ER Kandel (2006) Common molecular mechanisms in explicit and implicit memory. J Neurochem 97, 15201533.

67R Bourtchuladze , B Frenguelli , J Blendy , D Cioffi , G Schutz & AJ Silva (1994) Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 79, 5968.

68T Tully , R Bourtchouladze , R Scott & J Tallman (2003) Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov 2, 267277.

69TA Pham , S Impey , DR Storm & MP Stryker (1999) CRE-mediated gene transcription in neocortical neuronal plasticity during the developmental critical period. Neuron 22, 6372.

70S Impey , DM Smith , K Obrietan , R Donahue , C Wade & DR Storm (1998) Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat Neurosci 1, 595601.

71S Impey , M Mark , EC Villacres , S Poser , C Chavkin & DR Storm (1996) Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron 16, 973982.

72H Schroeter , JP Spencer , C Rice-Evans & RJ Williams (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, 547557.

73H Schroeter , P Bahia , JPE Spencer , O Sheppard , M Rattray , C Rice-Evans & RJ Williams (2007) ( − )-Epicatechin stimulates ERK-dependent cyclic AMP response element activity and upregulates GLUR2 in cortical neurons J Neurochem 101, 15961606..

74P Maher , T Akaishi & K Abe (2006) Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci U S A 103, 1656816573.

75MD Conkright , E Guzman , L Flechner , AI Su , JB Hogenesch & M Montminy (2003) Genome-wide analysis of CREB target genes reveals a core promoter requirement for cAMP responsiveness. Mol Cell 11, 11011108.

76X Tao , S Finkbeiner , DB Arnold , AJ Shaywitz & ME Greenberg (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20, 709726.

77PB Shieh , SC Hu , K Bobb , T Timmusk & A Ghosh (1998) Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron 20, 727740.

78CR Bramham & E Messaoudi (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol 76, 99125.

79SL Patterson , LM Grover , PA Schwartzkroin & M Bothwell (1992) Neurotrophin expression in rat hippocampal slices: a stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs. Neuron 9, 10811088.

80K Thomas & A Davies (2005) Neurotrophins: a ticket to ride for BDNF. Curr Biol 15, R262R264.

81S Peng , J Wuu , EJ Mufson & M Fahnestock (2005) Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease. J Neurochem 93, 14121421.

82B Michalski & M Fahnestock (2003) Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer's disease. Brain Res Mol Brain Res 111, 148154.

83MF Egan , M Kojima , JH Callicott , (2003) The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257269.

84S Linnarsson , A Bjorklund & P Ernfors (1997) Learning deficit in BDNF mutant mice. Eur J Neurosci 9, 25812587.

85JS Mu , WP Li , ZB Yao & XF Zhou (1999) Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats. Brain Res 835, 259265.

86L Minichiello , M Korte , D Wolfer , R Kuhn , K Unsicker , V Cestari , C Rossi-Arnaud , HP Lipp , T Bonhoeffer & R Klein (1999) Essential role for TrkB receptors in hippocampus-mediated learning. Neuron 24, 401414.

87S Wullschleger , R Loewith & MN Hall (2006) TOR signaling in growth and metabolism. Cell 124, 471484.

88GM Schratt , EA Nigh , WG Chen , L Hu & ME Greenberg (2004) BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci 24, 73667377.

89Y Yin , GM Edelman & PW Vanderklish (2002) The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc Natl Acad Sci U S A 99, 23682373.

91J Soule , E Messaoudi & CR Bramham (2006) Brain-derived neurotrophic factor and control of synaptic consolidation in the adult brain. Biochem Soc Trans 34, 600604.

92GL Lyford , K Yamagata , WE Kaufmann , CA Barnes , LK Sanders , NG Copeland , DJ Gilbert , NA Jenkins , AA Lanahan & PF Worley (1995) Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14, 433445.

94EC Hirsch , S Hunot & A Hartmann (2005) Neuroinflammatory processes in Parkinson's disease. Parkinsonism Relat Disord 11, Suppl. 1, S9S15.

95EG McGeer & PL McGeer (2003) Inflammatory processes in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 27, 741749.

96Z Zheng , JE Lee & MA Yenari (2003) Stroke: molecular mechanisms and potential targets for treatment. Curr Mol Med 3, 361372.

97D Casper , U Yaparpalvi , N Rempel & P Werner (2000) Ibuprofen protects dopaminergic neurons against glutamate toxicity in vitro. Neurosci Lett 289, 201204.

98H Chen , SM Zhang , MA Hernan , MA Schwarzschild , WC Willett , GA Colditz , FE Speizer & A Ascherio (2003) Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease. Arch Neurol 60, 10591064.

99EG McGeer & PL McGeer (1997) The role of the immune system in neurodegenerative disorders. Mov Disord 12, 855858.

100M Vila , V Jackson-Lewis , C Guegan , DC Wu , P Teismann , DK Choi , K Tieu & S Przedborski (2001) The role of glial cells in Parkinson's disease. Curr Opin Neurol 14, 483489.

101YS Kim & TH Joh (2006) Microglia, major player in the brain inflammation: their roles in the pathogenesis of Parkinson's disease. Exp Mol Med 38, 333347.

102SM Allan & NJ Rothwell (2003) Inflammation in central nervous system injury. Philos Trans R Soc Lond B Biol Sci 358, 16691677.

103VC Stewart & SJ Heales (2003) Nitric oxide-induced mitochondrial dysfunction: implications for neurodegeneration. Free Radic Biol Med 34, 287303.

104S Moncada & JP Bolanos (2006) Nitric oxide, cell bioenergetics and neurodegeneration. J Neurochem 97, 16761689.

105N Kozuka , R Itofusa , Y Kudo & M Morita (2005) Lipopolysaccharide and proinflammatory cytokines require different astrocyte states to induce nitric oxide production. J Neurosci Res 82, 717728.

106A Bal-Price , A Matthias & GC Brown (2002) Stimulation of the NADPH oxidase in activated rat microglia removes nitric oxide but induces peroxynitrite production. J Neurochem 80, 7380.

107BL Fiebich , K Lieb , S Engels & M Heinrich (2002) Inhibition of LPS-induced p42/44 MAP kinase activation and iNOS/NO synthesis by parthenolide in rat primary microglial cells. J Neuroimmunol 132, 1824.

109JS Marcus , SL Karackattu , MA Fleegal & C Sumners (2003) Cytokine-stimulated inducible nitric oxide synthase expression in astroglia: role of Erk mitogen-activated protein kinase and NF-kappaB. Glia 41, 152160.

110S Pawate & NR Bhat (2006) C-Jun N-terminal kinase (JNK) regulation of iNOS expression in glial cells: predominant role of JNK1 isoform. Antioxid Redox Signal 8, 903909.

111R Li , YG Huang , D Fang & WD Le (2004) ( − )-Epigallocatechin gallate inhibits lipopolysaccharide-induced microglial activation and protects against inflammation-mediated dopaminergic neuronal injury. J Neurosci Res 78, 723731.

112Q Huang , LJ Wu , S Tashiro , HY Gao , S Onodera & T Ikejima (2005) (+)-Catechin, an ingredient of green tea, protects murine microglia from oxidative stress-induced DNA damage and cell cycle arrest. J Pharmacol Sci 98, 1624.

114SC Shen , WR Lee , HY Lin , HC Huang , CH Ko , LL Yang & YC Chen (2002) In vitro and in vivo inhibitory activities of rutin, wogonin, and quercetin on lipopolysaccharide-induced nitric oxide and prostaglandin E(2) production. Eur J Pharmacol 446, 187194.

115KJ Woo , JH Lim , SI Suh , YK Kwon , SW Shin , SC Kim , YH Choi , JW Park & TK Kwon (2006) Differential inhibitory effects of baicalein and baicalin on LPS-induced cyclooxygenase-2 expression through inhibition of C/EBPbeta DNA-binding activity. Immunobiology 211, 359368.

116H Kim , YS Kim , SY Kim & K Suk (2001) The plant flavonoid wogonin suppresses death of activated C6 rat glial cells by inhibiting nitric oxide production. Neurosci Lett 309, 6771.

117CJ Chen , SL Raung , SL Liao & SY Chen (2004) Inhibition of inducible nitric oxide synthase expression by baicalein in endotoxin/cytokine-stimulated microglia. Biochem Pharmacol 67, 957965.

118JC Chen , FM Ho , LC Pei-Dawn , CP Chen , KC Jeng , HB Hsu , ST Lee , TW Wen & WW Lin (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, 920.

119WF Matter , RF Brown & CJ Vlahos (1992) The inhibition of phosphatidylinositol 3-kinase by quercetin and analogs. Biochem Biophys Res Commun 186, 624631.

121G Agullo , L Gamet-Payrastre , S Manenti , C Viala , C Remesy , H Chap & B Payrastre (1997) Relationship between flavonoid structure and inhibition of phosphatidylinositol 3-kinase: a comparison with tyrosine kinase and protein kinase C inhibition. Biochem Pharmacol 53, 16491657.

122L Gamet-Payrastre , S Manenti , MP Gratacap , J Tulliez , H Chap & B Payrastre (1999) Flavonoids and the inhibition of PKC and PI 3-kinase. Gen Pharmacol 32, 279286.

123AN Kong , R Yu , C Chen , S Mandlekar & T Primiano (2000) Signal transduction events elicited by natural products: role of MAPK and caspase pathways in homeostatic response and induction of apoptosis. Arch Pharm Res 23, 116.

124CH Lin , SH Yeh , CH Lin , KT Lu , TH Leu , WC Chang & PW Gean (2001) A role for the PI-3 kinase signaling pathway in fear conditioning and synaptic plasticity in the amygdala. Neuron 31, 841851.

125JD Sweatt (2001) Memory mechanisms: the yin and yang of protein phosphorylation. Curr Biol 11, R391R394.

126G Conseil , H Baubichon-Cortay , G Dayan , JM Jault , D Barron & A Di Pietro (1998) Flavonoids: a class of modulators with bifunctional interactions at vicinal ATP- and steroid-binding sites on mouse P-glycoprotein. Proc Natl Acad Sci U S A 95, 98319836.

127A Di Pietro , C Godinot , ML Bouillant & DC Gautheron (1975) Pig heart mitochondrial ATPase: properties of purified and membrane-bound enzyme. Effects of flavonoids. Biochimie 57, 959967.

128A Barzilai & H Rahamimoff (1983) Inhibition of Ca2+-transport ATPase from synaptosomal vesicles by flavonoids. Biochim Biophys Acta 730, 245254.

129MP Revuelta , B Cantabrana & A Hidalgo (1997) Depolarization-dependent effect of flavonoids in rat uterine smooth muscle contraction elicited by CaCl2. Gen Pharmacol 29, 847857.

130SF Lee & JK Lin (1997) Inhibitory effects of phytopolyphenols on TPA-induced transformation, PKC activation, and c-jun expression in mouse fibroblast cells. Nutr Cancer 28, 177183.

131F Ursini , M Maiorino , P Morazzoni , A Roveri & G Pifferi (1994) A novel antioxidant flavonoid (IdB 1031) affecting molecular mechanisms of cellular activation. Free Radic Biol Med 16, 547553.

132S Kantengwa & BS Polla (1991) Flavonoids, but not protein kinase C inhibitors, prevent stress protein synthesis during erythrophagocytosis. Biochem Biophys Res Commun 180, 308314.

133M Rosenblat , P Belinky , J Vaya , R Levy , T Hayek , R Coleman , S Merchav & M Aviram (1999) Macrophage enrichment with the isoflavan glabridin inhibits NADPH oxidase-induced cell-mediated oxidation of low density lipoprotein. A possible role for protein kinase C. J Biol Chem 274, 1379013799.

135JH Medina , H Viola , C Wolfman , M Marder , C Wasowski , D Calvo & AC Paladini (1997) Overview—flavonoids: a new family of benzodiazepine receptor ligands. Neurochem Res 22, 419425.

136K Dekermendjian , P Kahnberg , MR Witt , O Sterner , M Nielsen & T Liljefors (1999) Structure–activity relationships and molecular modeling analysis of flavonoids binding to the benzodiazepine site of the rat brain GABA(A) receptor complex. J Med Chem 42, 43434350.

137PM Fischer & DP Lane (2000) Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics. Curr Med Chem 7, 12131245.

138YT Huang , JJ Hwang , PP Lee , FC Ke , JH Huang , CJ Huang , C Kandaswami , E Middleton Jr & MT Lee (1999) Effects of luteolin and quercetin, inhibitors of tyrosine kinase, on cell growth and metastasis-associated properties in A431 cells overexpressing epidermal growth factor receptor. Br J Pharmacol 128, 9991010.

139FV So , N Guthrie , AF Chambers , M Moussa & KK Carroll (1996) Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices. Nutr Cancer 26, 167181.

140DR Green & JC Reed (1998) Mitochondria and apoptosis. Science 281, 13091312.

141WG Tatton & CW Olanow (1999) Apoptosis in neurodegenerative diseases: the role of mitochondria. Biochim Biophys Acta 1410, 195213.

142L Goyal (2001) Cell death inhibition: keeping caspases in check. Cell 104, 805808.

143SM Srinivasula , R Hegde , A Saleh , (2001) A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis. Nature 410, 112116.

144MH Cobb & EJ Goldsmith (1995) How MAP kinases are regulated. J Biol Chem 270, 1484314846.

145EJ Goldsmith & MH Cobb (1994) Protein kinases. Curr Opin Struct Biol 4, 833840.

146CJ Marshall (1994) Signal transduction. Hot lips and phosphorylation of protein kinases. Nature 367, 686.

147M Karin (1995) The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 270, 1648316486.

148Z Xia , M Dickens , J Raingeaud , RJ Davis & ME Greenberg (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270, 13261331.

150A Bonni , A Brunet , AE West , SR Datta , MA Takasu & ME Greenberg (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 13581362.

151DR Kaplan & FD Miller (2000) Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol 10, 381391.

152AJ Crossthwaite , S Hasan & RJ Williams (2002) Hydrogen peroxide-mediated phosphorylation of ERK1/2, Akt/PKB and JNK in cortical neurones: dependence on Ca(2+) and PI3-kinase. J Neurochem 80, 2435.

153K Mielke & T Herdegen (2000) JNK and p38 stresskinases—degenerative effectors of signal-transduction-cascades in the nervous system. Prog Neurobiol 61, 4560.

154J Yuan & BA Yankner (2000) Apoptosis in the nervous system. Nature 407, 802809.

156RJ Davis (2000) Signal transduction by the JNK group of MAP kinases. Cell 103, 239252.

158T Herdegen , P Skene & M Bahr (1997) The c-Jun transcription factor—bipotential mediator of neuronal death, survival and regeneration. Trends Neurosci 20, 227231.

159V Castagne & PG Clarke (1999) Inhibitors of mitogen-activated protein kinases protect axotomized developing neurons. Brain Res 842, 215219.

160V Castagne , M Gautschi , K Lefevre , A Posada & PG Clarke (1999) Relationships between neuronal death and the cellular redox status. Focus on the developing nervous system. Prog Neurobiol 59, 397423.

161SP Hung , JR Hsu , CP Lo , HJ Huang , JP Wang & ST Chen (2005) Genistein-induced neuronal differentiation is associated with activation of extracellular signal-regulated kinases and upregulation of p21 and N-cadherin. J Cell Biochem 96, 10611070.

162F Llorens , L Garcia , E Itarte & N Gomez (2002) Apigenin and LY294002 prolong EGF-stimulated ERK1/2 activation in PC12 cells but are unable to induce full differentiation. FEBS Lett 510, 149153.

163DT Dudley , L Pang , SJ Decker , AJ Bridges & AR Saltiel (1995) A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A 92, 76867689.

164L Pang , T Sawada , SJ Decker & AR Saltiel (1995) Inhibition of MAP kinase kinase blocks the differentiation of PC-12 cells induced by nerve growth factor. J Biol Chem 270, 1358513588.

166DF Lazar , RJ Wiese , MJ Brady , CC Mastick , SB Waters , K Yamauchi , JE Pessin , P Cuatrecasas & AR Saltiel (1995) Mitogen-activated protein kinase kinase inhibition does not block the stimulation of glucose utilization by insulin. J Biol Chem 270, 2080120807.

167Y Levites , T Amit , MB Youdim & S Mandel (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, 3057430580.

168L Reznichenko , T Amit , MB Youdim & S Mandel (2005) Green tea polyphenol ( − )-epigallocatechin-3-gallate induces neurorescue of long-term serum-deprived PC12 cells and promotes neurite outgrowth. J Neurochem 93, 11571167.

169EH Walker , ME Pacold , O Perisic , L Stephens , PT Hawkins , MP Wymann & RL Williams (2000) Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Mol Cell 6, 909919.

171KA Jacobson , S Moro , JA Manthey , PL West & XD Ji (2002) Interactions of flavones and other phytochemicals with adenosine receptors. Adv Exp Med Biol 505, 163171.

172GA Johnston (2005) GABA(A) receptor channel pharmacology. Curr Pharm Des 11, 18671885.

173N Adachi , S Tomonaga , T Tachibana , DM Denbow & M Furuse (2006) ( − )-Epigallocatechin gallate attenuates acute stress responses through GABAergic system in the brain. Eur J Pharmacol 531, 171175.

174YS Han , S Bastianetto , Y Dumont & R Quirion (2006) Specific plasma membrane binding sites for polyphenols, including resveratrol, in the rat brain. J Pharmacol Exp Ther 318, 238245.

175AP Nifli , A Bosson-Kouame , N Papadopoulou , C Kogia , M Kampa , C Castagnino , C Stournaras , J Vercauteren & E Castanas (2005) Monomeric and oligomeric flavanols are agonists of membrane androgen receptors. Exp Cell Res 309, 329339.

176CM Klinge , KA Blankenship , KE Risinger , S Bhatnagar , EL Noisin , WK Sumanasekera , L Zhao , DM Brey & RS Keynton (2005) Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells. J Biol Chem 280, 74607468.

178Y Kim , AE Rice & JM Denu (2003) Intramolecular dephosphorylation of ERK by MKP3. Biochemistry 42, 1519715207.

180S Leppa & D Bohmann (1999) Diverse functions of JNK signaling and c-Jun in stress response and apoptosis. Oncogene 18, 61586162.

181H Ichijo (1999) From receptors to stress-activated MAP kinases. In Oncogene 18, pp. 60876093.

182H Ichijo , E Nishida , K Irie , P ten Dijke , M Saitoh , T Moriguchi , M Takagi , K Matsumoto , K Miyazono & Y Gotoh (1997) Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275, 9094.

184A Matsuzawa & H Ichijo (2001) Molecular mechanisms of the decision between life and death: regulation of apoptosis by apoptosis signal-regulating kinase 1. J Biochem (Tokyo) 130, 18.

185H Schroeter , RJ Williams , R Matin , L Iversen & CA Rice-Evans (2000) Phenolic antioxidants attenuate neuronal cell death following uptake of oxidized low-density lipoprotein. Free Radic Biol Med 29, 12221233.

186JPE Spencer , H Schroeter , G Kuhnle , SK Srai , RM Tyrrell , U Hahn & C Rice-Evans (2001) Epicatechin and its in vivo metabolite, 3′-O-methyl epicatechin, protect human fibroblasts from oxidative-stress-induced cell death involving caspase-3 activation. Biochem J 354, 493500.

187L Wang , K Matsushita , I Araki & M Takeda (2002) Inhibition of c-Jun N-terminal kinase ameliorates apoptosis induced by hydrogen peroxide in the kidney tubule epithelial cells (NRK-52E). Nephron 91, 142147.

188Y Ishikawa & M Kitamura (2000) Anti-apoptotic effect of quercetin: intervention in the JNK- and ERK-mediated apoptotic pathways. Kidney Int 58, 10781087.

189K Uchida , M Shiraishi , Y Naito , Y Torii , Y Nakamura & T Osawa (1999) Activation of stress signaling pathways by the end product of lipid peroxidation. 4-Hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J Biol Chem 274, 22342242.

190L Zhang , J Chen & H Fu (1999) Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14-3-3 proteins. Proc Natl Acad Sci U S A 96, 85118515.

191HS Park , E Park , MS Kim , K Ahn , IY Kim & EJ Choi (2000) Selenite inhibits the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) through a thiol redox mechanism. J Biol Chem 275, 25272531.

192V Adler , Z Yin , SY Fuchs , (1999) Regulation of JNK signaling by GSTp. EMBO J 18, 13211334.

193V Adler , Z Yin , KD Tew & Z Ronai (1999) Role of redox potential and reactive oxygen species in stress signaling. Oncogene 18, 61046111.

194R Monaco , FK Friedman , MJ Hyde , JM Chen , S Manolatus , V Adler , Z Ronai , W Koslosky & MR Pincus (1999) Identification of a glutathione-S-transferase effector domain for inhibition of jun kinase, by molecular dynamics. J Protein Chem 18, 859866.

196JPE Spencer , El Abd , MM Mohsen & C Rice-Evans (2003) Cellular uptake and metabolism of flavonoids and their metabolites: implications for their bioactivity. Arch Biochem Biophys 423, 148161.

197SG Kennedy , AJ Wagner , SD Conzen , J Jordan , A Bellacosa , PN Tsichlis & N Hay (1997) The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev 11, 701713.

198PJ Coffer , J Jin & JR Woodgett (1998) Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J 335, [Pt 1], 113.

199FD Miller & DR Kaplan (2001) Neurotrophin signalling pathways regulating neuronal apoptosis. Cell Mol Life Sci 58, 10451053.

201CL Carpenter & LC Cantley (1990) Phosphoinositide kinases. Biochemistry 29, 1114711156.

202L Simpson & R Parsons (2001) PTEN: life as a tumor suppressor. Exp Cell Res 264, 2941.

203LM Neri , P Borgatti , S Capitani & AM Martelli (2002) The nuclear phosphoinositide 3-kinase/AKT pathway: a new second messenger system. Biochim Biophys Acta 1584, 7380.

204TF Franke , DR Kaplan & LC Cantley (1997) PI3K: downstream AKTion blocks apoptosis. Cell 88, 435437.

205BM Burgering & PJ Coffer (1995) Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376, 599602.

206TF Franke , SI Yang , TO Chan , K Datta , A Kazlauskas , DK Morrison , DR Kaplan & PN Tsichlis (1995) The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81, 727736.

207MH Cardone , N Roy , HR Stennicke , GS Salvesen , TF Franke , E Stanbridge , S Frisch & JC Reed (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282, 13181321.

208BM Burgering & GJ Kops (2002) Cell cycle and death control: long live Forkheads. Trends Biochem Sci 27, 352360.

209A Brunet , A Bonni , MJ Zigmond , MZ Lin , P Juo , LS Hu , MJ Anderson , KC Arden , J Blenis & ME Greenberg (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857868.

210J Zha , H Harada , E Yang , J Jockel & SJ Korsmeyer (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87, 619628.

212SR Datta , H Dudek , X Tao , S Masters , H Fu , Y Gotoh & ME Greenberg (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231241.

213L del Peso , M Gonzalez-Garcia , C Page , R Herrera & G Nunez (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278, 687689.

214PC Ferriola , V Cody & E Middleton Jr (1989) Protein kinase C inhibition by plant flavonoids. Kinetic mechanisms and structure–activity relationships. Biochem Pharmacol 38, 16171624.

217B Dave , RR Eason , SR Till , Y Geng , MC Velarde , TM Badger & RC Simmen (2005) The soy isoflavone genistein promotes apoptosis in mammary epithelial cells by inducing the tumor suppressor PTEN. Carcinogenesis 26, 17931803.

218LC Cantley & BG Neel (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A 96, 42404245.

219MP Myers , I Pass , IH Batty , KJ Van der KJ , JP Stolarov , BA Hemmings , MH Wigler , CP Downes & NK Tonks (1998) The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A 95, 1351313518.

220X Wu , K Senechal , MS Neshat , YE Whang & CL Sawyers (1998) The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci U S A 95, 1558715591.

221AC Wild , HR Moinova & RT Mulcahy (1999) Regulation of gamma-glutamylcysteine synthetase subunit gene expression by the transcription factor Nrf2. J Biol Chem 274, 3362733636.

222HR Moinova & RT Mulcahy (1999) Up-regulation of the human gamma-glutamylcysteine synthetase regulatory subunit gene involves binding of Nrf-2 to an electrophile responsive element. Biochem Biophys Res Commun 261, 661668.

223R Venugopal & AK Jaiswal (1998) Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene 17, 31453156.

224R Venugopal & AK Jaiswal (1996) Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc Natl Acad Sci U S A 93, 1496014965.

225KW Kang , SJ Lee & SG Kim (2005) Molecular mechanism of nrf2 activation by oxidative stress. Antioxid Redox Signal 7, 16641673.

226K Itoh , KI Tong & M Yamamoto (2004) Molecular mechanism activating Nrf2-Keap1 pathway in regulation of adaptive response to electrophiles. Free Radic Biol Med 36, 12081213.

227L Leung , M Kwong , S Hou , C Lee & JY Chan (2003) Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress. J Biol Chem 278, 4802148029.

228D Bloom , S Dhakshinamoorthy & AK Jaiswal (2002) Site-directed mutagenesis of cysteine to serine in the DNA binding region of Nrf2 decreases its capacity to upregulate antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene. Oncogene 21, 21912200.

230A Banning , S Deubel , D Kluth , Z Zhou & R Brigelius-Flohe (2005) The GI-GPx gene is a target for Nrf2. Mol Cell Biol 25, 49144923.

231E Hernandez-Montes , SE Pollard , D Vauzour , L Jofre-Montseny , C Rota , G Rimbach , PD Weinberg & JP Spencer (2006) Activation of glutathione peroxidase via Nrf1 mediates genistein's protection against oxidative endothelial cell injury. Biochem Biophys Res Commun 346, 851859.

232K Itoh , N Wakabayashi , Y Katoh , T Ishii , K Igarashi , JD Engel & M Yamamoto (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13, 7686.

233JD Hayes & M McMahon (2001) Molecular basis for the contribution of the antioxidant responsive element to cancer chemoprevention. Cancer Lett 174, 103113.

234MJ Alcaraz , AM Vicente , A Araico , JN Dominguez , MC Terencio & ML Ferrandiz (2004) Role of nuclear factor-kappaB and heme oxygenase-1 in the mechanism of action of an anti-inflammatory chalcone derivative in RAW 264.7 cells. Br J Pharmacol 142, 11911199.

235M Kobayashi & M Yamamoto (2005) Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid Redox Signal 7, 385394.

236T Nguyen , PJ Sherratt , HC Huang , CS Yang & CB Pickett (2003) Increased protein stability as a mechanism that enhances Nrf2-mediated transcriptional activation of the antioxidant response element. Degradation of Nrf2 by the 26 S proteasome. J Biol Chem 278, 45364541.

237T Nguyen , HC Huang & CB Pickett (2000) Transcriptional regulation of the antioxidant response element. Activation by Nrf2 and repression by MafK. J Biol Chem 275, 1546615473.

238PJ Sherratt , HC Huang , T Nguyen & CB Pickett (2004) Role of protein phosphorylation in the regulation of NF-E2-related factor 2 activity. Methods Enzymol 378, 286301.

239R Yu , S Mandlekar , W Lei , WE Fahl , TH Tan & AN Kong (2000) p38 mitogen-activated protein kinase negatively regulates the induction of phase II drug-metabolizing enzymes that detoxify carcinogens. J Biol Chem 275, 23222327.

240G Shen , V Hebbar , S Nair , C Xu , W Li , W Lin , YS Keum , J Han , MA Gallo & AN Kong (2004) Regulation of Nrf2 transactivation domain activity. The differential effects of mitogen-activated protein kinase cascades and synergistic stimulatory effect of Raf and CREB-binding protein. J Biol Chem 279, 2305223060.

241KW Kang , SJ Lee , JW Park & SG Kim (2002) Phosphatidylinositol 3-kinase regulates nuclear translocation of NF-E2-related factor 2 through actin rearrangement in response to oxidative stress. Mol Pharmacol 62, 10011010.

242K Nakaso , H Yano , Y Fukuhara , T Takeshima , K Wada-Isoe & K Nakashima (2003) PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett 546, 181184.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

British Journal of Nutrition
  • ISSN: 0007-1145
  • EISSN: 1475-2662
  • URL: /core/journals/british-journal-of-nutrition
Please enter your name
Please enter a valid email address
Who would you like to send this to? *