Review | Open | Published:
Flavonoids and brain health: multiple effects underpinned by common mechanisms
Genes & Nutritionvolume 4, pages243–250 (2009)
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.
Macronutrients, such as lipids are vital components of both neurons and glial cells and their profile (saturated or un-saturated) has been proposed to play a huge role in brain function . Furthermore, the brain has a very high energy demand and as such utilises a large proportion of the dietary intake of carbohydrates in order to function effectively. However, it is less obvious how other dietary-derived nutrients or non-nutrient components may impact on the functioning of the brain. Despite this, a large number of dietary intervention studies in humans and animals, in particular those using foods and beverages derived from Vitis vinifera (grape), Camellia sinensis (tea), Theobroma cacao (cocoa) and Vaccinium spp. (blueberry) have demonstrated beneficial effects on human vascular function and on improving memory and learning [15, 16, 32, 60, 69, 76, 80]. While such foods and beverages differ greatly in chemical composition, macro- and micronutrient content and caloric load per serving, they have in common that they are amongst the major dietary sources of a group of phytochemicals called flavonoids.
Historically, the biological actions of flavonoids, including those on the brain, have been attributed to their ability to exert antioxidant actions , through their ability to scavenge reactive species, or through their possible influences on intracellular redox status . However, it has been speculated that this classical hydrogen-donating antioxidant activity cannot account for the bioactivity of flavonoids in vivo, particularly in the brain, where they are found at only very low concentrations . Instead, it has been postulated that their effects in the brain are mediated by an ability to protect vulnerable neurons, enhance existing neuronal function, stimulate neuronal regeneration and induce neurogenesis . Indeed, it has become evident that flavonoids are able to exert neuroprotective actions (at low concentration) via their interactions with critical neuronal intracellular signalling pathways pivotal in controlling neuronal survival and differentiation, long-term potentiation (LTP) and memory [61, 74, 78]. This review will examine the potential for flavonoids to influence brain function and will attempt to clarify the mechanisms which underpin such actions in the brain.
Inhibition of neuroinflammation
Neuroinflammatory processes in the brain are believed to play a crucial role in the development of Alzheimer’s and Parkinson’s disease [19, 47] as well as injury associated with stroke . Activated microglia and/or astrocytes release cytokines and other mediators which have been linked to the apoptotic death of neurons. In particular, increases in cytokine production (interleukin-1β, IL-1β; tumour necrosis factor-alpha, TNF-α), inducible nitric oxide synthase (iNOS) and nitric oxide (NO•), and increased NADPH oxidase activation  all contribute to glial-induced neuronal death (Fig. 1). The majority of these events are controlled by upstream mitogen-activated protein kinase (MAPK) signalling which mediates both the transcriptional and post-transcriptional regulation of iNOS and cytokines in activated microglia and astrocytes [6, 45]. Evidence suggests that the non-steroidal anti-inflammatory drug, ibuprofen, may be effective in delaying the onset of neurodegenerative disorders, particularly as Parkinson disease, by reducing inflammatory injury in specific brain regions . As such, there is a desire to develop new drugs capable of preventing progressive neuronal loss linked to neuroinflammation. Recently, the flavanone naringenin found at high concentrations in citrus fruits has been found to be highly effective in reducing LPS/IFN-γ-induced glial cell activation and resulting neuronal injury , via an inhibition of p38 and STAT-1, and a reduction in iNOS expression (Fig. 2). The structurally related flavanone hesperetin and other flavonoids appeared incapable of inhibiting pathways leading to NO• production, although they were found to partially alleviate neuroinflammation through the inhibition of TNF-α production .
Flavonoids present in blueberry have also been shown to inhibit NO•, IL-1β and TNF-α production in activated microglia cells , while the flavonol quercetin , the flavones wogonin and bacalein , the flavanols catechin and epigallocatechin gallate (EGCG)  and the isoflavone genistein  have all been shown to attenuate microglia and/or astrocyte mediated neuroinflammation via mechanisms that include inhibition of: (1) iNOS and cyclooxygenase (COX-2) expression, (2) NO• production, (3) cytokine release, and (4) NADPH oxidase activation and subsequent reactive oxygen species (ROS) generation, in astrocytes and microglia. All of these effects appear to rely via on an ability to directly modulate the protein and lipid kinase signalling pathways [58, 61, 78], for example, via the inhibition of MAPK signalling cascades, such as p38 or ERK1/2 which regulate both iNOS and TNF-α expression in activated glial cells  (Fig. 2). In this respect, fisetin inhibits p38 MAP kinase phosphorylation in LPS-stimulated BV-2 microglial cells  and the flavone luteolin inhibits IL-6 production in activated microglia via the inhibition of the JNK signalling pathway . The effects of flavonoids on these kinases may influence downstream pro-inflammatory transcription factors important in iNOS transcription. One of these, nuclear factor-Kappa B (NF-κB), responds to p38 signalling and is involved in iNOS induction , suggesting that there is interplay between signalling pathways, transcription factors and cytokine production in determining the neuroinflammatory response in the CNS. In support of this, some flavonoids have been shown to prevent transcription factor activation, with the flavonol quercetin and the flavanone naringenin able to suppress NF-κB, signal transducer and activator of transcription-1 (STAT-1) and activating protein-1 (AP-1) activation in LPS- and IFN-γ-activated microglial cells [9, 70].
Inhibition of neurodegeneration
The underlying neurodegeneration observed in Parkinson’s, Alzheimer’s, and other neurodegenerative diseases is believed to be triggered by multi-factorial processes, including neuroinflammation, glutamatergic excitotoxicity, increases in iron and/or depletion of endogenous antioxidants [5, 22, 67]. There is a growing body of evidence to suggest that flavonoids and other polyphenols may be able to counteract this neuronal injury, thereby delaying the progression of these brain pathology [41, 58, 59]. For example, a Ginkgo biloba extract has been shown to protect hippocampal neurons against nitric oxide- and beta-amyloid-induced neurotoxicity ; and studies have demonstrated that the consumption of green tea may have beneficial effect in reducing the risk of Parkinson’s disease [28, 42–44]. In agreement with the latter study, tea extracts and pure (−)-epigallocatechin-3-gallate (EGCG) have been shown to attenuate 6-hydroxydopamine-induced toxicity , to protect against hippocampal injury during transient global ischemia  and to prevent nigral damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) .
The death of nigral neurons in Parkinson’s disease is thought to involve the formation of the endogenous neurotoxin, 5-S-cysteinyl-dopamine (5-S-cys-DA) and its oxidation product, dihydrobenzothiazine (DHBT-1) [18, 65] (Fig. 1). 5-S-cysteinyl-catecholamine conjugates possess strong neurotoxicity and initiate a sustained increase in intracellular ROS in neurons leading to DNA oxidation, caspase-3 activation and delayed neuronal death  (Fig. 1). Such adducts may be generated by reactive species  and have been observed to be elevated in the human substantia nigra of patients who died of Parkinson’s disease , suggesting that such species may be potential endogenous nigral toxins. However, 5-S-cysteinyl-dopamine-induced neuronal injury is effectively counteracted by nanomolar concentrations of various flavonoids, including pelargonidin, quercetin, hesperetin, caffeic acid, the 4′-O-Me derivatives of catechin and epicatechin  (Fig. 2). Furthermore, in the presence of the flavanol, (+)-catechin, tyrosinase-induced formation of 5-S-cysteinyl-dopamine was inhibited by a mechanism linked to the capacity of catechin to undergo tyrosinase-induced oxidation to yield cysteinyl-catechin adducts . In contrast, the inhibition afforded by flavanones, such as hesperetin, was not accompanied with the formation of cysteinyl-hesperetin adducts, indicating that it may inhibit via direct interaction with tyrosinase .
Reactive oxygen and nitrogen species have also been proposed to play a role in the pathology of many neurodegenerative diseases  (Fig. 1). There is abundant evidence that flavonoids are effective in blocking this oxidant-induced neuronal injury, although their potential to do so is thought not to rely on direct radical or oxidant scavenging activity [63, 64]. Instead, they are believed to act by modulating a number of protein kinase and lipid kinase signalling cascades, such as the PI3 kinase (PI3K)/Akt, tyrosine kinase, protein kinase C (PKC) and MAPK signalling pathways [58, 78]. Inhibitory or stimulatory actions at these pathways are likely to profoundly affect neuronal function by altering the phosphorylation state of target molecules, leading to changes in caspase activity and/or by gene expression . For example, flavonoids have been observed to block oxidative-induced neuronal damage by preventing the activation of caspase-3, providing evidence in support of their potent anti-apoptotic action [63, 64]. The flavanols epicatechin and 3′-O-methyl-epicatechin also protect neurons against oxidative damage via a mechanism involving the suppression of JNK and downstream partners, c-jun and pro-caspase-3 . Flavanones, such as hesperetin and its metabolite, 5-nitro-hesperetin, have been observed to inhibit oxidant-induced neuronal apoptosis via a mechanism involving the activation/phosphorylation of signalling proteins important in the pro-survival pathways . Similarly, the flavone, bacalein, has been shown to significantly inhibit 6-hydroxydopamine-induced JNK activation and neuronal cell death and quercetin may suppress JNK activity and apoptosis induced by hydrogen peroxide [20, 75], 4-hydroxy-2-nonenal  and tumour necrosis factor-alpha (TNF-alpha) .
Modulation of memory and learning
There is now much evidence to suggest that fruit and vegetable derived phytochemicals, in particular flavonoids, are capable of promoting beneficial effects on memory and learning [23–27, 56, 57, 79]. It appears that these low molecular weight, non-nutrient components are able to impact upon memory through their ability to exert effects directly on the brains innate architecture for memory . This innate cellular and anatomical architecture of the brain, and its role in the acquisition, storage and retrieval of memories, was originally postulated by Immanuel Kant in 1781 in his revolutionary “Critique of pure reason” . Kant suggested that there must be such ‘architecture’ in the brain, in order that we may interpret sensory information (Kant’s so called ‘a priori’ or ‘innate knowledge’). This may now be interpreted not only psychologically but also physiologically [40, 46], in that one does not come to sensory data as a ‘blank tablet’, but rather brings a sort of relational structure within the nervous system to interpret sense data [1, 2, 46]. Consequently, the nature of our sensory impressions is determined a priori by the physiological apparatus of our senses or by the sensory nerve centres and the memory acquisition, storage and recall centres of the brain . It is now understood that this underlying structure has a molecular basis and thus interaction with this physiological apparatus may yield changes in the way we acquire, store and retrieve memory. Furthermore, this innate cellular architecture is well known to deteriorate with aging, with neuronal populations or synaptic connections lost over time, leaving the system less efficient in the processing and storage of sensory information.
The ability of flavonoids to impact upon this memory system appears to be, in part, underpinned by an ability to interact with this molecular and physiological apparatus. The concentrations of flavonoids and their metabolites which reach the brain are thought to be sufficiently high to exert pharmacological activity at receptors, kinases and transcription factors. Although the precise site of their interaction with signalling pathways remains unresolved, evidence indicates that they are capable of acting in a number of ways: (1) by binding to ATP sites on enzymes and receptors, (2) by modulating the activity of kinases directly, i.e. MAPKKK, MAPKK or MAPK, (3) by affecting the function of important phosphatases which act in opposition to kinases, (4) by preserving Ca2+ homeostasis, thereby preventing Ca2+-dependent activation of kinases in neurons, and (5) by modulating signalling cascades lying downstream of kinases, i.e. transcription factor activation and binding to promoter sequences. By affecting such pathways they have the potential to induce new protein synthesis in neurons and thus an ability to induce morphological changes which have a direct influence on memory acquisition, consolidation and storage.
Various individual cascades have been linked with this control of de novo protein synthesis in the context of LTP, synaptic plasticity and memory (Fig. 3): (i) cAMP-dependent protein kinase (protein kinase A), (ii) protein kinase B (PKB/Akt) 78, (iii) protein kinase C (PKC), (iv) calcium-calmodulin kinase (CaMK) 80 and (v) extracellular signal-regulated kinase (ERK) . All five pathways converge to signal to the cAMP-response element-binding protein (CREB), a transcription factor which binds to the promoter regions of many genes associated with synapse re-modelling, synaptic plasticity and memory (Fig. 3). Flavonoids are now well known to modulate neuronal signalling pathways crucial in inducing synaptic plasticity , and although each of these pathways are known to be involved in increasing the number of, and strength of, connections between neurons, flavonoids appear to interact primarily with the ERK and PKB/Akt pathways [55, 58, 66]. The activation of these pathways by blueberry flavonoids, along with the activation of the transcription factor CREB and production of neurotrophins such as brain-derived neurotrophic factor brain-derived neurotrophic factor (BDNF) is known to be required during memory acquisition and consolidation and agents capable of inducing pathways leading to CREB activation will have the potential to enhance both short-term and long-term memory , by providing a more efficient structure for interpreting afferent nerve or sensory information. One mechanism by which this may come about is through flavonoid-induced increases in neuronal spine density and morphology, two factors considered vital for learning and memory . Changes in spine density, morphology and motility have been shown to occur with paradigms that induce synaptic, as well as altered sensory experience, and lead to alterations in synaptic connectivity and strength between neuronal partners, affecting the efficacy of synaptic communication (Fig. 3). In support of this, high flavanol and anthocyanin supplementation has been shown to cause activation of mTOR and an increased expression of hippocampal Arc/Arg3.1 , events which are likely to facilitate changes in synaptic strength through the stimulation of the growth of small dendritic spines into large mushroom-shaped spines.
There is also evidence to suggest that flavonoids may be capable of preventing many forms of cerebrovascular disease, including those associated with stroke and dementia [10, 11]. Flavonoids may exert effects on endothelial function and peripheral blood flow , and these vascular effects are potentially significant as increased cerebrovascular function is known to facilitate adult neurogenesis in the hippocampus  (Fig. 3). Indeed, new hippocampal cells are clustered near blood vessels, proliferate in response to vascular growth factors and may influence memory . Efficient cerebral blood flow (CBF) is vital for optimal brain function, with several studies indicating that there is a decrease in CBF in patients with dementia [48, 52]. Brain imaging techniques, such as ‘functional magnetic resonance imaging’ (fMRI) and ‘trans-cranial Doppler ultrasound’ (TCD) has shown that there is a correlation between CBF and cognitive function in humans . For example, CBF velocity is significantly lower in patients with Alzheimer disease and low CBF is also associated with incipient markers of dementia. In contrast, non-demented subjects with higher CBF were less likely to develop dementia. In this context, flavonoids have been shown to cause significantly increased CBF in humans, 1–2 h post intervention [12, 13]. After consumption of a flavanol-rich cocoa drink, the ‘flow oxygenation level dependent’ (BOLD)-fMRI showed an increase in blood flow in certain regions of the brain, along with a modification of the BOLD response to task switching. Furthermore, ‘arterial spin-labelling sequence magnetic resonance imaging’ (ASL-MRI)  also indicated that cocoa flavanols increase CBF up to a maximum of 2 h after ingestion of the flavanol-rich drink. In support of these findings, an increase in CBF through the middle cerebral artery has been reported after the consumption of flavanol-rich cocoa using TCD .
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 in the brain leading to an inhibition of apoptosis triggered by neurotoxic species and to a promotion of neuronal survival and differentiation. These 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. It appears that the concentrations of flavonoids encountered in the brain may be sufficiently high to exert such pharmacological activity on receptors, kinases and transcription factors. Second, they are known to induce beneficial effects on the peripheral and cerebral vascular system, which lead to changes in cerebrovascular blood flow. Such changes are likely to induce angiogenesis, new nerve cell growth in the hippocampus and changes in neuronal morphology, all processes known to important in maintaining optimal neuronal function and neuro-cognitive performance.
The consumption of flavonoid-rich foods, such as berries and cocoa, throughout life holds a potential to limit neurodegeneration and prevent or reverse age-dependent deteriorations cognitive performance. However, at present, the precise temporal nature of the effects of flavonoids on these events is unclear. For example, it is presently unclear as to when one needs to begin consuming flavonoids in order to obtain maximum benefits. It is also unclear which flavonoids are most effective in inducing these changes. However, due to the intense interest in the development of drugs capable of enhancing brain function, flavonoids may represent important precursor molecules in the quest to develop of a new generation of brain enhancing drugs.
Abraham TH (2002) (Physio)logical circuits: the intellectual origins of the McCulloch-Pitts neural networks. J Hist Behav Sci 38:3–25
Abraham TH (2003) Integrating mind and brain: Warren S. McCulloch, cerebral localization, and experimental epistemology. Endeavour 27:32–36
Adibhatla RM, Hatcher JF (2007) Role of lipids in brain injury and diseases. Future Lipidol 2:403–422
Afaq F, Adhami VM, Ahmad N, Mukhtar H (2003) Inhibition of ultraviolet B-mediated activation of nuclear factor kappaB in normal human epidermal keratinocytes by green tea Constituent (−)-epigallocatechin-3-gallate. Oncogene 22:1035–1044
Barzilai A, Melamed E (2003) Molecular mechanisms of selective dopaminergic neuronal death in Parkinson’s disease. Trends Mol Med 9:126–132
Bhat NR, Zhang P, Lee JC, Hogan EL (1998) Extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J Neurosci 18:1633–1641
Bhat NR, Feinstein DL, Shen Q, Bhat AN (2002) p38 MAPK-mediated transcriptional activation of inducible nitric-oxide synthase in glial cells. Roles of nuclear factors, nuclear factor kappa B, cAMP response element-binding protein, CCAAT/enhancer-binding protein-beta, and activating transcription factor-2. J Biol Chem 277:29584–29592
Casper D, Yaparpalvi U, Rempel N, Werner P (2000) Ibuprofen protects dopaminergic neurons against glutamate toxicity in vitro. Neurosci Lett 289:201–204
Chen JC, Ho FM, Pei-Dawn LC, Chen CP, Jeng KC, Hsu HB, Lee ST, Wen TW, Lin WW (2005) Inhibition of iNOS gene expression by quercetin is mediated by the inhibition of IkappaB kinase, nuclear factor-kappa B and STAT1, and depends on heme oxygenase-1 induction in mouse BV-2 microglia. Eur J Pharmacol 521:9–20
Commenges D, Scotet V, Renaud S, Jacqmin-Gadda H, Barberger-Gateau P, Dartigues JF (2000) Intake of flavonoids and risk of dementia. Eur J Epidemiol 16:357–363
Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB (2006) Fruit and vegetable juices and Alzheimer’s disease: the Kame Project. Am J Med 119:751–759
Fisher ND, Sorond FA, Hollenberg NK (2006) Cocoa flavanols and brain perfusion. J Cardiovasc Pharmacol 47(Suppl 2):S210–S214
Francis ST, Head K, Morris PG, Macdonald IA (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):S215–S220
Gage FH (2000) Mammalian neural stem cells. Science 287:1433–1438
Galli RL, Shukitt-Hale B, Youdim KA, Joseph JA (2002) Fruit polyphenolics and brain aging: nutritional interventions targeting age-related neuronal and behavioral deficits. Ann N Y Acad Sci 959:128–132
Haque AM, Hashimoto M, Katakura M, Tanabe Y, Hara Y, Shido O (2006) Long-term administration of green tea catechins improves spatial cognition learning ability in rats. J Nutr 136:1043–1047
Harris KM, Kater SB (1994) Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function. Annu Rev Neurosci 17:341–371
Hastings TG (1995) Enzymatic oxidation of dopamine: the role of prostaglandin H synthase. J Neurochem 64:919–924
Hirsch EC, Hunot S, Hartmann A (2005) Neuroinflammatory processes in Parkinson’s disease. Parkinsonism Relat Disord 11(Suppl 1):S9–S15
Ishikawa Y, Kitamura M (2000) Anti-apoptotic effect of quercetin: intervention in the JNK- and ERK-mediated apoptotic pathways. Kidney Int 58:1078–1087
Jang S, Kelley KW, Johnson RW (2008) Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci USA 105:7534–7539
Jellinger KA (2001) Cell death mechanisms in neurodegeneration. J Cell Mol Med 5:1–17
Joseph JA, Shukitt-Hale B, Denisova NA, Prior RL, Cao G, Martin A, Taglialatela G, Bickford PC (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 18:8047–8055
Joseph JA, Shukitt-Hale B, Denisova NA, Bielinski D, Martin A, McEwen JJ, Bickford PC (1999) Reversals of age-related declines in neuronal signal transduction, cognitive, and motor behavioral deficits with blueberry, spinach, or strawberry dietary supplementation. J Neurosci 19:8114–8121
Joseph JA, Denisova NA, Arendash G, Gordon M, Diamond D, Shukitt-Hale B, Morgan D (2003) Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr Neurosci 6:153–162
Joseph JA, Shukitt-Hale B, Casadesus G (2005) Reversing the deleterious effects of aging on neuronal communication and behavior: beneficial properties of fruit polyphenolic compounds. Am J Clin Nutr 81:313S–316S
Joseph JA, Shukitt-Hale B, Lau FC (2007) Fruit polyphenols and their effects on neuronal signaling and behavior in senescence. Ann N Y Acad Sci 1100:470–485
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
Kant I (1781) Kritik der reinen Vernunft (Critique of pure reason). Cambridge University Press, Cambridge
Kobuchi H, Roy S, Sen CK, Nguyen HG, Packer L (1999) Quercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. Am J Physiol 277:C403–C411
Kozuka N, Itofusa R, Kudo Y, Morita M (2005) Lipopolysaccharide and proinflammatory cytokines require different astrocyte states to induce nitric oxide production. J Neurosci Res 82:717–728
Kuriyama S, Hozawa A, Ohmori K, Shimazu T, Matsui T, Ebihara S, Awata S, Nagatomi R, Arai H, Tsuji I (2006) Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project 1. Am J Clin Nutr 83:355–361
Lau FC, Bielinski DF, Joseph JA (2007) Inhibitory effects of blueberry extract on the production of inflammatory mediators in lipopolysaccharide-activated BV2 microglia. J Neurosci Res 85:1010–1017
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 287:191–194
Lee H, Kim YO, Kim H, Kim SY, Noh HS, Kang SS, Cho GJ, Choi WS, Suk K (2003) Flavonoid wogonin from medicinal herb is neuroprotective by inhibiting inflammatory activation of microglia. FASEB J 17:1943–1944
Levites Y, Weinreb O, Maor G, Youdim MB, Mandel S (2001) Green tea polyphenol (−)-epigallocatechin-3-gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration. J Neurochem 78:1073–1082
Levites Y, Youdim MB, Maor G, Mandel S (2002) Attenuation of 6-hydroxydopamine (6-OHDA)-induced nuclear factor-kappaB (NF-kappaB) activation and cell death by tea extracts in neuronal cultures. Biochem Pharmacol 63:21–29
Li R, Huang YG, Fang D, Le WD (2004) (−)-Epigallocatechin gallate inhibits lipopolysaccharide-induced microglial activation and protects against inflammation-mediated dopaminergic neuronal injury. J Neurosci Res 78:723–731
Luo Y, Smith JV, Paramasivam V, Burdick A, Curry KJ, Buford JP, Khan I, Netzer WJ, Xu H, Butko P (2002) Inhibition of amyloid-beta aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761. Proc Natl Acad Sci USA 99:12197–12202
Magnus R (1930) The physiological a priori, Lane lectures on experimental pharmacology and medicine. Stanford University Publications, University Series, Medical Sciences, Stanford, vol 2, pp 97–103
Mandel S, Youdim MB (2004) Catechin polyphenols: neurodegeneration and neuroprotection in neurodegenerative diseases. Free Radic Biol Med 37:304–317
Mandel SA, vramovich-Tirosh Y, Reznichenko L, Zheng H, Weinreb O, Amit T, Youdim MB (2005) Multifunctional activities of green tea catechins in neuroprotection. Modulation of cell survival genes, iron-dependent oxidative stress and PKC signaling pathway. Neurosignals 14:46–60
Mandel SA, Amit T, Kalfon L, Reznichenko L, Weinreb O, Youdim MB (2008) Cell signaling pathways and iron chelation in the neurorestorative activity of green tea polyphenols: special reference to epigallocatechin gallate (EGCG). J Alzheimers Dis 15:211–222
Mandel SA, Amit T, Weinreb O, Reznichenko L, Youdim MB (2008) Simultaneous manipulation of multiple brain targets by green tea catechins: a potential neuroprotective strategy for Alzheimer and Parkinson diseases. CNS Neurosci Ther 14:352–365
Marcus JS, Karackattu SL, Fleegal MA, Sumners C (2003) Cytokine-stimulated inducible nitric oxide synthase expression in astroglia: role of Erk mitogen-activated protein kinase and NF-kappaB. Glia 41:152–160
McCulloch WS, Pitts W (1990) A logical calculus of the ideas immanent in nervous activity. 1943. Bull Math Biol 52:99–115
McGeer EG, McGeer PL (2003) Inflammatory processes in Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 27:741–749
Nagahama Y, Nabatame H, Okina T, Yamauchi H, Narita M, Fujimoto N, Murakami M, Fukuyama H, Matsuda M (2003) Cerebral correlates of the progression rate of the cognitive decline in probable Alzheimer’s disease. Eur Neurol 50:1–9
Palmer TD, Willhoite AR, Gage FH (2000) Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 425:479–494
Pollard SE, Kuhnle GG, Vauzour D, VafeiAdou K, Tzounis X, Whiteman M, Rice-Evans C, Spencer JPE (2006) The reaction of flavonoid metabolites with peroxynitrite. Biochem Biophys Res Commun 350:960–968
Rice-Evans CA, Miller NJ, Paganga G (1996) Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med 20:933–956
Ruitenberg A, den Heijer T, Bakker SL, van Swieten JC, Koudstaal PJ, Hofman A, Breteler MM (2005) Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ann Neurol 57:789–794
Schroeter H, Spencer JPE, Rice-Evans C, Williams RJ (2001) Flavonoids protect neurons from oxidized low-density-lipoprotein-induced apoptosis involving c-Jun N-terminal kinase (JNK), c-Jun and caspase-3. Biochem J 358:547–557
Schroeter H, Heiss C, Balzer J, Kleinbongard P, Keen CL, Hollenberg NK, Sies H, Kwik-Uribe C, Schmitz HH, Kelm M (2006) (−)-Epicatechin mediates beneficial effects of flavanol-rich cocoa on vascular function in humans. Proc Natl Acad Sci USA 103:1024–1029
Schroeter H, Bahia P, Spencer JPE, Sheppard O, Rattray M, Rice-Evans C, Williams RJ (2007) (−)-Epicatechin stimulates ERK-dependent cyclic AMP response element activity and upregulates GLUR2 in cortical neurons. J Neurochem 101:1596–1606
Shukitt-Hale B, Carey A, Simon L, Mark DA, Joseph JA (2006) Effects of Concord grape juice on cognitive and motor deficits in aging. Nutrition 22:295–302
Shukitt-Hale B, Lau FC, Joseph JA (2008) Berry fruit supplementation and the aging brain. J Agric Food Chem 56:636–641
Spencer JPE (2007) The interactions of flavonoids within neuronal signalling pathways. Genes Nutr 2:257–273
Spencer JPE (2008) Flavonoids: modulators of brain function? Br J Nutr 99(E Suppl 1):ES60–ES77
Spencer JPE (2008) Food for thought: the role of dietary flavonoids in enhancing human memory, learning and neuro-cognitive performance. Proc Nutr Soc 67:238–252
Spencer JPE (2009) The impact of flavonoids on memory: physiological and molecular considerations. Chem Soc Rev 38:1152–1161
Spencer JPE, Jenner P, Daniel SE, Lees AJ, Marsden DC, Halliwell B (1998) Conjugates of catecholamines with cysteine and GSH in Parkinson’s disease: possible mechanisms of formation involving reactive oxygen species. J Neurochem 71:2112–2122
Spencer JPE, Schroeter H, Crossthwaithe AJ, Kuhnle G, Williams RJ, Rice-Evans C (2001) Contrasting influences of glucuronidation and O-methylation of epicatechin on hydrogen peroxide-induced cell death in neurons and fibroblasts. Free Radic Biol Med 31:1139–1146
Spencer JPE, Schroeter H, Kuhnle G, Srai SK, Tyrrell RM, Hahn U, Rice-Evans C (2001) Epicatechin and its in vivo metabolite, 3′-O-methyl epicatechin, protect human fibroblasts from oxidative-stress-induced cell death involving caspase-3 activation. Biochem J 354:493–500
Spencer JPE, Whiteman M, Jenner P, Halliwell B (2002) 5-s-Cysteinyl-conjugates of catecholamines induce cell damage, extensive DNA base modification and increases in caspase-3 activity in neurons. J Neurochem 81:122–129
Spencer JPE, Rice-Evans C, Williams RJ (2003) Modulation of pro-survival Akt/PKB and ERK1/2 signalling cascades by quercetin and its in vivo metabolites underlie their action on neuronal viability. J Biol Chem 278:34783–34793
Spires TL, Hannan AJ (2005) Nature, nurture and neurology: gene-environment interactions in neurodegenerative disease. FEBS Anniversary Prize Lecture delivered on 27 June 2004 at the 29th FEBS Congress in Warsaw. FEBS J 272:2347–2361
Uchida K, Shiraishi M, Naito Y, Torii Y, Nakamura Y, Osawa T (1999) Activation of stress signaling pathways by the end product of lipid peroxidation. 4-Hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J Biol Chem 274:2234–2242
Unno K, Takabayashi F, Kishido T, Oku N (2004) Suppressive effect of green tea catechins on morphologic and functional regression of the brain in aged mice with accelerated senescence (SAMP10). Exp Gerontol 39:1027–1034
VafeiAdou K, Vauzour D, Lee HY, Rodriguez-Mateos A, Williams RJ, Spencer JP (2009) The citrus flavanone naringenin inhibits inflammatory signalling in glial cells and protects against neuroinflammatory injury. Arch Biochem Biophys 484:100–109
Vauzour D, VafeiAdou K, Rice-Evans C, Williams RJ, Spencer JPE (2007) Activation of pro-survival Akt and ERK1/2 signaling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons. J Neurochem 103:1355–1367
Vauzour D, VafeiAdou K, Spencer JP (2007) Inhibition of the formation of the neurotoxin 5-S-cysteinyl-dopamine by polyphenols. Biochem Biophys Res Commun 362:340–346
Vauzour D, Ravaioli G, VafeiAadou K, Rodriguez-Mateos A, Angeloni C, Spencer JP (2008) Peroxynitrite induced formation of the neurotoxins 5-S-cysteinyl-dopamine and DHBT-1: implications for Parkinson’s disease and protection by polyphenols. Arch Biochem Biophys 476:145–151
Vauzour D, VafeiAdou K, Rodriguez-Mateos A, Rendeiro C, Spencer JP (2008) The neuroprotective potential of flavonoids: a multiplicity of effects. Genes Nutr 3:115–126
Wang L, Matsushita K, Araki I, Takeda M (2002) Inhibition of c-Jun N-terminal kinase ameliorates apoptosis induced by hydrogen peroxide in the kidney tubule epithelial cells (NRK-52E). Nephron 91:142–147
Wang Y, Wang L, Wu J, Cai J (2006) The in vivo synaptic plasticity mechanism of EGb 761-induced enhancement of spatial learning and memory in aged rats. Br J Pharmacol 148:147–153
Wang Z, Fernandez-Seara M, Alsop DC, Liu WC, Flax JF, Benasich AA, Detre JA (2008) Assessment of functional development in normal infant brain using arterial spin labeled perfusion MRI. Neuroimage 39:973–978
Williams RJ, Spencer JP, Rice-Evans C (2004) Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med 36:838–849
Williams CM, El Mohsen MA, Vauzour D, Rendeiro C, Butler LT, Ellis JA, Whiteman M, Spencer JPE (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 45:295–305
Youdim KA, Shukitt-Hale B, Joseph JA (2004) Flavonoids and the brain: interactions at the blood-brain barrier and their physiological effects on the central nervous system. Free Radic Biol Med 37:1683–1693
Zheng Z, Lee JE, Yenari MA (2003) Stroke: molecular mechanisms and potential targets for treatment. Curr Mol Med 3:361–372
Zheng LT, Ock J, Kwon BM, Suk K (2008) Suppressive effects of flavonoid fisetin on lipopolysaccharide-induced microglial activation and neurotoxicity. Int Immunopharmacol 8:484–494
Dr. Spencer is funded by the Biotechnology and Biological Sciences Research Council (BB/F008953/1; BB/E023185/1; BB/G005702/1).