Flavonoids and cognition: The molecular mechanisms underlying their behavioural effects

Evidence Suggests that a group of phytochemicals known as flavonoids are highly effective in reversing age-related declines in neuro-cognitive performance through their ability to interact with the cellular and molecular architecture of the brain responsible for memory and by reducing neuronal loss due to neurodegenerative Processes. In particular, they may increase the number of, and strength of, connections between neurons, via their specific interactions with the ERK and Akt signalling pathways, leading to an increase in neurotrophins Such as BDNF. Concurrently, their effects on the peripheral and Cerebral vascular system may also lead to enhancements in cognitive performance through increased brain blood flow and an ability to initiate neurogenesis in the hippocampus. Finally, they have also been shown to reduce neuronal damage and losses induced by various neurotoxic species and neuroinflammation. Together, these processes act to maintain the number and quality of synaptic connections in the brain. a factor known to be essential for efficient LTP, synaptic plasticity and ultimately the efficient working of memory. (C) 2009 Elsevier Inc. All rights reserved.

Biomarkers of the intake of dietary polyphenols: strengths, limitations and application in nutrition research

In order to establish firm evidence for the health effects of dietary polyphenol consumption, it is essential to have quantitative information regarding their dietary intake. The usefulness of the current methods, which rely mainly on the assessment of polyphenol intake using food records and food composition tables, is limited as they fail to assess total intake accurately. This review highlights the problems associated with such methods with regard to polyphenol-intake predictions. We suggest that the development of biological biomarkers, measured in both blood and urine, are essential for making accurate estimates of polyphenol intake. However, the relationship between dietary intakes and nutritional biomarkers are often highly complex. This review identifies the criteria that must be considered in the development of such biomarkers. In addition, we provide an assessment of the limited number of potential biomarkers of polyphenol intake currently available.

The genotypic variation of the antioxidant potential of different tomato varieties

There is increasing interest in the ability of diets rich in polyphenols to modulate age-related diseases and promote healthy ageing. We have conducted a pilot experiment with eight tomato varieties to correlate the total antioxidant capacity of the tomato variants with the specific constituent flavonoids present. A strong correlation was observed with the flavonol rhamnoglucoside rutin but not with other flavonoids, such as naringenin chalcone, or hydroxycinnamates, such as chlorogenic, which are also present in the tomato. To test the rigor of this correlation a second study was undertaken with a further 37 tomato varieties selected for low, medium and high rutin levels. We show that the flavonol rutin contributes to the greatest extent to the antioxidant capacity of tomatoes and suggest that this flavonoid may be a useful target for up-regulation in tomatoes in order to improve their antioxidant status.

Cellular uptake and metabolism of flavonoids and their metabolites: implications for their bioactivity

Flavonoids have been proposed to act as beneficial agents in a multitude of disease states, including cancer, cardiovascular disease, and neurodegenerative disorders. The biological effect of these polyphenols and their in vivo circulating metabolites will ultimately depend on the extent to which they associate with cells, either by interactions at the membrane or more importantly their uptake. This review summarises the current knowledge on the cellular uptake of flavonoids and their metabolites with particular relevance to further intracellular metabolism and the generation of potential new bioactive forms. Uptake and metabolism of the circulating forms of flavanols, flavonols, and flavanones into cells of the skin, the brain, and cancer cells is reviewed and potential biological relevance to intracellular formed metabolites is discussed.

Metabolism of dietary phytochemicals: a review of the metabolic forms identified in humans

Dietary derived phytochemicals have been proposed to act as beneficial agents in a multitude of disease states, including cancer, cardiovascular disease and neurodegenerative disorders. However, the biological effect of such compounds will ultimately depend on the cellular effects of their circulating metabolites. The focus of this review is to examine the current knowledge regarding the biotransformation of different classes of phytochemicals in humans. Notably, the data compiled here represents only that obtained from human studies following consumption of phytochemicals in meals or in a dose comparable with normal dietary intake. In addition, we have considered only those studies where more powerful analytical techniques have been used in the characterisation of metabolic forms. We provide clear information regarding the types of metabolites that are likely to be present in humans following oral ingestion. Ultimately this will help identify metabolic forms that should represent the focus of future cellular mechanistic investigations.

Flavonoids and brain health: multiple effects underpinned by common mechanisms

The neuroprotective actions of dietary flavonoids involve a number of effects within the brain, including a potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation, and the potential to promote memory, learning and cognitive function. This multiplicity of effects appears to be underpinned by two processes. Firstly, they interact with important neuronal signalling cascades leading to an inhibition of apoptosis triggered by neurotoxic species and to a promotion of neuronal survival and differentiation. These interactions include selective actions on a number of protein kinase and lipid kinase signalling cascades, most notably the PI3K/Akt and MAP kinase pathways which regulate pro-survival transcription factors and gene expression. Secondly, they induce peripheral and cerebral vascular blood flow in a manner which may lead to the induction of angiogenesis, and new nerve cell growth in the hippocampus. Therefore, the consumption of flavonoid-rich foods, such as berries and cocoa, throughout life holds a potential to limit the neurodegeneration associated with a variety of neurological disorders and to prevent or reverse normal or abnormal deteriorations in cognitive performance.

The impact of flavonoids on memory: physiological and molecular considerations

Emerging evidence suggests that a group of dietary-derived phytochemicals known as flavonoids are able to induce improvements in memory acquisition, consolidation, storage and retrieval. These low molecular weight polyphenols are widespread in the human diet, are absorbed to only a limited degree and localise in the brain at low concentration. However, they have been found to be highly effective in reversing age-related declines in memory via their ability to interact with the cellular and molecular architecture of the brain responsible for memory. These interactions include an ability to activate signalling pathways, critical in controlling synaptic plasticity, and a potential to induce vascular effects capable of causing new nerve cell growth in the hippocampus. Their ability to activate the extracellular signal-regulated kinase (ERK1/2) and the protein kinase B (PKB/Akt) signalling pathways, leading to the activation of the cAMP response element-binding protein (CREB), a transcription factor responsible for increasing the expression of a number of neurotrophins important in de. ning memory, will be discussed. How these effects lead to improvements in memory through induction of synapse growth and connectivity, increases in dendritic spine density and the functional integration of old and new neurons will be illustrated. The overall goal of this critical review is to emphasize future areas of investigation as well as to highlight these dietary agents as promising candidates for the design of memory-enhancing drugs with relevance to normal and pathological brain ageing (161 references).

Food for thought: the role of dietary flavonoids in enhancing human memory, learning and neuro-cognitive performance

Emerging evidence suggests that dietary-derived flavonoids have the potential to improve human memory and neuro-cognitive performance via their ability to protect vulnerable neurons, enhance existing neuronal function and stimulate neuronal regeneration. Long-term potentiation (LTP) is widely considered to be one of the major mechanisms underlying memory acquisition, consolidation and storage in the brain and is known to be controlled at the molecular level by the activation of a number of neuronal signalling pathways. These pathways include the phosphatidylinositol-3 kinase/protein kinase B/Akt (Akt), protein kinase C, protein kinase A, Ca-calmodulin kinase and mitogen-activated protein kinase pathways. Growing evidence suggests that flavonoids exert effects on LTP, and consequently memory and cognitive performance, through their interactions with these signalling pathways. Of particular interest is the ability of flavonoids to activate the extracellular signal-regulated kinase and the Akt signalling pathways leading to the activation of the cAMP-response element-binding protein, a transcription factor responsible for increasing the expression of a number of neurotrophins important in LTP and long-term memory. One such neurotrophin is brain-derived neurotrophic factor, which is known to be crucial in controlling synapse growth, in promoting an increase in dendritic spine density and in enhancing synaptic receptor density. The present review explores the potential of flavonoids and their metabolite forms to promote memory and learning through their interactions with neuronal signalling pathways pivotal in controlling LTP and memory in human subjects.

The interactions of flavonoids within neuronal signalling pathways

Emerging evidence suggests that dietary phytochemicals, in particular flavonoids, may exert beneficial effects in the central nervous system by protecting neurons against stress-induced injury, by suppressing neuroinflammation and by promoting neurocognitive performance, through changes in synaptic plasticity. It is likely that flavonoids exert such effects in neurons, through selective actions on different components within a number of protein kinase and lipid kinase signalling cascades, such as phosphatidylinositol-3 kinase (PI3K)/Akt, protein kinase C and mitogen-activated protein kinase. This review details the potential inhibitory or stimulatory actions of flavonoids within these pathways, and describes how such interactions are likely to affect cellular function through changes in the activation state of target molecules and/or by modulating gene expression. Although, precise sites of action are presently unknown, their abilities to: (1) bind to ATP binding sites on enzymes and receptors; (2) modulate the activity of kinases directly; (3) affect the function of important phosphatases; (4) preserve neuronal Ca2+ homeostasis; and (5) modulate signalling cascades lying downstream of kinases, are explored. Future research directions are outlined in relation to their precise site(s) of action within the signalling pathways and the sequence of events that allow them to regulate neuronal function in the central nervous system.

(-)Epicatechin stimulates ERK-dependent cyclic AMP response element activity and up-regulates GluR2 in cortical neurons

Emerging evidence suggests that the cellular actions of flavonoids relate not simply to their antioxidant potential but also to the modulation of protein kinase signalling pathways. We investigated in primary cortical neurons, the ability of the flavan-3-ol, (-)epicatechin, and its human metabolites at physiologically relevant concentrations, to stimulate phosphorylation of the transcription factor cAMP-response element binding protein (CREB), a regulator of neuronal viability and synaptic plasticity. (-)Epicatechin at 100-300 nmol/L stimulated a rapid, extracellular signal-regulated kinase (ERK)- and PI3K-dependent, increase in CREB phosphorylation. At micromolar concentrations, stimulation was no longer apparent and at the highest concentration tested (30 mu mol/L) (-)epicatechin was inhibitory. (-)Epicatechin also stimulated ERK and Akt phosphorylation with similar bell-shaped concentration-response characteristics. The human metabolite 3 '-O-methyl-(-)epicatechin was as effective as (-)epicatechin at stimulating ERK phosphorylation, but (-)epicatechin glucuronide was inactive. (-)Epicatechin and 3 '-O-methyl-(-)epicatechin treatments (100 nmol/L) increased CRE-luciferase activity in cortical neurons in a partially ERK-dependent manner, suggesting the potential to increase CREB-mediated gene expression. mRNA levels of the glutamate receptor subunit GluR2 increased by 60%, measured 18 h after a 15 min exposure to (-)epicatechin and this translated into an increase in GluR2 protein. Thus, (-)epicatechin has the potential to increase CREB-regulated gene expression and increase GluR2 levels and thus modulate neurotransmission, plasticity and synaptogenesis.

The impact of flavonoids on spatial memory in rodents: from behaviour to underlying hippocampal mechanisms

Emerging evidence suggests that a group of dietary-derived phytochemicals known as flavonoids are able to induce improvements in memory, learning and cognition. Flavonoids have been shown to modulate critical neuronal signalling pathways involved in processes of memory, and therefore are likely to affect synaptic plasticity and long-term potentiation mechanisms, widely considered to provide a basis for memory. Animal dietary supplementation studies have further shown that flavonoid-rich foods are able to reverse age-related spatial memory and spatial learning impairments. A more accurate understanding of how a particular spatial memory task works and of which aspects of memory and learning can be assessed in each case, are necessary for a correct interpretation of data relating to diet-cognition experiments. Further understanding of how specific behavioural tasks relate to the functioning of hippocampal circuitry during learning processes might be also elucidative of the specific observed memory improvements. The overall goal of this review is to give an overview of how the hippocampal circuitry operates as a memory system during behavioural tasks, which we believe will provide a new insight into the underlying mechanisms of the action of flavonoids on cognition.

Modulation of peroxynitrite-induced fibroblast injury by hesperetin: a role for intracellular scavenging and modulation of ERK signalling

Peroxynitrite is thought to contribute to the progression of many diseases including cardiovascular disease, cancer, and neurodegenerative disorders. We report that pre-treatment of fibroblasts with the citrus flavanone, hesperetin, prior to peroxynitrite exposure protects against peroxynitrite-mediated cytotoxicity. This protection was partially mediated by the intracellular scavenging of peroxynitrite by hesperctin as exposure of fibroblasts to peroxynitrite following hesperetin loading led to the formation of two intracellular nitrohesperetin derivatives. In addition, protection appeared to be mediated by hesperetin-induced changes in MAP kinase signalling. Exposure of fibroblasts to hesperetin led to concentration-dependent increases in the phosphorylation of ERK1/2 and was observed to restore peroxynitrite-mediated decreases in ERK1/2 phosphorylation. We propose that the protective potential of hesperetin in fibroblasts may be mediated both by intracellular scavenging of peroxynitrite and by modulation of fibroblast signalling. (c) 2006 Elsevier Inc. All rights reserved.

The reaction of flavonoid metabolites with peroxynitrite

There is much interest in the bioactivity of in vivo flavonoid metabolites. We report for the first time the hierarchy of reactivity of flavonoid metabolites with peroxynitrite and characterise novel reaction products. O-Methylation of the B-ring catechol containing flavonoids epicatechin and quercetin, and O-glucuronidation of all flavonoids reduced their reactivity with peroxynitrite. The reaction of the flavanones hesperetin and naringenin and their glucuronides resulted in the formation of multiple mono-nitrated and nitrosated products. In contrast, the catechol-containing flavonoids epicatechin and quercetin yielded oxidation products which when trapped with glutathione led to the production of glutathionyl-conjugates. However, the O-methylated metabolites of epicatechin yielded both mono-and di-nitrated products and nitrosated metabolites. The 3'-O-methyl metabolite of quercetin also yielded a nitrosated species, although its counterpart 4'-O-methyl quercetin yielded only oxidation products. Such products may represent novel metabolic products in vivo and may also express cellular activity. (c) 2006 Elsevier Inc. All rights reserved.

The intracellular genistein metabolite 5,7,3 ',4 '-tetrahydroxyisoflavone mediates G2-M cell cycle arrest in cancer cells via modulation of the p38 signaling pathway

The cellular actions of genistein are believed to mediate the decreased risk of breast cancer associated with high soy consumption. We have investigated the intracellular metabolism of genistein in T47D tumorigenic and MCF-10A nontumorigenic cells and assessed the cellular actions of resultant metabolites. Genistein selectively induced growth arrest and G2-M phase cell cycle block in T47D but not MCF10A breast epithelial cells. These antiproliferative effects were paralleled by significant differences in the association of genistein to cells and in particular its intracellular metabolism. Genistein was selectively taken up into T47D cells and was subject to metabolism by CYP450 enzymes leading to the formation of both 5,7,3',4'-tetrahydroxyisoflavone (THIF) and two glutathionyl conjugates of THIF THIF inhibited cdc2 activation via the phosphorylation of p38 MAP kinase, suggesting that this species may mediate genistein's cellular actions. THIF exposure activated p38 and caused subsequent inhibition of cyclin B1 (Ser 147) and cdc2 (Thr 161) phosphorylation, two events critical for the correct functioning of the cdc2-cyclin B1 complex. We suggest that the formation of THIF may mediate the cellular actions of genistein in tumorigenic breast epithelial cells via the activation of signaling through p38. (c) 2006 Elsevier Inc. All rights reserved.