Open access peer-reviewed chapter

Flavonoids as Modulators of Synaptic Plasticity: Implications for the Development of Novel Therapeutic Strategies for Healthy Lifestyle

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Adriana Aparecida Ferraz Carbonel, Marianna Nogueira Cecyn, João Henrique Rodrigues Castello Girão, Gisela Rodrigues da Silva Sasso, Bárbara de Mello Ponteciano, Eliana Pereira Vellozo, Ricardo Santos Simões, Manuel de Jesus Simões, Manoel João Batista Castello Girão and Daniela Rodrigues de Oliveira

Submitted: September 13th, 2018 Reviewed: January 4th, 2019 Published: October 17th, 2019

DOI: 10.5772/intechopen.84164

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Abstract

Flavonoids are potential group of phytochemicals found in normal diets capable of mediating improvements in cognition and may reverse age-related declines in memory. Aging is associated with alteration of hippocampal synaptic plasticity and contribute to decline in cognitive functions. The current studies are directed at a greater understanding of how and why the brain modifies synaptic strength with dietary-derived phytochemicals (flavonoids) and age-related declines in cognitive functions (such as learning and memory). Flavonoids modulate neuronal function and thereby influence cognition. In addition, it has been suggested that flavonoids may delay the development of Alzheimer’s disease-like pathology, anxiety, and depression disorders, suggesting a novel therapeutic strategy. Emerging evidence suggest that flavonoids are modulators of signaling pathways critical for controlling synaptic plasticity in the brain. For example, phosphatidylinositol-3 kinase (PI3K)/Akt, mitogen-activated protein kinase, protein kinase C, pathways could be involved Ca2+ signaling. Significants questions such as: (i) How does flavonoids affect plasticity? (ii) What receptors are modulating by flavonoids and how are they regulated? (iii) Do flavonoids have a neuroprotective effect in aging? are asked.

Keywords

  • flavonoids
  • synaptic plasticity
  • health lifestyle
  • brain

1. Introduction

Advances in medicine over the last century have resulted in a considerable increase in human life expectancy. Despite this positive outcome, with increase in age, comes a decline of metabolic and immune functions with impact on the cognitive functions. Although, some decline in cognitive function does occur with normal aging, there is also an increased age-associated risk of neurodegenerative disorders such as Alzheimer’s disease (AD) [1]. At the same time, it highlights the need for a more comprehensive understanding of how different aspects of lifestyle such as physical exercise, meditation, musical experience, and diet may influence brain disorders in a preventative manner, affecting long-term neural function that affects cognitive performance [2]. In relation to the diet, flavonoids have been described as promising plant-based bioactives capable of modulating different aspects of neuroplasticity, resulting in improvements in memory in both rodents [2] and humans [3, 4]. For example, flavonoids have been correlated with their ability to modulate the phosphorylation state of intracellular proteins by the activation or inhibition of phosphoinositide 3-kinase (PI3K), protein kinase C (PKC), mitogen-activated protein kinase (MAP), CAMP responsive element binding protein 1 (CREB-1), growth associated protein 43 (GAP-43), brain-derived neurotrophic factor (BDNF), or to alter expression of N-methyl d-aspartic acid (NMDA) receptors (NMDARs), GABAA receptors (GABAARs), and 5-HT receptors (5-HTRs) [5, 6]. In addition, flavonoids can modulate epigenetic modifications [7]. These mechanisms are critical for the neuroplasticity and they are also related with inflammatory processes in the brain.

The aim of this chapter is to highlight the potential of flavonoid-rich food, flavonoid-rich extract, and medicinal plants that act as modulators of neuroplasticity in the central nervous system of mammals. We provide an outline of the neuroplasticity and how flavonoids affect this mechanism, and we will also describe their interaction in the neuroinflammation mechanism that affects the cognition. It will highlight the probable mechanisms that flavonoids promote neuroprotective effect in aging.

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2. Flavonoids structure and brain bioavailability

Flavonoids are a large group of naturally occurring plant-based compounds that are commonly consumed through a diet rich in fruit, vegetables, tea, wine, and soy-based foods, being of considerable scientific and therapeutic interest. Flavonoids are responsible for numerous functions in plants. Among them, we can mention protection against ultraviolet rays, against insects, fungi, viruses, and bacteria, and the ability to provide the attraction of pollinating animals. In addition to these characteristics, many of these compounds also possess important pharmacological properties, such as antiviral, antitumor, anti-inflammatory, antioxidant, anti-inflammatory activity, and neuroprotective actions.

Flavonoids consist of two aromatic carbon rings, benzopyran (A and C rings) and benzene (B ring) (Figure 1). Flavonoids can be subdivided into different subclasses depending on the carbon of the C ring on which the B ring is attached and the degree of unsaturation and oxidation of the C ring on which the B ring is attached and the degree of unsaturation and oxidation of C ring. Thus, they may be divided in seven subclasses as: (1) flavones (e.g. apigenin, luteolin); (2) flavonols (e.g. kaempferol, quercetin); (3) isoflavones (e.g. daidzein, genistein); (4) chalcones (e.g. phloretin, chalconaringenin); (5) flavanones (e.g. naringenin, hesperetin); (6) anthocyanidins (e.g. delphinidin, cyanidin) and, (7) flavanols [e.g. catechin, epicatechin, epigallocatechin, epigallocatechin gallate (EGCG)] [8]. For further information regarding the structure and classes of flavonoids, you can see references Andersen and Markhan [8].

Figure 1.

Basic skeleton structure of flavonoids, subclasses, and their natural sources.

Although flavonoids display directly modulate brain function, during absorption; they are extensive metabolized, resulting in a wide variety of metabolic derivatives. Do flavonoids access the brain?

In order to understand whether flavonoids are capable of modulating brain function, it is important to understand the bioavailability. Bioavailability is a crucial factor determining their biological activity in vivo. Therefore, information on the absorption and metabolism of dietary flavonoids in the digestive tract is important for determining their physiological functions, and what if flavonoids and their metabolic derivatives cross the Blood-Brain Barrier (BBB) [9, 10, 11]. This point is still a matter of debate, despite a number of studies shows the presence of flavonoids and their metabolites in brain tissue following oral administration of flavonol, e.g. (−) epicatechin [10], flavanones, e.g. hesperetin [11] and flavone, e. g. baicalein [12, 13]. The capacity of flavonoids and their metabolites to cross BBB is dependent on the degree of lipophilicity of each compound, i.e., less polar O-methylated metabolites may be capable of greater brain uptake than the more polar flavonoid glucuronides [14].

Bioavailability studies using flavonoids labeled with radioactive were found in various brain tissues such as hypothalamus, superior colliculus, cerebellum, striatum, and in limbic system structures as cortex and hippocampus [9, 11, 15], both important for memory formation, and are also adversely affected by aging and neurodegenerative diseases. It is a necessary work to discuss bioavailability of flavonoids in brain; however, some studies showed the direct and protective effects of flavonoids in modulating brain function, which will be discussed below.

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3. Impact of flavonoids on cognition

The common medicine has focused on symptoms and treatment but the majority of chronical diseases are the result of unhealthy habits. The lifestyle medicine has focused on prevention, which means an increase in life quality, well-being, and avoids morbidity conditions [16]. Habitual consumption of dietary flavonoids has been consistently linked with improving cognitive functions [17, 18, 19]. For this reason, the flavonoids have been described as a class promised to maintain cognition functions and/or to delay in the progression of age-related cognitive. Despite a growing body of animal studies demonstrating positive effects in learning and memory after flavonoid intake (discussed in the next session), the human clinical trials are somewhat scarcer.

The neurobehavioral effects of phytoestrogens have been the limited data that exist regarding the influence of soy-derived dietary isoflavones on brain structure and function [20]. Clinical trial studies showed the efficacy of isoflavones on cognitive function in postmenopausal women. For example, Long term soy-isoflavone-based supplement (110 mg/d) for 6 months showed better verbal memory than the placebo control group [21]. Similarly, in women aged 50–65 found that intake of 60 mg/d for 3 months resulted in cognitive improvement in several categories related to frontal cortical functions [22]. Another study, involving younger postmenopausal women receiving 160 mg/d isoflavones for 6 months, and results showed an improvement cognitive flexibility [23].

With respect to anthocyanins, blueberry flavonoids supplement (579 mg/d) for 7 days induce cognitive improvements in young and aged adults [24]. Similar results were found after 3 months (long-term supplementation) with blueberry juice in older adults with cognitive impairment in working memory [25]. Some studies address the cognitive impact of a single dose of a blueberry juice in children (8–10 years old) [26]. This study showed for the first time a cognitive benefit for acute flavonoid intervention in children. Another study with 30 g of lyophilized anthocyanins, equivalent to 240 g or 1½ cups of fresh blueberries, demonstrated beneficial cognitive effects on memory and attention, not extending reading ability, in healthy children of 7–10 years of age. These findings increase the growing body of evidence that flavonoids are beneficial to healthy brain function [27].

Finally, precise estimation of nutrient intake is essential for establishing a relationship between diet and cognitive function. However, estimations of dietary flavonoid intake need to take into account their complexity and variability. More recently, a review reported wide range for mean total flavonoid intakes between 209 and 1017 mg/d (mean 435 mg/d) in European, US, and Australian adult populations [28]. In Brazil, the estimate is between 60 and 106 mg/d [29]. There are substantial variations in population estimates of dietary flavonoid intake, which may be associated to true differences in dietary patterns, such as differences in the food supply and cultural eating patterns between countries. Further studies are required to address and to detect effects of dietary interventions on human cognitive functions.

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4. Mechanisms underpinning the actions of flavonoids as synaptic plasticity modulators

Flavonoid subclass has been extensively studied. For this reason, flavonoids have been recognized as promising agents capable of influencing different aspects of synaptic plasticity resulting in improvements in learning and memory. It is not completely clear how flavonoids affect synaptic plasticity. A growing body of evidence suggests that they can (1) modulate receptor function, and (2) promote the expression of synaptic plasticity-related genes and proteins (Figure 2). The next sections outline the effects of flavonoids in synaptic plasticity and how these may underpin improvements in memory.

Figure 2.

Mechanisms underpinning the actions of flavonoids.

4.1 Flavonoid-receptor interactions

There are a number of studies that support the flavonoid-receptor interactions. For example, blueberry intake by young rodents increases the levels of GluN2b subunit of N-methy-d-aspartate receptor (NMDAR) in hippocampus [30]. Similarly, in young rodents, acute effect of oral flavonoid-rich fraction (Ff) intake up-regulated mRNA expression of the GluN2b subunit in dorsal hippocampus [5]. The flavonoid-rich fraction (Ff) containing flavones (Vitexin, Isovitexin, and 6-C-glycoside-Diosmetin) and improves learning and memory in young rodents. It is known that NMDARs are centrally involved in synaptic transmission, synaptic plasticity (long-term potentiation – LTP and long-term depression – LTD), and learning and memory [31]. According to this, quercetin resulted in improvements of hippocampal CA1 long-term potentiation in acute hippocampal slice from young rats [32].

The serotoninergic and GABAergic neurotransmissions are involved in learning and memory; the major targets are 5-HT1ARs and GABAARs, and the modulation of these receptors in the hippocampus is essential for the acquisition and consolidation of memory [33, 34, 35]. Supporting, acute effect of oral Ff up-regulated mRNA expression of the 5-HT1AR and GABA(A) alpha 5 receptor in dorsal hippocampus from young rats [5]. Molecular docking study showed that flavones such as Isovitexin and 6-C-glycoside-Diosmetin exhibited a strong interaction with the GABAA BZ binding pocket. Those flavones showed a lack of interaction with α1His101, which may explain the memory-enhancing effect identified in the behavioral test in young rats [36].

Flavonoids can modulate other receptors such as TrKB [37], δ-opioid [38, 39], nicotinic [40, 41], estrogen [42, 43], and adenosine [44, 45, 46]. For example, 7,8-dihydroxyflavone, a flavone, was shown high-affinity agonist of the TrKB receptor [47]. In addition, the flavones may improve cognition by modulating the acetylcholine and neurotrophic factors synthesis in hippocampus and frontal cortex [27, 48]. Those flavonoid-binding sites show many possibilities of flavonoids action mechanisms to modulate cognition and brain physiology.

4.2 Flavonoid-signaling pathways interactions

Receptor binding by flavonoids is responsible by changes in the up-regulated and down-regulated pathways such as, PI3K, PKC, MAP kinases, and nuclear factor-κB pathway. Their influence on such pathways suggests that they may modulate synaptic plasticity involved in neurodegenerative diseases, and memory acquisition, consolidation, and storage.

Short-term and long-term treatment of oral Ginkgo biloba (EGb) extract up-regulated mRNA and protein of the CREB-1 and GAP-43 in dorsal hippocampus from young rats [49, 50]. These molecules are associated with molecular mechanism LTP, and it has been shown that the transcription factor, cAMP response element-binding protein (CREB), may regulate the synthesis of new proteins necessary for the formation of memory. Another potential protein associated with LTP is the protein 43-kDa growth-associated protein (GAP-43), and they dramatically enhances during LTP [51, 52, 53]. Quercetin-increased expression of activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) [54] pathway is important for memory.

Flavanols and flavanones activate the ERK pathway [55, 56, 57, 58] and ERK modulate cAMP response element binding protein (CREB) activation, which is involved in long-term changes in synapses and memory formation [37, 38, 39]. Similarly, acute effect of oral Ff up-regulated mRNA expression of the ERK in dorsal hippocampus from young rats [5].

In addition, the flavonoids may modulate the protein kinases, as MAP-kinase and PI3-kinase [59, 60, 61, 62], the alteration on activation of kinase may influence directly on modulation of activity-dependent plasticity and morphological changes in synapses involved in memory acquisition, consolidation, and storage [63].

In summary, the ability of flavonoids to influence receptor activity and synaptic plasticity suggest that these might underpin enhancements in cognitive functions in both health conditions and neurological/psychiatric disorders. Additional approaches are required to understand the molecular mechanisms involved in these processes, for example, electrophysiological studies in rodents and human.

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5. Prevention of cognitive decline through lifestyle interventions

There is increasing evidence that diet rich in flavonoid or supplements might delay the initiation of and/or slow the progression of cognitive decline related to aging and Alzheimer’s diseases (AD). Among existing dietary patterns, adherence to a Mediterranean diet is associated with less cognitive decline, dementia, or AD [64, 65]. For example, a meta-analysis showed that greater adherence to a Mediterranean-style dietary pattern during older adulthood was associated with a lower risk of developing several different health outcomes such as CVD, neurodegenerative disorders, cancer, and overall mortality [66].

With regard to AD, the consumption of food rich in flavonoids such as red wine, fruit juice, and vegetables has been shown to delay the onset of AD [17, 67]. This is in accordance with previous studies linking high consumption of flavonoids to decline related to aging and dementia [19, 68]. A number of studies using animal models of AD have begun to investigate the possible mechanisms involved in these effects. For example, oral administration of the green tea flavonoid EGCG for 6 months to mice overexpressing the Swedish mutation of APP (Tg2576) reduced amyloid β (Aβ) pathology as well as improving cognition [69], and similarly long-term green tea catechin administration improved spatial learning and memory in senescence-prone mice [70]. Furthermore, feeding APP+PS1 double-transgenic mice blueberry from 4 months of age prevented deficits in Y-maze performance at 12 months, without altering the Aβ burden [71]. The myricetin and morin are successful to inhibit the β-sheet of Aβ oligomers. Apigenin, a flavone, and quercetin, a flavonol, have shown promising results with animal model of AD, and quercetin has shown to be benefit to early-stage AD patients [72].

The mechanism underlying these changes is not clear but might be linked to increase α-secretase activity [73] reported in vitro and in vivo after i.p. injection of EGCG [42, 74] or due to disruption of cAbl/Fe65 interactions [75]. Gallic acid and catechin-rich grape seed polyphenolic extract (GSPE) administered for 5 months to Tg2576 mice inhibited cognitive deterioration coincident with reduced levels of soluble high-molecular-weight oligomers of Aβ [76]. Moreover, GSPE also inhibits tau fibrillization, promotes the loss of preformed tau aggregates, and disrupts paired helical filaments [77, 78, 79, 80]. EGCG seems to have broadly similar effects. (−)-Epicatechin and hesperetin hold the potential to inhibit the development of tau pathology through an alternative mechanism relating to their ability to enhance Akt phosphorylation, thereby inhibiting GSK3β-induced tau hyperphosphorylation [55, 56]. Overall, this supports the claim that orally active flavonoids could have the utility in AD beyond anti-Aβ actions. The challenge ahead is to determine if flavonoids have efficacy in individuals affected by dementia.

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6. Discussion: future directions

The consumption of flavonoid-rich foods and supplements throughout life may have the potential to limit or even reverse the progression of cognitive decline related of aging and potentially delay the onset and progression of dementia. The mechanisms by which flavonoids modulate cognitive functions are yet to be fully established.

In relation to synaptic plasticity, it will be particularly important to investigate the potential effect of flavonoids that mediate the induction of long-term depression (LTD), short-term potentiation (STP), and long-term potentiation (LTP) in hippocampus area. To dementia, it will be important to investigate the potential utility of flavonoids in the modulation of amyloid β pathology in more detail. In addition, it will be important to clearer dietary recommendations on flavonoid intake (including potentially a “recommended daily intake” level). Indeed, there are a number of important questions still to be resolved.

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Conflict of interest

None.

References

  1. 1. Wu YT, Beiser AS, Breteler MMB, Fratiglioni L, Helmer C, Hendrie HC, et al. The changing prevalence and incidence of dementia over time-current evidence. Nature Reviews. Neurology. 2017;13(6):327-339
  2. 2. Kivipelto M, Mangialasche F, Ngandu T. Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nature Reviews Neurology. 2018;14(11):653-666
  3. 3. Mills CE, Flury A, Marmet C, Poquet L, Rimoldi SF, Sartori C, et al. Mediation of coffee-induced improvements in human vascular function by chlorogenic acids and its metabolites: Two randomized, controlled, crossover intervention trials. Clinical Nutrition. 2017;36(6):1520-1529
  4. 4. Gildawie KR, Galli RL, Shukitt-Hale B, Carey AN. Protective effects of foods containing flavonoids on age-related cognitive decline. Current Nutrition Reports. 2018;7(2):39-48
  5. 5. de Oliveira DR, Zamberlam CR, Rêgo GM, Cavalheiro A, Cerutti JM, Cerutti SM. Effects of a flavonoid-rich fraction on the acquisition and extinction of fear memory: Pharmacological and molecular approaches. Frontiers in Behavioral Neuroscience. 2016;9:345
  6. 6. Zamberlam C, Vendrasco N, Oliveira D, Gaiardo R, Cerutti S. Effects of standardized Ginkgo biloba extract on the acquisition, retrieval and extinction of conditioned suppression: Evidence that short-term memory and long-term memory are differentially modulated. Physiology & Behavior. 2016;165:55-68
  7. 7. Busch C, Burkard M, Leischner C, Lauer UM, Frank J, Venturelli S. Epigenetic activities of flavonoids in the prevention and treatment of cancer. Clinical Epigenetics. 2015;7(1):64
  8. 8. Andersen OM, Markham KR. Flavonoids: Chemistry, Biochemistry and Applications. New York, USA: CRC Press. Taylor & Francis Group; 2005
  9. 9. Milbury PE, Kalt W. Xenobiotic metabolism and berry flavonoid transport across the blood-brain barrier. Journal of Agricultural and Food Chemistry. 2010;58(7):3950-3956
  10. 10. Faria A, Meireles M, Fernandes I, Santos-Buelga C, Gonzalez-Manzano S, Dueñas M, et al. Flavonoid metabolites transport across a human BBB model. Food Chemistry. 2014;149:190-196
  11. 11. Datla KP, Christidou M, Widmer WW, Rooprai HK, Dexter DT. Tissue distribution and neuroprotective effects of citrus flavonoid tangeretin in a rat model of Parkinson’s disease. Neuroreport. 2001;12(17):3871-3875
  12. 12. Tsai T, Liu S, Tsai P, Ho L, Shum A, Chen C. The effects of the cyclosporin A, a P-glycoprotein inhibitor, on the pharmacokinetics of baicalein in the rat: A microdialysis study. British Journal of Pharmacology. 2002;137(8):1314-1320
  13. 13. Schaffer S, Halliwell B. Do polyphenols enter the brain and does it matter? Some theoretical and practical considerations. Genes & Nutrition. 2012;7(2):99
  14. 14. Youdim KA, Dobbie MS, Kuhnle G, Proteggente AR, Abbott NJ, Rice-Evans C. Interaction between flavonoids and the blood-brain barrier: In vitro studies. Journal of Neurochemistry. 2003;85(1):180-192
  15. 15. Passamonti S, Vrhovsek U, Vanzo A, Mattivi F. Fast access of some grape pigments to the brain. Journal of Agricultural and Food Chemistry. 2005;53(18):7029-7034
  16. 16. Bodai BI, Nakata TE, Wong WT, Clark DR, Lawenda S, Tsou C, et al. Lifestyle medicine: A brief review of its dramatic impact on health and survival. The Permanente Journal. 2018;22:17-25
  17. 17. Dai Q , Borenstein AR, Wu Y, Jackson JC, Larson EB. Fruit and vegetable juices and Alzheimer’s disease: The kame project. The American Journal of Medicine. 2006;119(9):751-759
  18. 18. Laurin D, Masaki KH, Foley DJ, White LR, Launer LJ. Midlife dietary intake of antioxidants and risk of late-life incident dementia: The Honolulu-Asia Aging Study. American Journal of Epidemiology. 2004;159(10):959-967
  19. 19. Letenneur L, Proust-Lima C, Le Gouge A, Dartigues J-F, Barberger-Gateau P. Flavonoid intake and cognitive decline over a 10-year period. American Journal of Epidemiology. 2007;165(12):1364-1371
  20. 20. Lephart ED, Setchell KD, Lund TD. Phytoestrogens: Hormonal action and brain plasticity. Brain Research Bulletin. 2005;65(3):193-198
  21. 21. Kritz-Silverstein D, Von Mühlen D, Barrett-Connor E, Bressel MA. Isoflavones and cognitive function in older women: The SOy and Postmenopausal Health in Aging (SOPHIA) Study. Menopause. 2003;10(3):196-202
  22. 22. File SE, Jarrett N, Fluck E, Duffy R, Casey K, Wiseman H. Eating soya improves human memory. Psychopharmacology. 2001;157(4):430-436
  23. 23. Kreijkamp-Kaspers S, Kok L, Grobbee DE, De Haan EH, Aleman A, Lampe JW, et al. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: A randomized controlled trial. Journal of the American Medical Association. 2004;292(1):65-74
  24. 24. Dodd GF. The Acute Effects of Flavonoid-Rich Blueberries on Cognitive Function in Healthy Younger and Older Adults. Berkshire, UK: University of Reading, School of Chemistry, Food & Pharmacy; 2012
  25. 25. Krikorian R, Shidler MD, Nash TA, Kalt W, Vinqvist-Tymchuk MR, Shukitt-Hale B, et al. Blueberry supplementation improves memory in older adults. Journal of Agricultural and Food Chemistry. 2010;58(7):3996-4000
  26. 26. Whyte AR, Williams CM. Effects of a single dose of a flavonoid-rich blueberry drink on memory in 8 to 10 y old children. Nutrition. 2015;31(3):531-534
  27. 27. Pan Y, Anthony M, Clarkson TB. Evidence for up-regulation of brain-derived neurotrophic factor mRNA by soy phytoestrogens in the frontal cortex of retired breeder female rats. Neuroscience Letters. 1999;261(1-2):17-20
  28. 28. Peterson JJ, Dwyer JT, Jacques PF, McCullough ML. Improving the estimation of flavonoid intake for study of health outcomes. Nutrition Reviews. 2015;73(8):553-576
  29. 29. Arabbi PR, Genovese MI, Lajolo FM. Flavonoids in vegetable foods commonly consumed in Brazil and estimated ingestion by the Brazilian population. Journal of Agricultural and Food Chemistry. 2004;52(5):1124-1131
  30. 30. Rendeiro C, Foley A, Lau VC, Ring R, Rodriguez-Mateos A, Vauzour D, et al. A role for hippocampal PSA-NCAM and NMDA-NR2B receptor function in flavonoid-induced spatial memory improvements in young rats. Neuropharmacology. 2014;79:335-344
  31. 31. Bliss TV, Collingridge GL. Expression of NMDA receptor-dependent LTP in the hippocampus: Bridging the divide. Molecular Brain. 2013;6(1):5
  32. 32. Yao Y, Han D, Zhang T, Yang Z. Quercetin improves cognitive deficits in rats with chronic cerebral ischemia and inhibits voltage-dependent sodium channels in hippocampal CA1 pyramidal neurons. Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives. 2010;24(1):136-140
  33. 33. Izquierdo I, Medina JH. Memory formation: The sequence of biochemical events in the hippocampus and its connection to activity in other brain structures. Neurobiology of Learning and Memory. 1997;68(3):285-316
  34. 34. Alonso M, Viola H, Izquierdo I, Medina JH. Aversive experiences are associated with a rapid and transient activation of ERKs in the rat hippocampus. Neurobiology of Learning and Memory. 2002;77(1):119-124
  35. 35. Milad MR, Wright CI, Orr SP, Pitman RK, Quirk GJ, Rauch SL. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biological Psychiatry. 2007;62(5):446-454
  36. 36. de Oliveira DR, Todo AH, Rêgo GM, Cerutti JM, Cavalheiro AJ, Rando DGG, et al. Flavones-bound in benzodiazepine site on Gabaa receptor: Concomitant anxiolytic-like and cognitive-enhancing effects produced by isovitexin and 6-c-glycoside-diosmetin. European Journal of Pharmacology. 2018;831:77-86
  37. 37. Impey S, Smith DM, Obrietan K, Donahue R, Wade C, Storm DR. Stimulation of cAMP response element (CRE)-mediated transcription during contextual learning. Nature Neuroscience. 1998;1(7):595
  38. 38. Pham TA, Impey S, Storm DR, Stryker MP. CRE-mediated gene transcription in neocortical neuronal plasticity during the developmental critical period. Neuron. 1999;22(1):63-72
  39. 39. Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM, Greenberg ME. CREB: A major mediator of neuronal neurotrophin responses. Neuron. 1997;19(5):1031-1047
  40. 40. Lee B-H, Choi S-H, Shin T-J, Pyo MK, Hwang S-H, Kim B-R, et al. Quercetin enhances human α7 nicotinic acetylcholine receptor-mediated ion current through interactions with Ca2+ binding sites. Molecules and Cells. 2010;30(3):245-253
  41. 41. Lee B-H, Choi S-H, Shin T-J, Pyo MK, Hwang S-H, Lee S-M, et al. Effects of quercetin on α9α10 nicotinic acetylcholine receptor-mediated ion currents. European Journal of Pharmacology. 2011;650(1):79-85
  42. 42. Fernandez JW, Rezai-Zadeh K, Obregon D, Tan J. EGCG functions through estrogen receptor-mediated activation of ADAM10 in the promotion of non-amyloidogenic processing of APP. FEBS Letters. 2010;584(19):4259-4267
  43. 43. Collins-Burow BM, Burow ME, Duong BN, McLachlan JA. Estrogenic and antiestrogenic activities of flavonoidphytochemicals through estrogen receptorbinding-dependent and -independent mechanisms. Nutrition and Cancer. 2000;38(2):229-244
  44. 44. Jacobson KA, Moro S, Manthey JA, West PL, Ji XD Interactions of flavones and other phytochemicals with adenosine receptors. Advances in Experimental Medicine and Biology. 2002;505:163-171
  45. 45. Alexander SP. Flavonoids as antagonists at A1 adenosine receptors. Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives. 2006;20(11):1009-1012
  46. 46. Moro S, van Rhee AM, Sanders LH, Jacobson KA. Flavonoid derivatives as adenosine receptor antagonists: A comparison of the hypothetical receptor binding site based on a comparative molecular field analysis model. Journal of Medicinal Chemistry. 1998;41(1):46-52
  47. 47. Jang S-W, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, et al. A selective TrkB agonist with potent neurotrophic activities by 7, 8-dihydroxyflavone. Proceedings of the National Academy of Sciences. 2010;107(6):2687-2692
  48. 48. Pan Y, Anthony M, Clarkson TB. Effect of estradiol and soy phytoestrogens on choline acetyltransferase and nerve growth factor mRNAs in the frontal cortex and hippocampus of female rats. Proceedings of the Society for Experimental Biology and Medicine. 1999;221(2):118-125
  49. 49. Oliveira DR, Sanada PF, Saragossa FA, Innocenti L, Oler G, Cerutti JM, et al. Neuromodulatory property of standardized extract Ginkgo biloba L.(EGb 761) on memory: Behavioral and molecular evidence. Brain Research. 2009;1269:68-89
  50. 50. Oliveira D, Sanada P, Conceição G, Cerutti J, Cerutti S. Long-term treatment with standardized extract of Ginkgo biloba L. enhances the conditioned suppression of licking in rats by the modulation of neuronal and glial cell function in the dorsal hippocampus and central amygdala. Neuroscience. 2013;235:70-86
  51. 51. Lamprecht R. CREB: A message to remember. Cellular and Molecular Life Sciences CMLS. 1999;55(4):554-563
  52. 52. Holahan MR, Honegger KS, Tabatadze N, Routtenberg A. GAP-43 gene expression regulates information storage. Learning & Memory. 2007;14(6):407-415
  53. 53. Routtenberg A, Cantallops I, Zaffuto S, Serrano P, Namgung U. Enhanced learning after genetic overexpression of a brain growth protein. Proceedings of the National Academy of Sciences. 2000;97(13):7657-7662
  54. 54. Williams CM, El Mohsen MA, Vauzour D, Rendeiro C, Butler LT, Ellis JA, et al. Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radical Biology and Medicine. 2008;45(3):295-305
  55. 55. Schroeter H, Bahia P, Spencer JP, Sheppard O, Rattray M, Cadenas E, et al. (−) Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons. Journal of Neurochemistry. 2007;101(6):1596-1606
  56. 56. Vauzour D, Vafeiadou K, Rice-Evans C, Williams RJ, Spencer JP. Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons. Journal of Neurochemistry. 2007;103(4):1355-1367
  57. 57. Maher P, Akaishi T, Abe K. Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proceedings of the National Academy of Sciences. 2006;103(44):16568-16573
  58. 58. Schroeter H, Spencer JP, Catherine R-E, Williams RJ. Flavonoids protect neurons from oxidized low-density-lipoprotein-induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3. Biochemical Journal. 2001;358(3):547-557
  59. 59. Spencer JP. The impact of flavonoids on memory: Physiological and molecular considerations. Chemical Society Reviews. 2009;38(4):1152-1161
  60. 60. Spencer JP. The impact of fruit flavonoids on memory and cognition. British Journal of Nutrition. 2010;104(S3):S40-SS7
  61. 61. Spencer JP. The interactions of flavonoids within neuronal signalling pathways. Genes & Nutrition. 2007;2(3):257-273
  62. 62. Fraga CG, Oteiza PI. Dietary flavonoids: Role of (−)-epicatechin and related procyanidins in cell signaling. Free Radical Biology and Medicine. 2011;51(4):813-823
  63. 63. Williams RJ, Spencer JP. Flavonoids, cognition, and dementia: Actions, mechanisms, and potential therapeutic utility for Alzheimer disease. Free Radical Biology and Medicine. 2012;52(1):35-45
  64. 64. Cao L, Tan L, Wang H-F, Jiang T, Zhu X-C, Lu H, et al. Dietary patterns and risk of dementia: A systematic review and meta-analysis of cohort studies. Molecular Neurobiology. 2016;53(9):6144-6154
  65. 65. van de Rest O, Berendsen AA, Haveman-Nies A, de Groot LC. Dietary patterns, cognitive decline, and dementia: A systematic review. Advances in Nutrition. 2015;6(2):154-168
  66. 66. Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the Mediterranean diet on health: An updated systematic review and meta-analysis. The American Journal of Clinical Nutrition. 2010;92(5):1189-1196
  67. 67. Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues J-F, et al. Dietary patterns and risk of dementia the Three-City cohort study. Neurology. 2007;69(20):1921-1930
  68. 68. Commenges D, Scotet V, Renaud S, Jacqmin-Gadda H, Barberger-Gateau P, Dartigues J-F. Intake of flavonoids and risk of dementia. European Journal of Epidemiology. 2000;16(4):357-363
  69. 69. Rezai-Zadeh K, Arendash GW, Hou H, Fernandez F, Jensen M, Runfeldt M, et al. Green tea epigallocatechin-3-gallate (EGCG) reduces β-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice. Brain Research. 2008;1214:177-187
  70. 70. Li Q , Zhao H, Zhang Z, Liu Z, Pei X, Wang J, et al. Long-term green tea catechin administration prevents spatial learning and memory impairment in senescence-accelerated mouse prone-8 mice by decreasing Aβ1-42 oligomers and upregulating synaptic plasticity–related proteins in the hippocampus. Neuroscience. 2009;163(3):741-749
  71. 71. Joseph JA, Arendash G, Gordon M, Diamond D, Shukitt-Hale B, Morgan D, et al. Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutritional Neuroscience. 2003;6(3):153-162
  72. 72. Nakagawa T, Itoh M, Ohta K, Hayashi Y, Hayakawa M, Yamada Y, et al. Improvement of memory recall by quercetin in rodent contextual fear conditioning and human early-stage Alzheimer’s disease patients. Neuroreport. 2016;27(9):671-676
  73. 73. Obregon DF, Rezai-Zadeh K, Bai Y, Sun N, Hou H, Ehrhart J, et al. ADAM10 activation is required for green tea (−)-epigallocatechin-3-gallate-induced α-secretase cleavage of amyloid precursor protein. Journal of Biological Chemistry. 2006;281(24):16419-16427
  74. 74. Rezai-Zadeh K, Shytle D, Sun N, Mori T, Hou H, Jeanniton D, et al. Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice. Journal of Neuroscience. 2005;25(38):8807-8814
  75. 75. Lin C-L, Chen T-F, Chiu M-J, Way T-D, Lin J-K. Epigallocatechin gallate (EGCG) suppresses β-amyloid-induced neurotoxicity through inhibiting c-Abl/FE65 nuclear translocation and GSK3β activation. Neurobiology of Aging. 2009;30(1):81-92
  76. 76. Wang J, Ho L, Zhao W, Ono K, Rosensweig C, Chen L, et al. Grape-derived polyphenolics prevent Aβ oligomerization and attenuate cognitive deterioration in a mouse model of Alzheimer’s disease. Journal of Neuroscience. 2008;28(25):6388-6392
  77. 77. Ksiezak-Reding H, Ho L, Santa-Maria I, Diaz-Ruiz C, Wang J, Pasinetti GM. Ultrastructural alterations of Alzheimer’s disease paired helical filaments by grape seed-derived polyphenols. Neurobiology of Aging. 2012;33(7):1427-1439
  78. 78. Wang J, Santa-Maria I, Ho L, Ksiezak-Reding H, Ono K, Teplow DB, et al. Grape derived polyphenols attenuate tau neuropathology in a mouse model of Alzheimer’s disease. Journal of Alzheimer’s Disease. 2010;22(2):653-661
  79. 79. Pasinetti GM, Ksiezak-Reding H, Santa-Maria I, Wang J, Ho L. Development of a grape seed polyphenolic extract with anti-oligomeric activity as a novel treatment in progressive supranuclear palsy and other tauopathies. Journal of Neurochemistry. 2010;114(6):1557-1568
  80. 80. Ho L, Yemul S, Wang J, Pasinetti GM. Grape seed polyphenolic extract as a potential novel therapeutic agent in tauopathies. Journal of Alzheimer's Disease. 2009;16(2):433-439

Written By

Adriana Aparecida Ferraz Carbonel, Marianna Nogueira Cecyn, João Henrique Rodrigues Castello Girão, Gisela Rodrigues da Silva Sasso, Bárbara de Mello Ponteciano, Eliana Pereira Vellozo, Ricardo Santos Simões, Manuel de Jesus Simões, Manoel João Batista Castello Girão and Daniela Rodrigues de Oliveira

Submitted: September 13th, 2018 Reviewed: January 4th, 2019 Published: October 17th, 2019