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Flavonoids as modulators of memory and learning: molecular interactions resulting in behavioural effects

  • Catarina Rendeiro (a1) (a2), João D. T. Guerreiro (a3), Claire M. Williams (a2) and Jeremy P. E. Spencer (a1)

There is considerable interest in the potential of a group of dietary-derived phytochemicals known as flavonoids in modulating neuronal function and thereby influencing memory, learning and cognitive function. The present review begins by detailing the molecular events that underlie the acquisition and consolidation of new memories in the brain in order to provide a critical background to understanding the impact of flavonoid-rich diets or pure flavonoids on memory. Data suggests that despite limited brain bioavailability, dietary supplementation with flavonoid-rich foods, such as blueberry, green tea and Ginkgo biloba lead to significant reversals of age-related deficits on spatial memory and learning. Furthermore, animal and cellular studies suggest that the mechanisms underpinning their ability to induce improvements in memory are linked to the potential of absorbed flavonoids and their metabolites to interact with and modulate critical signalling pathways, transcription factors and gene and/or protein expression which control memory and learning processes in the hippocampus; the brain structure where spatial learning occurs. Overall, current evidence suggests that human translation of these animal investigations are warranted, as are further studies, to better understand the precise cause-and-effect relationship between flavonoid intake and cognitive outputs.

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* Corresponding author: Professor Jeremy P. E. Spencer, fax +44 0118 931 0080, email:
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1.Parrott, MD & Greenwood, CE (2007) Dietary influences on cognitive function with aging: from high-fat diets to healthful eating. Ann N Y Acad Sci 1114, 389397.
2.Gomez-Pinilla, F (2008) Brain foods: the effects of nutrients on brain function. Nat Rev Neurosci 9, 568578.
3.Greenwood, CE & Winocur, G (2005) High-fat diets, insulin resistance and declining cognitive function. Neurobiol Aging 26, Suppl. 1, 4245.
4.Molteni, R, Barnard, RJ, Ying, Z et al. (2002) A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience 112, 803814.
5.Ingram, DK, Weindruch, R, Spangler, EL et al. (1987) Dietary restriction benefits learning and motor performance of aged mice. J Gerontol 42, 7881.
6.Johnson, JB, Summer, W, Cutler, RG et al. (2007) Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radic Biol Med 42, 665674.
7.Letenneur, L, Proust-Lima, C, Le Gouge, A et al. (2007) Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol 165, 13641371.
8.Patel, AK, Rogers, JT & Huang, X (2008) Flavanols, mild cognitive impairment, and Alzheimer's dementia. Int J Clin Exp Med 1, 181191.
9.Beking, K & Vieira, A (2011) Flavonoid intake and disability-adjusted life years due to Alzheimer's and related dementias: a population-based study involving twenty-three developed countries. Public Health Nutr 13, 14031409.
10.Nurk, E, Refsum, H, Drevon, CA et al. (2009) Intake of flavonoid-rich wine, tea, and chocolate by elderly men and women is associated with better cognitive test performance. J Nutr 139, 120127.
11.Chan, YC, Hosoda, K, Tsai, CJ et al. (2006) Favorable effects of tea on reducing the cognitive deficits and brain morphological changes in senescence-accelerated mice. J Nutr Sci Vitaminol (Tokyo) 52, 266273.
12.Haque, AM, Hashimoto, M, Katakura, M et al. (2006) Long-term administration of green tea catechins improves spatial cognition learning ability in rats. J Nutr 136, 10431047.
13.Kaur, T, Pathak, CM, Pandhi, P et al. (2008) Effects of green tea extract on learning, memory, behavior and acetylcholinesterase activity in young and old male rats. Brain Cogn 67, 2530.
14.Kuriyama, S, Hozawa, A, Ohmori, K et al. (2006) Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project 1. Am J Clin Nutr 83, 355361.
15.Lai, HC, Chao, WT, Chen, YT et al. (2004) Effect of EGCG, a major component of green tea, on the expression of Ets-1, c-Fos, and c-Jun during angiogenesis in vitro. Cancer Lett 213, 181188.
16.Unno, K, Takabayashi, F, Yoshida, H et al. (2007) Daily consumption of green tea catechin delays memory regression in aged mice. Biogerontology 8, 8995.
17.Oliveira, DR, Sanada, PF, Saragossa Filho, AC et al. (2009) Neuromodulatory property of standardized extract Ginkgo biloba L. (EGb 761) on memory: behavioral and molecular evidence. Brain Res 1269, 6889.
18.Shif, O, Gillette, K, Damkaoutis, CM et al. (2006) Effects of Ginkgo biloba administered after spatial learning on water maze and radial arm maze performance in young adult rats. Pharmacol Biochem Behav 84, 1725.
19.Cohen-Salmon, C, Venault, P, Martin, B et al. (1997) Effects of Ginkgo biloba extract (EGb 761) on learning and possible actions on aging. J Physiol Paris 91, 291300.
20.Itil, TM, Eralp, E, Ahmed, I et al. (1998) The pharmacological effects of Gingko Biloba, a plant extract, on the brain of dementia patients in comparison with tacrine. Psychopharmacology 34, 391396.
21.Fisher, ND, Sorond, FA & Hollenberg, NK (2006) Cocoa flavanols and brain perfusion. J Cardiovasc Pharmacol 47, Suppl. 2, S210S214.
22.Francis, ST, Head, K, Morris, PG et al. (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.
23.Dinges, DF (2006) Cocoa flavanols, cerebral blood flow, cognition, and health: going forward. J Cardiovasc Pharmacol 47, Suppl. 2, S221S223.
24.Williams, CM, El Mohsen, MA, Vauzour, D et al. (2008) Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radic Biol Med 45, 295305.
25.Casadesus, G, Shukitt-Hale, B, Stellwagen, HM et al. (2004) Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats. Nutr Neurosci 7, 309316.
26.Shukitt-Hale, B, Lau, FC & Joseph, JA (2008) Berry fruit supplementation and the aging brain. J Agric Food Chem 56, 636641.
27.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, or strawberry dietary supplementation. J Neurosci 19, 81148121.
28.Krikorian, R, Shidler, MD, Nash, TA et al. (2010) Blueberry supplementation improves memory in older adults. J Agric Food Chem 58, 39964000.
29.Mandel, S & Youdim, MB (2004) Catechin polyphenols: neurodegeneration and neuroprotection in neurodegenerative diseases. Free Radic Biol Med 37, 304317.
30.Spencer, JP (2007) The interactions of flavonoids within neuronal signalling pathways. Genes Nutr 2, 257273.
31.Spencer, JP (2008) Flavonoids: modulators of brain function? Br J Nutr 99E, Suppl. 1, ES60ES77.
32.Shukitt-Hale, B, Carey, A & Joseph, JA (2005) Phytochemicals in foods and beverages: effects on the central nervous system. In Nutritional Neuroscience, pp. 393403 [Prasad, C]. Boca Raton: CRC Press.
33.Beking, K & Vieira, A (2011) An assessment of dietary flavonoid intake in the UK and Ireland. Int J Food Sci Nutr 62, 1719.
34.Harnly, JM, Doherty, RF, Beecher, GR et al. (2006) Flavonoid content of U.S. fruits, vegetables, and nuts. J Agric Food Chem 54, 99669977.
35.Rice-Evans, CA, Miller, NJ & Paganga, G (1996) Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20, 933956.
36.Scalbert, A & Williamson, G (2000) Dietary intake and bioavailability of polyphenols. J Nutr 130, 8S Suppl., 2073S2085S.
37.Manach, C, Scalbert, A, Morand, C et al. (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79, 727747.
38.Scalbert, A, Morand, C, Manach, C et al. (2002) Absorption and metabolism of polyphenols in the gut and impact on health. Biomed Pharmacother 56, 276282.
39.Spencer, JP, Chowrimootoo, G, Choudhury, R et al. (1999) The small intestine can both absorb and glucuronidate luminal flavonoids. FEBS Lett 458, 224230.
40.Crozier, A, Jaganath, IB & Clifford, MN (2009) Dietary phenolics: chemistry, bioavailability and effects on health. Nat Prod Rep 26, 10011043.
41.Spencer, JP (2003) Metabolism of tea flavonoids in the gastrointestinal tract. J Nutr 133, 3255S3261S.
42.Crozier, A, Del Rio, D & Clifford, MN (2010) Bioavailability of dietary flavonoids and phenolic compounds. Mol Aspects Med 31, 446467.
43.Stalmach, A, Mullen, W, Steiling, H et al. (2010) Absorption, metabolism, and excretion of green tea flavan-3-ols in humans with an ileostomy. Mol Nutr Food Res 54, 323334.
44.Renouf, M, Guy, P, Marmet, C et al. (2010) Plasma appearance and correlation between coffee and green tea metabolites in human subjects. Br J Nutr 104, 16351640.
45.Del Rio, D, Borges, G & Crozier, A (2010) Berry flavonoids and phenolics: bioavailability and evidence of protective effects. Br J Nutr 104, Suppl. 3, S67S90.
46.Kay, CD (2006) Aspects of anthocyanin absorption, metabolism and pharmacokinetics in humans. Nutr Res Rev 19, 137146.
47.Mazza, G, Kay, CD, Cottrell, T et al. (2002) Absorption of anthocyanins from blueberries and serum antioxidant status in human subjects. J Agric Food Chem 50, 77317737.
48.Wu, X, Cao, G & Prior, RL (2002) Absorption and metabolism of anthocyanins in elderly women after consumption of elderberry or blueberry. J Nutr 132, 18651871.
49.Borges, G, Roowi, S, Rouanet, JM et al. (2007) The bioavailability of raspberry anthocyanins and ellagitannins in rats. Mol Nutr Food Res 51, 714725.
50.Sakakibara, H, Ogawa, T, Koyanagi, A et al. (2009) Distribution and excretion of bilberry anthocyanins [corrected] in mice. J Agric Food Chem 57, 76817686.
51.Kay, CD, Kroon, PA & Cassidy, A (2009) The bioactivity of dietary anthocyanins is likely to be mediated by their degradation products. Mol Nutr Food Res 53, Suppl. 1, S92–S101.
52.Kahle, K, Kraus, M, Scheppach, W et al. (2006) Studies on apple and blueberry fruit constituents: do the polyphenols reach the colon after ingestion? Mol Nutr Food Res 50, 418423.
53.Spencer, JP, Abd El Mohsen, MM, Minihane, AM et al. (2008) Biomarkers of the intake of dietary polyphenols: strengths, limitations and application in nutrition research. Br J Nutr 99, 1222.
54.Aura, AM, Martin-Lopez, P, O'Leary, KA et al. (2005) In vitro metabolism of anthocyanins by human gut microflora. Eur J Nutr 44, 133142.
55.Tsuda, T, Horio, F & Osawa, T (1999) Absorption and metabolism of cyanidin 3-O-beta-d-glucoside in rats. FEBS Lett 449, 179182.
56.Vitaglione, P, Donnarumma, G, Napolitano, A et al. (2007) Protocatechuic acid is the major human metabolite of cyanidin-glucosides. J Nutr 137, 20432048.
57.Williamson, G & Clifford, MN (2010) Colonic metabolites of berry polyphenols: the missing link to biological activity? Br J Nutr 104, Suppl. 3, S48S66.
58.Milbury, PE & Kalt, W (2010) Xenobiotic metabolism and berry flavonoid transport across the blood-brain barrier. J Agric Food Chem 58, 39503956.
59.Youdim, KA, Dobbie, MS, Kuhnle, G et al. (2003) Interaction between flavonoids and the blood-brain barrier: in vitro studies. J Neurochem 85, 180192.
60.Aasmundstad, TA, Morland, J & Paulsen, RE (1995) Distribution of morphine 6-glucuronide and morphine across the blood-brain barrier in awake, freely moving rats investigated by in vivo microdialysis sampling. J Pharmacol Exp Ther 275, 435441.
61.Sperker, B, Backman, JT & Kroemer, HK (1997) The role of beta-glucuronidase in drug disposition and drug targeting in humans. Clin Pharmacokinet 33, 1831.
62.Suganuma, M, Okabe, S, Oniyama, M et al. (1998) Wide distribution of [3H](−)-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue. Carcinogenesis 19, 17711776.
63.Abd El Mohsen, MM, Kuhnle, G, Rechner, AR et al. (2002) Uptake and metabolism of epicatechin and its access to the brain after oral ingestion. Free Radic Biol Med 33, 16931702.
64.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, 39023908.
65.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, 5158.
66.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, 369374.
67.Andres-Lacueva, C, Shukitt-Hale, B, Galli, RL et al. (2005) Anthocyanins in aged blueberry-fed rats are found centrally and may enhance memory. Nutr Neurosci 8, 111120.
68.Kalt, W, Blumberg, JB, McDonald, JE et al. (2008) Identification of anthocyanins in the liver, eye, and brain of blueberry-fed pigs. J Agric Food Chem 56, 705712.
69.Passamonti, S, Vrhovsek, U, Vanzo, A et al. (2005) Fast access of some grape pigments to the brain. J Agric Food Chem 53, 70297034.
70.van Praag, H, Lucero, MJ, Yeo, GW et al. (2007) Plant-derived flavanol ( −)epicatechin enhances angiogenesis and retention of spatial memory in mice. J Neurosci 27, 58695878.
71.Squire, LR & Zola, SM (1996) Structure and function of declarative and nondeclarative memory systems. Proc Natl Acad Sci USA 93, 1351513522.
72.Squire, LR & Kandel, ER (2009) From Mind to Molecules, 2nd ed. Singapore: Ben Roberts.
73.Cohen, NJ & Eichenbaum, H (1993) Memory, Amnesia and the Hippocampal System. Cambridge, MA: MIT Press.
74.Lechner, HA, Squire, LR & Byrne, JH (1999) 100 years of consolidation – remembering Muller and Pilzecker. Learn Mem 6, 7787.
75.Kandel, ER & Squire, LR (2000) Memory: From Mind to Molecules. New York: W. H. Freeman.
76.Frankland, PW & Bontempi, B (2005) The organization of recent and remote memories. Nat Rev Neurosci 6, 119130.
77.Squire, LR, Stark, CEL & Clark, RE (2004) The medial temporal lobe. Ann Rev Neurosci 27, 279306.
78.Zola-Morgan, SM & Squire, LR (1990) The primate hippocampal formation: evidence for a time-limited role in memory storage. Science 250, 288290.
79.King, JA, Burgess, N, Hartley, T et al. (2002) Human hippocampus and viewpoint dependence in spatial memory. Hippocampus 12, 811820.
80.Burgess, N, Maguire, EA & O'Keefe, J (2002) The human hippocampus and spatial and episodic memory. Neuron 35, 625641.
81.O'Keefe, J (1984) Spatial memory within and without the hippocampal system. In Neurobiology of the Hippocampus, pp. 375403 [Seifert, W]. London: Academic Press.
82.Poucet, B & Benhamou, S (1997) The neuropsychology of spatial cognition in the rat. Crit Rev Neurobiol 11, 101120.
83.Shrager, Y, Bayley, PJ, Bontempi, B et al. (2007) Spatial memory and the human hippocampus. Proc Natl Acad Sci USA 104, 29612966.
84.Kesner, RP & Hopkins, RO (2006), Mnemonic functions of the hippocampus: A comparison between animals and humans. Biol Psychol 73, 3–18.
85.Astur, RS, Taylor, LB, Mamelak, AN et al. (2002) Humans with hippocampus damage display severe spatial memory impairments in a virtual Morris water task. Behav Brain Res 132, 7784.
86.Olton, DS & Samuelson, RJ (1976) Remembrance of places past – spatial memory in rats. J Exp Psychol Anim Behav Process 2, 97–116.
87.Morris, R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Methods 11, 4760.
88.Olton, DS & Papas, BC (1979) Spatial memory and hippocampal function. Neuropsychologia 17, 669682.
89.Sutherland, RJ, Kolb, B, Whishaw, IQ et al. (1982) Cortical noradrenaline depletion eliminates sparing of spatial-learning after neonatal frontal-cortex damage in the rat. Neurosci Lett 32, 125130.
90.Bannerman, DM, Yee, BK, Good, MA et al. (1999) Double dissociation of function within the hippocampus: a comparison of dorsal, ventral and complete hippocampal cytotoxic lesions. Behav Neurosci 113, 11701188.
91.Barnes, CA (1990) Animal models of age-related cognitive decline. In Handbook of Neuropsychology, pp. 169196 [Boller, F and Grafman, J]. Amsterdam: Elsevier.
92.Barnes, CA (1979) Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol 93, 74–104.
93.Moffat, SD, Zonderman, AB & Resnick, SM (2001) Age differences in spatial memory in a virtual environment navigation task. Neurobiol Aging 22, 787796.
94.Gallagher, M, Burwell, R & Burchinall, M (1993) Severity of spatial learning impairments in aging: development of a learning index for performance in the Morris Water Maze. Behav Neurosci 107, 618636.
95.Wilson, IA, Ikonen, S, Gallagher, M et al. (2005) Age-associated alterations of hippocampal place cells are subregion specific. J Neurosci 25, 68776886.
96.Li, Q, Zhao, HF, Zhang, ZF et al. (2009) Long-term green tea catechin administration prevents spatial learning and memory impairment in senescence-accelerated mouse prone-8 mice by decreasing Abeta1–42 oligomers and upregulating synaptic plasticity-related proteins in the hippocampus. Neuroscience 163, 741749.
97.McGaugh, JL (2000) Memory – a century of consolidation. Science 287, 248251.
98.Lamprecht, R & LeDoux, J (2004) Structural plasticity and memory. Nat Rev Neurosci 5, 4554.
99.Muller, D, Nikonenko, I, Jourdain, P et al. (2002) LTP, memory and structural plasticity. Curr Mol Med 2, 605611.
100.Malenka, RC & Nicoll, RA (1999) Long-term potentiation – a decade of progress? Science 285, 18701874.
101.Bliss, TV & Collingridge, GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361, 3139.
102.Lynch, G, Rex, CS & Gall, CM (2007) LTP consolidation: substrates, explanatory power, and functional significance. Neuropharmacology 52, 1223.
103.Kandel, ER (2001) The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 10301038.
104.Arnsten, AF, Ramos, BP, Birnbaum, SG et al. (2005) Protein kinase A as a therapeutic target for memory disorders: rationale and challenges. Trends Mol Med 11, 121128.
105.van der Heide, LP, Ramakers, GM & Smidt, MP (2006) Insulin signaling in the central nervous system: learning to survive. Prog Neurobiol 79, 205221.
106.Kumar, V, Zhang, MX, Swank, MW et al. (2005) Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J Neurosci 25, 1128811299.
107.Alkon, DL, Sun, MK & Nelson, TJ (2007) PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer's disease. Trends Pharmacol Sci 28, 5160.
108.Bach, ME, Hawkins, RD, Osman, M et al. (1995) Impairment of spatial but not contextual memory in CaMKII mutant mice with a selective loss of hippocampal LTP in the range of the theta frequency. Cell 81, 905915.
109.Lisman, J, Schulman, H & Cline, H (2002) The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci 3, 175190.
110.Sweatt, JD (2001) The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 76, 110.
111.Sweatt, JD (2004) Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 14, 311317.
112.Esteban, JA, Shi, SH, Wilson, C et al. (2003) PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nat Neurosci 6, 136143.
113.Kim, MJ, Dunah, AW, Wang, YT et al. (2005) Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Neuron 46, 745760.
114.Malinow, R & Malenka, RC (2002) AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci 25, 103126.
115.Zhu, JJ, Qin, Y, Zhao, M et al. (2002) Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell 110, 443455.
116.Kelleher, RJ III, Govindarajan, A, Jung, HY et al. (2004) Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116, 467479.
117.Bozon, B, Kelly, A, Josselyn, SA et al. (2003) MAPK, CREB and zif268 are all required for the consolidation of recognition memory. Philos Trans R Soc Lond B Biol Sci 358, 805814.
118.Davis, HP & Squire, LR (1984) Protein synthesis and memory: a review. Psychol Bull 96, 518559.
119.Goelet, P, Castellucci, VF, Schacher, S et al. (1986) The long and the short of long-term memory – a molecular framework. Nature 322, 419422.
120.Hoeffer, CA & Klann, E (2010) mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 33, 6775.
121.Bekinschtein, P, Katche, C, Slipczuk, LN et al. (2007) mTOR signaling in the hippocampus is necessary for memory formation. Neurobiol Learn Mem 87, 303307.
122.Hou, L & Klann, E (2004) Activation of the phosphoinositide 3-kinase–Akt–mammalian target of rapamycin signaling pathway is required for metabotropic glutamate receptor-dependent long-term depression. J Neurosci 24, 63526361.
123.Brightwell, JJ, Smith, CA, Neve, RL et al. (2007) Long-term memory for place learning is facilitated by expression of cAMP response element-binding protein in the dorsal hippocampus. Learn Mem 14, 195199.
124.Sekeres, MJ, Neve, RL, Frankland, PW et al. (2010) Dorsal hippocampal CREB is both necessary and sufficient for spatial memory. Learn Mem 17, 280283.
125.Barco, A, Pittenger, C & Kandel, ER (2003) CREB, memory enhancement and the treatment of memory disorders: promises, pitfalls and prospects. Expert Opin Ther Targets 7, 101114.
126.Impey, S, McCorkle, SR, Cha-Molstad, H et al. (2004) Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119, 10411054.
127.Impey, S, Smith, DM, Obrietan, K et al. (1998) Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nat Neurosci 1, 595601.
128.Leil, TA, Ossadtchi, A, Nichols, TE et al. (2003) Genes regulated by learning in the hippocampus. J Neurosci Res 71, 763768.
129.Finkbeiner, S (2000) CREB couples neurotrophin signals to survival messages. Neuron 25, 1114.
130.Lonze, BE & Ginty, DD (2002) Function and regulation of CREB family transcription factors in the nervous system. Neuron 35, 605623.
131.McAllister, AK, Katz, LC & Lo, DC (1999) Neurotrophins and synaptic plasticity. Annu Rev Neurosci 22, 295318.
132.Poo, MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2, 2432.
133.Cohen-Cory, S & Fraser, SE (1995) Effects of brain-derived neurotrophic factor on optic axon branching and remodelling in vivo. Nature 378, 192196.
134.Lu, B (2003) BDNF and activity-dependent synaptic modulation. Learn Mem 10, 8698.
135.Thomas, K & Davies, A (2005) Neurotrophins: a ticket to ride for BDNF. Curr Biol 15, R262R264.
136.Bailey, CH & Kandel, ER (1993) Structural changes accompanying memory storage. Annu Rev Physiol 55, 397426.
137.Tanaka, J, Horiike, Y, Matsuzaki, M et al. (2008) Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science 319, 16831687.
138.Nimchinsky, EA, Sabatini, BL & Svoboda, K (2002) Structure and function of dendritic spines. Annu Rev Physiol 64, 313353.
139.Fischer, M, Kaech, S, Wagner, U et al. (2000) Glutamate receptors regulate actin-based plasticity in dendritic spines. Nat Neurosci 3, 887894.
140.Messaoudi, E, Kanhema, T, Soule, J et al. (2007) Sustained Arc/Arg3.1 synthesis controls long-term potentiation consolidation through regulation of local actin polymerization in the dentate gyrus in vivo. J Neurosci 27, 1044510455.
141.Tzingounis, AV & Nicoll, RA (2006) Arc/Arg3.1: linking gene expression to synaptic plasticity and memory. Neuron 52, 403407.
142.Bonfanti, L (2006) PSA-NCAM in mammalian structural plasticity and neurogenesis. Prog Neurobiol 80, 129164.
143.Dityatev, A, Dityateva, G, Sytnyk, V et al. (2004) Polysialylated neural cell adhesion molecule promotes remodeling and formation of hippocampal synapses. J Neurosci 24, 93729382.
144.Gascon, E, Vutskits, L & Kiss, JZ (2007) Polysialic acid-neural cell adhesion molecule in brain plasticity: from synapses to integration of new neurons. Brain Res Rev 56, 101118.
145.Kiss, JZ, Troncoso, E, Djebbara, Z et al. (2001) The role of neural cell adhesion molecules in plasticity and repair. Brain Res Brain Res Rev 36, 175184.
146.Li, Q, Zhao, HF, Zhang, ZF et al. (2009) Long-term administration of green tea catechins prevents age-related spatial learning and memory decline in C57BL/6J mice by regulating hippocampal cyclic amp-response element binding protein signaling cascade. Neuroscience 159, 12081215.
147.Winter, JC (1998) The effects of an extract of Ginkgo biloba, EGb 761, on cognitive behavior and longevity in the rat. Physiol Behav 63, 425433.
148.Rice-Evans, C (2001) Flavonoid antioxidants. Curr Med Chem 8, 797807.
149.Williams, RJ, Spencer, JP & Rice-Evans, C (2004) Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med 36, 838849.
150.Goyarzu, P, Malin, DH, Lau, FC et al. (2004) Blueberry supplemented diet: effects on object recognition memory and nuclear factor-kappa B levels in aged rats. Nutr Neurosci 7, 7583.
151.Galli, RL, Bielinski, DF, Szprengiel, A et al. (2006) Blueberry supplemented diet reverses age-related decline in hippocampal HSP70 neuroprotection. Neurobiol Aging 27, 344350.
152.Shukitt-Hale, B, Lau, FC, Carey, AN et al. (2008) Blueberry polyphenols attenuate kainic acid-induced decrements in cognition and alter inflammatory gene expression in rat hippocampus. Nutr Neurosci 11, 172182.
153.Mandel, SA, Amit, T, Kalfon, L et al. (2008) Targeting multiple neurodegenerative diseases etiologies with multimodal-acting green tea catechins. J Nutr 138, 1578S1583S.
154.Mandel, SA, Avramovich-Tirosh, Y, Reznichenko, L et al. (2005) Multifunctional activities of green tea catechins in neuroprotection. Modulation of cell survival genes, iron-dependent oxidative stress and PKC signaling pathway. Neurosignals 14, 4660.
155.Khokhar, S & Magnusdottir, SG (2002) Total phenol, catechin, and caffeine contents of teas commonly consumed in the United kingdom. J Agric Food Chem 50, 565570.
156.Higdon, JV & Frei, B (2003) Tea catechins and polyphenols: health effects, metabolism, and antioxidant functions. Crit Rev Food Sci Nutr 43, 89–143.
157.Graham, HN (1992) Green tea composition, consumption, and polyphenol chemistry. Prev Med 21, 334350.
158.Kim, HK, Kim, M, Kim, S et al. (2004) Effects of green tea polyphenol on cognitive and acetylcholinesterase activities. Biosci Biotechnol Biochem 68, 19771979.
159.Hu, G, Bidel, S, Jousilahti, P et al. (2007) Coffee and tea consumption and the risk of Parkinson's disease. Mov Disord 22, 22422248.
160.Assuncao, M, Santos-Marques, MJ, Carvalho, F et al. (2011) Chronic green tea consumption prevents age-related changes in rat hippocampal formation. Neurobiol Aging 32, 707717.
161.Nanjo, F, Goto, K, Seto, R et al. (1996) Scavenging effects of tea catechins and their derivatives on 1,1-diphenyl-2-picrylhydrazyl radical. Free Radic Biol Med 21, 895902.
162.Grinberg, LN, Newmark, H, Kitrossky, N et al. (1997) Protective effects of tea polyphenols against oxidative damage to red blood cells. Biochem Pharmacol 54, 973978.
163.Guo, Q, Zhao, B, Li, M et al. (1996) Studies on protective mechanisms of four components of green tea polyphenols against lipid peroxidation in synaptosomes. Biochim Biophys Acta 1304, 210222.
164.Aktas, O, Prozorovski, T, Smorodchenko, A et al. (2004) Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis. J Immunol 173, 57945800.
165.Lee, S, Suh, S & Kim, S (2000) Protective effects of the green tea polyphenol (−)-epigallocatechin gallate against hippocampal neuronal damage after transient global ischemia in gerbils. Neurosci Lett 287, 191194.
166.Weinreb, O, Amit, T & Youdim, MB (2007) A novel approach of proteomics and transcriptomics to study the mechanism of action of the antioxidant-iron chelator green tea polyphenol ( −)-epigallocatechin-3-gallate. Free Radic Biol Med 43, 546556.
167.Mandel, SA, Amit, T, Weinreb, O et al. (2008) Simultaneous manipulation of multiple brain targets by green tea catechins: a potential neuroprotective strategy for Alzheimer and Parkinson diseases. CNS Neurosci Ther 14, 352365.
168.Choi, YT, Jung, CH, Lee, SR et al. (2001) The green tea polyphenol (−)-epigallocatechin gallate attenuates beta-amyloid-induced neurotoxicity in cultured hippocampal neurons. Life Sci 70, 603614.
169.Mandel, S, Maor, G & Youdim, MB (2004) Iron and alpha-synuclein in the substantia nigra of MPTP-treated mice: effect of neuroprotective drugs R-apomorphine and green tea polyphenol (−)-epigallocatechin-3-gallate. J Mol Neurosci 24, 401416.
170.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 23, 605612.
171.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, 3057430580.
172.Koh, SH, Kim, SH, Kwon, H et al. (2003) Epigallocatechin gallate protects nerve growth factor differentiated PC12 cells from oxidative-radical-stress-induced apoptosis through its effect on phosphoinositide 3-kinase/Akt and glycogen synthase kinase-3. Brain Res Mol Brain Res 118, 7281.
173.Levites, Y, Amit, T, Mandel, S et al. (2003) Neuroprotection and neurorescue against Abeta toxicity and PKC-dependent release of nonamyloidogenic soluble precursor protein by green tea polyphenol (−)-epigallocatechin-3-gallate. FASEB J 17, 952954.
174.Kalfon, L, Youdim, MB & Mandel, SA (2007) Green tea polyphenol (−)-epigallocatechin-3-gallate promotes the rapid protein kinase C- and proteasome-mediated degradation of Bad: implications for neuroprotection. J Neurochem 100, 992–1002.
175.Maher, P (2001) How protein kinase C activation protects nerve cells from oxidative stress-induced cell death. J Neurosci 21, 29292938.
176.Dempsey, EC, Newton, AC, Mochly-Rosen, D et al. (2000) Protein kinase C isozymes and the regulation of diverse cell responses. Am J Physiol Lung Cell Mol Physiol 279, L429L438.
177.Sun, MK, Hongpaisan, J & Alkon, DL (2009) Postischemic PKC activation rescues retrograde and anterograde long-term memory. Proc Natl Acad Sci USA 106, 1467614680.
178.Hongpaisan, J, Sun, MK & Alkon, DL (2011) PKC epsilon activation prevents synaptic loss, Abeta elevation, and cognitive deficits in Alzheimer's disease transgenic mice. J Neurosci 31, 630643.
179.Sun, MK & Alkon, DL (2010) Pharmacology of protein kinase C activators: cognition-enhancing and antidementic therapeutics. Pharmacol Ther 127, 6677.
180.Joseph, JA, Denisova, NA, Arendash, G et al. (2003) Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr Neurosci 6, 153162.
181.Joseph, JA, Shukitt-Hale, B, Denisova, NA et al. (1998) Long-term dietary strawberry, spinach, or vitamin E supplementation retards the onset of age-related neuronal signal-transduction and cognitive behavioral deficits. J Neurosci 18, 80478055.
182.Shukitt-Hale, B, Cheng, V & Joseph, JA (2009) Effects of blackberries on motor and cognitive function in aged rats. Nutr Neurosci 12, 135140.
183.Shukitt-Hale, B, Cheng, V, Bielinski, D et al. (2006) Differential brain regional specificity to blueberry and strawberry polyphenols in improved motor and cognitive function in aged rats. Soc Neurosci Abstr 32, 81.15.
184.Borges, G, Degeneve, A, Mullen, W et al. (2010) Identification of flavonoid and phenolic antioxidants in black currants, blueberries, raspberries, red currants, and cranberries. J Agric Food Chem 58, 39013909.
185.Shukitt-Hale, B, Galli, RL, Meterko, V et al. (2005) Dietary supplementation with fruit polyphenolics ameliorates age-related deficits in behavior and neuronal markers of inflammation and oxidative stress. Age 27, 4957.
186.Ramirez, MR, Izquierdo, I, do Carmo Bassols Raseira, M et al. (2005) Effect of lyophilised Vaccinium berries on memory, anxiety and locomotion in adult rats. Pharmacol Res 52, 457462.
187.Shukitt-Hale, B, Carey, AN, Jenkins, D et al. (2007) Beneficial effects of fruit extracts on neuronal function and behavior in a rodent model of accelerated aging. Neurobiol Aging 28, 11871194.
188.Coultrap, SJ, Bickford, PC & Browning, MD (2008) Blueberry-enriched diet ameliorates age-related declines in NMDA receptor-dependent LTP. Age (Dordr) 30, 263272.
189.Drapeau, E, Mayo, W, Aurousseau, C et al. (2003) Spatial memory performances of aged rats in the water maze predict levels of hippocampal neurogenesis. Proc Natl Acad Sci USA 100, 1438514390.
190.Drapeau, E, Montaron, MF, Aguerre, S et al. (2007) Learning-induced survival of new neurons depends on the cognitive status of aged rats. J Neurosci 27, 60376044.
191.Kempermann, G & Gage, FH (2002) Genetic determinants of adult hippocampal neurogenesis correlate with acquisition, but not probe trial performance, in the water maze task. Eur J Neurosci 16, 129136.
192.Kempermann, G, Kuhn, HG & Gage, FH (1998) Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci 18, 32063212.
193.Nilsson, M, Perfilieva, E, Johansson, U et al. (1999) Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. J Neurobiol 39, 569578.
194.Shors, TJ, Miesegaes, G, Beylin, A et al. (2001) Neurogenesis in the adult is involved in the formation of trace memories. Nature 410, 372376.
195.Shors, TJ, Townsend, DA, Zhao, M et al. (2002) Neurogenesis may relate to some but not all types of hippocampal-dependent learning. Hippocampus 12, 578584.
196.van Praag, H (2008) Neurogenesis and exercise: past and future directions. Neuromol Med 10, 128140.
197.DeFeudis, FV & Drieu, K (2000) Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. Curr Drug Targets 1, 2558.
198.Le Bars, PL, Katz, MM, Berman, N et al. (1997) A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group. JAMA 278, 13271332.
199.Hoerr, R (2003) Behavioural and psychological symptoms of dementia (BPSD): effects of EGb 761. Pharmacopsychiatry 36, Suppl. 1, S56S61.
200.Kanowski, S & Hoerr, R (2003) Ginkgo biloba extract EGb 761 in dementia: intent-to-treat analyses of a 24-week, multi-center, double-blind, placebo-controlled, randomized trial. Pharmacopsychiatry 36, 297303.
201.Kanowski, S, Herrmann, WM, Stephan, K et al. (1996) Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia. Pharmacopsychiatry 29, 4756.
202.Chan, PC, Xia, Q & Fu, PP (2007) Ginkgo biloba leave extract: biological, medicinal, and toxicological effects. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 25, 211244.
203.Le Bars, PL, Velasco, FM, Ferguson, JM et al. (2002) Influence of the severity of cognitive impairment on the effect of the Ginkgo biloba extract EGb 761 in Alzheimer's disease. Neuropsychobiology 45, 1926.
204.Oken, BS, Storzbach, DM & Kaye, JA (1998) The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 55, 14091415.
205.Sierpina, VS, Wollschlaeger, B & Blumenthal, M (2003) Ginkgo biloba. Am Fam Phys 68, 923926.
206.Winter, E (1991) Effects of an extract of Ginkgo biloba on learning and memory in mice. Pharmacol Biochem Behav 38, 109114.
207.Topic, B, Hasenohrl, RU, Hacker, R et al. (2002) Enhanced conditioned inhibitory avoidance by a combined extract of Zingiber officinale and Ginkgo biloba. Phytother Res 16, 312315.
208.Hoffman, JR, Donato, A & Robbins, SJ (2004) Ginkgo biloba promotes short-term retention of spatial memory in rats. Pharmacol Biochem Behav 77, 533539.
209.Walesiuk, A, Trofimiuk, E & Braszko, JJ (2006) Ginkgo biloba normalizes stress- and corticosterone-induced impairment of recall in rats. Pharmacol Res 53, 123128.
210.Blecharz-Klin, K, Piechal, A, Joniec, I et al. (2009) Pharmacological and biochemical effects of Ginkgo biloba extract on learning, memory consolidation and motor activity in old rats. Acta Neurobiol Exp (Wars) 69, 217231.
211.Huang, SH, Duke, RK, Chebib, M et al. (2004) Ginkgolides, diterpene trilactones of Ginkgo biloba, as antagonists at recombinant alpha1beta2gamma2L GABAA receptors. Eur J Pharmacol 494, 131138.
212.Hadjiivanova, CI & Petkov, VV (2002) Effect of Ginkgo biloba extract on beta-adrenergic receptors in different rat brain regions. Phytother Res 16, 488490.
213.Ivic, L, Sands, TT, Fishkin, N et al. (2003) Terpene trilactones from Ginkgo biloba are antagonists of cortical glycine and GABA(A) receptors. J Biol Chem 278, 4927949285.
214.Williams, B, Watanabe, CM, Schultz, PG et al. (2004) Age-related effects of Ginkgo biloba extract on synaptic plasticity and excitability. Neurobiol Aging 25, 955962.
215.Tchantchou, F, Xu, Y, Wu, Y et al. (2007) EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer's disease. FASEB J 21, 24002408.
216.Watanabe, CM, Wolffram, S, Ader, P et al. (2001) The in vivo neuromodulatory effects of the herbal medicine Ginkgo biloba. Proc Natl Acad Sci USA 98, 65776580.
217.Wang, Y, Wang, L, Wu, J et al. (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.
218.Maher, P, Akaishi, T & Abe, K (2006) Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proc Natl Acad Sci USA 103, 1656816573.
219.Jin, CH, Shin, EJ, Park, JB et al. (2009) Fustin flavonoid attenuates beta-amyloid (1–42)-induced learning impairment. J Neurosci Res 87, 36583670.
220.Maher, P (2009) Modulation of multiple pathways involved in the maintenance of neuronal function during aging by fisetin. Genes Nutr 4(4), 297307.
221.Schroeter, H, Bahia, P, Spencer, JP et al. (2007) ( −)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons. J Neurochem 101, 15961606.
222.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, 3478334793.
223.Weinreb, O, Amit, T & Youdim, MB (2008) The application of proteomics for studying the neurorescue activity of the polyphenol ( −)-epigallocatechin-3-gallate. Arch Biochem Biophys 476, 152160.
224.Tully, T, Bourtchouladze, R, Scott, R et al. (2003) Targeting the CREB pathway for memory enhancers. Nat Rev Drug Discov 2, 267277.
225.Radecki, DT, Brown, LM, Martinez, J et al. (2005) BDNF protects against stress-induced impairments in spatial learning and memory and LTP. Hippocampus 15, 246253.
226.Garzon, D, Yu, G & Fahnestock, M (2002) A new brain-derived neurotrophic factor transcript and decrease in brain-derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer's disease parietal cortex. J Neurochem 82, 10581064.
227.Hwang, IK, Yoo, KY, Jung, BK et al. (2006) Correlations between neuronal loss, decrease of memory, and decrease expression of brain-derived neurotrophic factor in the gerbil hippocampus during normal aging. Exp Neurol 201, 7583.
228.Laske, C, Banschbach, S, Stransky, E et al. . (2010) Exercise-induced normalization of decreased BDNF serum concentration in elderly women with remitted major depression. Int J Neuropsychopharmacol 13, 595602.
229.Laske, C, Stransky, E, Leyhe, T et al. (2006) Stage-dependent BDNF serum concentrations in Alzheimer's disease. J Neural Transm 113, 12171224.
230.Fumagalli, F, Racagni, G & Riva, MA (2006) The expanding role of BDNF: a therapeutic target for Alzheimer's disease? Pharmacogenomics J 6, 8–15.
231.Marvanova, M, Lakso, M, Pirhonen, J et al. (2001) The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain. Mol Cell Neurosci 18, 247258.
232.Lauterborn, JC, Lynch, G, Vanderklish, P et al. (2000) Positive modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J Neurosci 20, 8–21.
233.Mackowiak, M, O'Neill, MJ, Hicks, CA et al. (2002) An AMPA receptor potentiator modulates hippocampal expression of BDNF: an in vivo study. Neuropharmacology 43, 110.
234.Burke, SN & Barnes, CA (2006) Neural plasticity in the ageing brain. Nat Rev Neurosci 7, 3040.
235.Gallagher, M (2003) Aging and hippocampal/cortical circuits in rodents. Alzheimer Dis Assoc Disord 17, Suppl. 2, S45S47.
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