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Flavonoids are a group of plant metabolites thought to provide health benefits through cell signaling pathways and antioxidant effects. These molecules are found in a variety of fruits and vegetables.

Flavonoids are polyphenolic molecules containing 15 carbon atoms and are soluble in water. They consist of two benzene rings connected by a short three carbon chain. One of the carbons in this chain is connected to a carbon in one of the benzine rings, either through an oxygen bridge or directly, which gives a third middle ring. The flavonoids can be divided into six major subtypes, which include chalcones, flavones, isoflavonoids, flavanones, anthoxanthins and anthocyanins. Many of these molecules, particularly the anthoxanthins give rise to the yellow color of some petals, while anthocyanins are often responsible for the red color of buds and the purple-red color of autumn leaves.

Flavonoids are abundant in plants, in which they perform several functions. They are essential pigments for producing the colors needed to attract pollinating insects. In higher order plants, flavonoids are also required for UV filtration, nitrogen fixation, cell cycle inhibition, and as chemical messengers. Flavonoids secreted by a plant's roots aid the symbiotic relationship between rhizobia and certain vegetables such as peas, clover and beans. The rhizobia present in soil produce Nod factors in response to the presence of flavonoids. These Nod factors are then recognized by the plant, which induces certain responses such as ion fluxes and root nodule formation. Some flavonoids also inhibit certain spores to protect against certain plant diseases. Flavonoids are ubiquitous in plants and are the most common type of polyphenolic compound found in the human diet.

The abundance of flavonoids coupled with their low toxicity relative to other plant compounds means they can be ingested in large quantities by animals, including humans. Examples of foods that are rich in flavonoids include onions, parsley, blueberries, bananas, dark chocolate and red wine.

Health benefits to humans

Flavonoids are important antioxidants and promote several health effects. Aside from antioxidant activity, these molecules provide the following beneficial effects:

One flavonoid called quercetin can help to alleviate eczema, sinusitis, asthma, and hay fever. Some studies have shown that flavonoid intake is inversely related to heart disease, with these molecules inhibiting the oxidation of low-density lipoproteins and therefore reducing the risk of atherosclerosis developing.

Flavonoids are also abundant in red wine, which some have theorized is the reason why the incidence of heart disease may be lower among the French (who have a relatively high red wine intake) compared with other Europeans, despite a higher consumption of foods rich in cholesterol (French paradox). Many studies have also shown that one to two glasses of wine a day can help protect against heart disease.

Some types of tea are also rich in flavonoids and their consumption is thought to lower levels of triglycerides and cholesterol in the blood. Soy flavonoids or isoflavones also lower cholesterol, as well as protecting against osteoporosis and alleviating the symptoms of menopause.

The daily intake of dietary flavonoids typically ranges from anywhere between 50 and 500 mg, meaning the contribution to antioxidant activity varies widely between individuals.

Food sources

Almost all fruits, vegetables and herbs contain a certain amount of flavonoids. They can also be found in other food sources including dry beans, grains, red wine and green and black teas. The general rule is that the more colorful a food item is, the richer it will be in flavonoids. Oranges, however, are an exception to the rule because the flavonoids contained in this fruit are mainly found in the white and pulp interior of the skin.

The best way to ensure a good intake of flavonoids is to consume plenty of fresh fruit and vegetables on a daily basis. Experts advise eating five servings of vegetables and four of fruit. Regarding the intake of red wine, men are advised not to drink more than two glasses per day and women should not drink more than one glass per day.

Flavonoid supplements are also available, but people who buy these should note that experts have not confirmed what the ideal flavonoid intake is and an excess intake may even be harmful.

Interactions

Certain drugs do interact with flavonoids. Studies have shown that the enzyme cytochrome P450, which is involved in the metabolism of drugs, is inhibited by flavonoids. An efflux transporter called P- glycoprotein, which decreases the absorption of certain drugs, is also affected.

Flavonoids have also been shown to interact with certain nutrients. They can bind to nonheme iron, thereby decreasing its absorption in the intestine. Some flavonoids also inhibit cellular uptake of vitamin C and some experts advise avoiding flavonoid-rich foods or drinks when taking vitamin C.

Further Reading

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Flavonoids are a group of plant metabolites thought to provide health benefits through cell signaling pathways and antioxidant effects. These molecules are found in a variety of fruits and vegetables. Flavonoids are polyphenolic molecules containing 15 carbon atoms and are soluble in water. They consist of two benzene rings connected by a short three carbon chain.

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In this article, this group of authors explained the benefits of flavonoids to the brain when it begins to have a cognitive decline. The authors indicate that not only do flavonoids help with the prevention of different kinds of dementia, that relate to the brain retaining memories, but also other kinds of neurodegenerative diseases

This helped make my essay develop stronger because of the new information about how flavonoids can halt other neurodegenerative diseases such as motor neuron disease which makes your body lose its ability to use the nerves in your spine severing the connection to the brain and immobilizing you.

"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"

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Abstract

Flavonoids exert a multiplicity of neuroprotective actions 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. These effects appear to be underpinned by two common processes. Firstly, they interact with critical protein and lipid kinase signalling cascades in the brain leading to an inhibition of apoptosis triggered by neurotoxic species and to a promotion of neuronal survival and synaptic plasticity. Secondly, they induce beneficial effects on the vascular system leading to changes in cerebrovascular blood flow capable of causing angiogenesis, neurogenesis and changes in neuronal morphology. Through these mechanisms, the consumption of flavonoid-rich foods throughout life holds the potential to limit neurodegeneration and to prevent or reverse age-dependent loses in cognitive performance. The intense interest in the development of drugs capable of enhancing brain function means that flavonoids may represent important precursor molecules in the quest to develop of a new generation of brain enhancing drugs.

Keywords: Flavonoid, Brain, Neuroprotection, Neuroinflammation, Memory, Cognitive function

Introduction

Recently, there has been intense interest in the potential of flavonoids to modulate neuronal function and prevent against age-related neurodegeneration. The use of flavonoid-rich plant or food extracts in humans and animal dietary supplementation studies have shown improvements in cognition function possibly by protecting vulnerable neurons, enhancing existing neuronal function or by stimulating neuronal regeneration [ 134]. Their neuroprotective potential has been shown in both oxidative stress [ 41] and Aβ-induced neuronal death models [ 65]. Evidence also exists for the beneficial and neuromodulatory effects of flavonoid-rich ginkgo biloba extracts, particularly in connection with age-related dementias and Alzheimer's disease [ 7]. Furthermore, individual flavonoids such as the citrus flavanone tangeretin, has been observed to maintain nigro-striatal integrity and functionality following lesioning with 6-hydroxydopamine, suggesting that it may serve as a potential neuroprotective agent against the underlying pathology associated with Parkinson's disease [ 24]. In addition, flavonoids may also exert beneficial effects on memory and may prevent cognitive losses associated with ageing and even reverse certain age-related declines [ 45, 46]. This review will highlight the neuroprotective mechanisms of flavonoids and other polyphenols, in particular their ability interact with neuronal signalling pathways [ 91, 97] and their potential to inhibit neuroinflammatory processes in the brain [ 17, 48].

Flavonoid: sources and structure

Flavonoids are major constituents of fruit, vegetables and beverages, such as wine, tea, cocoa and fruit juices. Most commonly, flavonoids share a common structure consisting of two aromatic rings (A and B), which are bound together by three carbon atoms, forming an oxygenated heterocycle (ring C) (Fig. ). Based on variations in the saturation of the basic flavan ring system, their alkylation and/or glycosylation and the hydroxylation pattern of the molecules, flavonoids may be divided into seven subclasses: flavonols, flavones, flavanones, flavanonols, flavanols, anthocyanidins, and isoflavones (reviewed by Manach et al. [ 67]).

The flavanols, sometimes referred to as flavan-3-ols, are found predominantly in green and black teas, red wine and chocolate. Variations in their structures lie in the hydroxylation pattern of the B ring and the presence of gallic acid in position 3. The lack of a double bond at the 2-3 position and the presence of a 3-hydroxyl group on the C-ring create two centres of asymmetry. Typical dietary flavanols include catechin, epicatechin, epigallocatechin (EGC) and epigallocatechin gallate (EGCG) (Fig. ). Flavanols exist also as oligomers or polymers, referred to as condensed tannins or proanthocyanidins, which are found in high concentration in cocoa, tea, red wine and fruits such as apples, grapes and strawberries. These differ in nature based on their constitutive units (e.g. catechins and epicatechin), their sequence and the position of interflavanic linkages. The sources of anthocyanins such as pelargonidin, cyanidin and malvidin include red wine and berry fruits such as blueberries, blackberries cherries and strawberries. These compounds exist as glycosides in plants, are water-soluble and appear red or blue according to pH. Individual anthocyanins arise from the variation in number and arrangement of the hydroxyl and methoxy groups around the three rings (Fig. ). Flavones such as apigenin, luteolin are found in parsley, chives, artichoke and celery. Hydroxylation on position 3 of the flavone structure gives rise to the 3-hydroxyflavones also known as the flavonols (e.g. kaempferol, quercetin), which are found in onions, leeks, broccoli (Fig. ). The diversity of these compounds stems from the varying positions of phenolic -OH groups around the three rings. Dietary flavanones include naringenin, hesperetin and taxifolin and are found predominantly in citrus fruit and tomatoes. Hydroxylation of flavanones in position 3 of C-ring gives rise to the flavanonols (Fig. ). Finally, isoflavones such as daidzein and genistein are a subclass of the flavonoid family found in soy and soy products. They have a large structural variability and more than 600 isoflavones have been identified to date and are classified according to oxidation level of the central pyran ring (Fig. ).

Absorption, metabolism and distribution of flavonoids

Although flavonoids have been identified as powerful antioxidants in vitro [ 84- 86], their ability to act as antioxidants in vivo is limited by the extensive biotransformation and conjugation which occurs during their absorption from the gastrointestinal (GI) tract, in the liver and finally in cells (reviewed in [ 103, 107]). In the small intestine and liver, dietary flavonoids (and other polyphenols) are substrates for phase I (hydrolysing and oxidizing) and phase II (conjugating and detoxifying), meaning that they are de-glucosylated and metabolised into glucuronides, sulphates and O-methylated derivatives [ 99, 103, 104]. Further metabolism occurs in the colon, where the enzymes of the gut microflora induce the breakdown of flavonoids to simple phenolics acids that may then undergo absorption and further metabolized in the liver [ 88]. Furthermore, flavonoids may undergo at least three types of intracellular metabolism: (1) Oxidative metabolism, (2) P450-related metabolism and (3) Conjugation with thiols, particularly GSH [ 100]. Circulating metabolites of flavonoids, such as glucuronides, sulphates and conjugated O-methylated forms, or intracellular metabolites like flavonoid-GSH adducts, have significantly reduced antioxidant potential relative to the forms found in plants [ 102]. Indeed, studies have indicated that although such conjugates and metabolites may participate antioxidant reactions and may scavenge reactive oxygen and nitrogen species in the circulation, their effectiveness to do so is reduced compared to their parent aglycones [ 22, 70, 94, 117, 132].

In order for flavonoids to access the brain, they must first cross the blood brain barrier (BBB), which controls entry of xenobiotics into the brain [ 2]. Flavanones such as hesperetin, naringenin and their in vivo metabolites, along with some dietary anthocyanins, cyanidin-3-rutinoside and pelargonidin-3-glucoside, have been shown to traverse the BBB in relevant in vitro and in situ models [ 135]. Their degree of BBB penetration is dependent on compound lipophilicity [ 133], meaning that less polar O-methylated metabolites may be capable to greater brain uptake than the more polar flavonoid glucuronides. However, evidence exists to suggest that certain drug glucuronides may cross the BBB [ 1] and exert pharmacological effects [ 52, 112], suggesting that there may be a specific uptake mechanism for glucuronides in vivo. Their brain entry may also depend on their interactions with specific efflux transporters expressed in the BBB, such as P-glycoprotein [ 63] which appears to be responsible for the differences between naringenin and quercetin flux into the brain in situ [ 135]. In animals, flavanones have been found to enter the brain following their intravenous administration [ 79], whilst epigallocatechin gallate [ 115], epicatechin [ 3] and anthocyanins [ 26, 116] are found in the brain after their oral administration. Furthermore, several anthocyanins have been identified in different regions of the rat [ 78] and pig brains [ 47] of blueberry fed animals, with 11 intact anthocyanins found in the cortex and cerebellum. Studies have indicated that the accumulation of flavonoids in the brain is not dependent on the brain region, with levels of anthocyanins reaching 0.45 ± 0.12 nmol/g in the hippocampus and 0.46 ± 0.11 nmol/g in the cortex following intervention with a 2% w/w blueberry diet for 12 weeks [ 129]. Flavanols have been shown to accumulate at significantly higher levels (Hippocampus: 2.65 ± 0.17 nmol/g tissue; cortex levels were 2.54 ± 0.18), following the same dietary intervention. These results indicate that flavonoids traverse the BBB and are able to localize in the brain, suggesting that they are candidates for direct neuroprotective and neuromodulatory actions.

Protection against neuronal injury induced by neurotoxins

Neurodegeneration in Parkinson's, Alzheimer's, and other neurodegenerative diseases appears to be triggered by multi-factorial events including neuroinflammation, glutamatergic excitotoxicity, increases in iron and/or depletion of endogenous antioxidants [ 6, 44, 113]. There is a growing body of evidence to suggest that flavonoids may be able to counteract the neuronal injury underlying these disorders [ 68, 98, 105]. For example, a Ginkgo biloba extract has been shown to protect hippocampal neurons from nitric oxide- and beta-amyloid-induced neurotoxicity [ 65] and studies have demonstrated that the consumption of green tea may have beneficial effect in reducing the risk of Parkinson's disease [ 16]. In agreement with the latter study, tea extracts and (−)-epigallocatechin-3-gallate (EGCG) have also been shown to attenuate 6-hydroxydopamine-induced toxicity [ 61], to protect against hippocampal injury during transient global ischemia [ 56] and to prevent nigral damage induced by MPTP [ 60].

The death of nigral neurons in Parkinson's disease is thought to involve the formation of the endogenous neurotoxin, 5-S-cysteinyl-dopamine [ 108, 109]. Recent investigations have shown that 5-S-cysteinyl-catecholamine conjugates possess strong neurotoxicity and initiate a sustained increase in intracellular reactive oxygen species (ROS) in neurons leading to DNA oxidation, caspase-3 activation and delayed neuronal death [ 37, 111] (Fig. ). Such adducts may be generated by reactive species [ 121] and have been observed to be been elevated in the human substantia nigra of patients who died of Parkinson's disease [ 108], suggesting that such species may be potential endogenous nigral toxins. However, 5-S-cysteinyldopamine-induced neuronal injury is counteracted by nanomolar concentrations of various flavonoids including pelargonidin, quercetin, hesperetin, caffeic acid, the 4′-O-Me derivatives of catechin and epicatechin [ 121]. Furthermore, in 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 [ 123]. 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 [ 123].

Reactive oxygen and nitrogen species have also been proposed to play a role in the pathology of many neurodegenerative diseases [ 44] (Fig. ). 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 [ 98, 102, 110]. Instead, they are believed to act by modulating a number of protein kinase and lipid kinase signalling cascades, such as the PI3 kinase (PI3 K)/Akt, tyrosine kinase, protein kinase C (PKC) and mitogen-activated protein kinase (MAP kinase) signalling pathways [ 98, 130]. Inhibitory or stimulatory actions of 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 [ 130]. 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 [ 91, 92, 102]. 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 [ 91]. 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 [ 122]. Similarly, the flavone, baicalein, 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 [ 42, 124], 4-hydroxy-2-nonenal [ 119] and tumour necrosis factor-alpha (TNF-alpha) [ 49].

Inhibition of neuroinflammation

Neuroinflammatory processes in the CNS are believed to play a crucial role in the development of neurodegenerative diseases such as Alzheimer's and Parkinson's disease [ 39] as well as with neuronal injury associated with stroke [ 137]. Glial cells (microglia and astrocytes) activation leads to the production of cytokines and other inflammatory mediators which may contribute to the apoptotic cell death of neurons observed in many neurodegenerative diseases. In particular, increases in cytokine production (interleukin-1β, IL-1β; tumor necrosis factor-alpha, TNF-α) [ 50], inducible nitric oxide synthase (iNOS) and nitric oxide (NO), and increased NADPH oxidase activation [ 4] all contribute to glial-induced neuronal death (Fig. ). These events are controlled by MAPK signalling which mediate both the transcriptional and post-transcriptional regulation of iNOS and cytokines in activated microglia and astrocytes [ 9, 69]. Whilst ibuprofen, a non-steroidal anti-inflammatory drug, has been shown to delay the onset of neurodegenerative disorders, such as Parkinson disease [ 14], the majority of existing drug therapies for neurodegenerative disorders has failed to prevent the underlying degeneration of neurons. Consequently, there is a desire to develop alternative strategies capable of preventing the progressive neuronal loss resulting from neuroinflammation.

Flavonoid-rich blueberry extracts have been observed to inhibit NO, IL-1β and TNF-α production in activated microglia cells [ 53, 54], whilst the flavonol quercetin [ 17], the flavones wogonin and bacalein [ 55], the flavanols catechin and epigallocatechin gallate (EGCG) [ 62], and the isoflavone genistein [ 125] 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 generation, in astrocytes and microglia. Flavonoids may exert these effects via direct modulation of protein and lipid kinase signalling pathways [ 98, 105, 130], 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 [ 9]. In this respect, fisetin inhibits p38 MAP kinase phosphorylation in LPS-stimulated BV-2 microglial cells [ 136] and the flavone luteolin inhibits IL-6 production in activated microglia via 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 [ 8], suggesting that there is interplay between signalling pathways, transcription factors and cytokine production in determining the neuroinflammatory response in the CNS. However, flavonoids have also been shown to prevent transcription factor activation, with the flavonol quercetin 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 [ 17].

Flavonoid-induced improvements in memory, learning and cognitive performance

There is a growing interest in the potential of phytochemicals to improve memory, learning and general cognitive ability [ 105, 106]. A recent prospective study aimed at examining flavonoid intake in relation to cognitive function and decline, has provided strong evidence that dietary flavonoid intake is associated with better cognitive evolution, i.e. the preservation of cognitive performance with ageing [ 59]. In this PAQUID study (Personnes Agées QUID), a total of 1,640 subjects (aged 65 years or older) free from dementia at baseline and with reliable dietary assessment data were examined for their cognitive performance (Mini-Mental State Examination, Benton's Visual Retention Test, "Isaacs" Set Test) four times over a 10-year-period. After adjustment for age, sex, and educational level, flavonoid intake was found to be associated with significantly better cognitive performance at baseline and with a significantly better evolution of the performance over time. In particular, subjects included in the two highest quartiles of flavonoid intake had better cognitive evolution than subjects in the lowest quartile and after 10 years follow-up, subjects with the lowest flavonoid intake had lost on average 2.1 points on the Mini-Mental State Examination, whereas subjects with the highest quartile had lost 1.2 points. Such data provides a strong indication that regular flavonoid consumption may have a positive effect on neuro-cognitive performance as we age.

There has been much interest in the neuro-cognitive effects of soy isoflavones (Fig. ), primarily in post-menopausal women [ 10, 28, 57, 128]. Isoflavone supplementation has been observed to have a favourable effect on cognitive function [ 13], particularly verbal memory, in postmenopausal women [ 51] and a 6 and 12-week supplementation was observed to have a positive effect of frontal lobe function [ 27]. Furthermore, animal studies have also indicated that isoflavones are capable of improving cognitive function [ 58, 64, 77]. However, there is still uncertainty regarding their effects as some large intervention trials have reported that isoflavone supplementation does not lead to cognitive improvements [ 30]. The rationale behind the potential of isoflavones to exert positive effects on cognitive function is believed to lie primarily in their potential to mimic the actions and functions of oestrogens in the brain [ 10]. For example, postmenopausal women who undertake oestrogen-replacement therapy have a significantly lower risk for the onset of Alzheimer's disease than women who do not [ 38]. They may also be effective by affecting the synthesis of acetylcholine and neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in hippocampus and frontal cortex [ 75, 76].

There is also extensive evidence that berries, in particular blueberries, are effective at reversing age-related deficits in motor function and spatial working memory [ 5, 12, 45, 46, 129]. In addition to spatial memory, blueberry supplementation has been shown to improve 'object recognition memory' [ 34] and 'inhibitory fear conditioning learning' [ 5]. Blueberry appears to have a pronounced effect on short-term memory [ 82] and has also been shown to improve long-term reference memory following 8 weeks of supplementation. [ 12]. Tests using a radial arm maze have supported these findings and have provided further evidence for the efficacy of blueberries [ 129]. Indeed, these have shown that improvements in spatial memory may emerge within 3 weeks, the equivalent of about 3 years in humans. The beneficial effects of flavonoid-rich foods and beverages on psychomotor activity in older animals have also been reported [ 95, 96]. In addition to those with berries, animal studies with tea [ 15] and pomegranate juice [ 36], or pure flavonols such as quercetin, rutin [ 80] or fisetin [ 66] have provided further evidence that dietary flavonoids are beneficial in reversing the course of neuronal and behavioural aging.

The flavonoid-rich plant extract, Ginkgo Biloba has also been shown to induce positive effects on memory, learning and concentration [ 19, 20, 25]. Ginkgo Biloba has a prominent effect on brain activity and short-term memory in animals and humans suffering from cognitive impairment [ 43, 93, 131] and promotes spatial learning in aged rodents [ 40, 114, 126, 131]. Furthermore, Ginkgo Biloba promotes inhibitory avoidance conditioning in rats with high-dose intake leading to short-term, but not long-term, passive avoidance learning in senescent mice [ 114, 118]. However, the pharmacological mechanisms by which Ginkgo Biloba promotes cognitive effects are unclear, with its ability to elicit a reduction in levels of ROS [ 72, 73], to increase cerebral blood flow [ 33], to modulate brain fluidity [ 114], to interact with the muscarinic cholinergic system [ 18] and to protect the striatal dopaminergic system [ 81] all being suggested as possible mechanisms of brain action.

The effects of flavonoid-rich foods on neuro-cognitive function have been linked to the ability of flavonoids to interact with the cellular and molecular architecture responsible for memory and learning [ 105, 106], including those involved in long-term potentiation and synaptic plasticity [ 98] (Fig. ). These effects are likely to lead to the enhanced neuronal connection and communication and thus a greater capacity for memory acquisition, storage and retrieval [ 106]. For example, the flavanol (-)-epicatechin, especially in combination with exercise, has been observed to enhance the retention of rat spatial memory by a mechanism involving increased angiogenesis and neuronal spine density in the dentate gyrus of the hippocampus, and an up-regulation of genes associated with learning in the hippocampus [ 120]. Fisetin, a flavonoid found in strawberries, has been shown to improve long-term potentiation and to enhance object recognition in mice by a mechanism dependent on the activation of ERK and CREB [ 66]. Similarly, the flavanol (-)-epicatechin induces both ERK1/2 and CREB activation in cortical neurons and subsequently increases CREB regulated gene expression [ 89], whilst nanomolar concentrations of quercetin are effective at enhancing CREB activation [ 101]. Blueberry-induced improvements in memory have been shown to be mediated by increases in the phosphorylation state of ERK1/2, rather than that of calcium calmodulin kinase (CaMKII and CaMKIV) or protein kinase A [ 129]. Other flavonoids have also been found to influence the ERK pathway, with the citrus flavanone hesperetin capable to activating ERK1/2 signalling in cortical neurons [ 122] and flavanols such as EGCG restoring both protein kinase C and ERK1/2 activities in 6-hydroxy dopamine toxicity and serum deprived neurons [ 61, 83].

Cerebrovascular effects of flavonoids

Dementia is a serious degenerative disease effecting predominantly elderly people with the two most common forms of this illness being Alzheimer's and vascular dementia. The factors affecting dementia are age, hypertension, arteriosclerosis, diabetes mellitus, smoking, atrial fibrillation and those with the ApoE4 genotype [ 11]. There is evidence to suggest that flavonoids may be capable of preventing many forms of cerebrovascular disease, including those associated with stroke and dementia [ 21, 23]. There is powerful evidence for the beneficial effects of flavonoids on endothelial function and peripheral blood flow [ 90] and these vascular effects are potentially significant as increased cerebrovascular function is known to facilitate adult neurogenesis in the hippocampus [ 32] (Fig. ). Indeed, new hippocampal cells are clustered near blood vessels, proliferate in response to vascular growth factors and may influence memory [ 74]. As well as new neuronal growth, increases in neuronal spine density and morphology are considered vital for learning and memory [ 35]. 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. These events are mediated at the cellular and molecular level and are strongly correlated with memory and learning.

Efficient cerebral blood flow is also vital for optimal brain function, with several studies indicating that there is a decrease in cerebral blood flow (CBF) in patients with dementia [ 71, 87]. 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 [ 87]. For example, cerebral blood flow 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. Flavonoids have been shown to exert a positive effect on cerebral blood flow (CBF) in humans [ 29, 31]. 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) [ 127] also indicated that cocoa flavanols increase CBF up to a maximum of two hours after ingestion of the flavanol-rich drink. In support of these findings, an increase in cerebral blood flow through the middle cerebral artery has been reported after the consumption of flavanol-rich cocoa using TCD [ 29].

Conclusion

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 common 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 PI3 K/Akt and MAP kinase pathways which regulate pro-survival transcription factors and gene expression (Fig. ). 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. Secondly, 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 (Fig. ).

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.

Acknowledgments

The authors are funded by the Biotechnology and Biological Sciences Research Council (BB/F008953/1; BB/C518222/1; BB/G005702/1) and the Medical Research Council (G0400278/NI02).

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The neuroprotective potential of flavonoids: a multiplicity of effects

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Flavonoids exert a multiplicity of neuroprotective actions 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. These effects appear to be underpinned by two common processes.

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In the article, the author shares information on how flavonoids affect the brain’s health. He said that if you have a flavonoid-rich diet then you can protect your neurons from neurotoxins and more. You are also able to slow down neuroinflammation and improve your memory.

In Spencer JP’s article, he has a lot of useful information for why flavonoids are good for the brain. He backs up all his claims with scientific proof and examples of how flavonoids improve the brain’s health however he did clarify that it can also be a different factor because the science behind flavonoids is still unclear.

"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"

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Abstract

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.

Keywords: Flavonoid, Brain, Neurodegeneration, Neuroinflammation, Memory, Cognitive performance, Signalling

Introduction

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 [ 3]. 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 [ 51], through their ability to scavenge reactive species, or through their possible influences on intracellular redox status [ 50]. 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 [ 59]. 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 [ 60]. 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 [ 81]. 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 [ 31] all contribute to glial-induced neuronal death (Fig. ). 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 [ 8]. 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 [ 70], via an inhibition of p38 and STAT-1, and a reduction in iNOS expression (Fig. ). 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 [ 70].

Flavonoids present in blueberry have also been shown to inhibit NO *, IL-1β and TNF-α production in activated microglia cells [ 33], while the flavonol quercetin [ 9], the flavones wogonin and bacalein [ 35], the flavanols catechin and epigallocatechin gallate (EGCG) [ 38] and the isoflavone genistein [ 4] 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 [ 6] (Fig. ). In this respect, fisetin inhibits p38 MAP kinase phosphorylation in LPS-stimulated BV-2 microglial cells [ 82] and the flavone luteolin inhibits IL-6 production in activated microglia via the inhibition of the JNK signalling pathway [ 21]. 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 [ 7], 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 [ 39]; 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 [ 37], to protect against hippocampal injury during transient global ischemia [ 34] and to prevent nigral damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [ 36].

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. ). 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 [ 65] (Fig. ). Such adducts may be generated by reactive species [ 73] and have been observed to be elevated in the human substantia nigra of patients who died of Parkinson's disease [ 62], 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 [ 73] (Fig. ). 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 [ 72]. 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 [ 72].

Reactive oxygen and nitrogen species have also been proposed to play a role in the pathology of many neurodegenerative diseases [ 22] (Fig. ). 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 [ 78]. 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 [ 53]. 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 [ 71]. 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 [ 68] and tumour necrosis factor-alpha (TNF-alpha) [ 30].

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 [ 60]. 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" [ 29]. 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 [ 2]. 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 Ca ²⁺ homeostasis, thereby preventing Ca ²⁺-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. ): (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) [ 61]. 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. ). Flavonoids are now well known to modulate neuronal signalling pathways crucial in inducing synaptic plasticity [ 61], 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 [ 79], 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 [ 17]. 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. ). 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 [ 79], 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 [ 54], and these vascular effects are potentially significant as increased cerebrovascular function is known to facilitate adult neurogenesis in the hippocampus [ 14] (Fig. ). Indeed, new hippocampal cells are clustered near blood vessels, proliferate in response to vascular growth factors and may influence memory [ 49]. 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 [ 52]. 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) [ 77] 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 [ 12].

Summary

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.

Acknowledgment

Dr. Spencer is funded by the Biotechnology and Biological Sciences Research Council (BB/F008953/1; BB/E023185/1; BB/G005702/1).

References

29. Kant I (1781) Kritik der reinen Vernunft (Critique of pure reason). Cambridge University Press, Cambridge

40. 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

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Flavonoids and brain health: multiple effects underpinned by common mechanisms

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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.

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Radioprotective Effect of Flavonoids on Ionizing Radiation-Induced Brain Damage

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This study talks about how radiation can be extremely dangerous and can cause damage to the brain. However, they bring up information about how flavonoids are able to protect the brain from radiation and prevent brain damage.

This article is effective in my essay because it provides another example of how flavonoids affect the brain. It also recites previous information that was already stated in my essay.

“Flavonoids and their metabolites can cross the blood–brain barrier (BBB), which is made up of capillary endothelial cells and basement membrane, neuroglial membrane and glial podocytes, i.e., projections of astrocytes, and reach brain cells to reduce brain damage and alleviate neurodegenerative diseases and cognitive impairment”

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My family is no stranger to dementia I have seen my own grandfather struggle against it for the last years of his life. He wasn't able to connect with his grandchildren even though our father told us he wanted to. If he had known that the food he eats will be able to help him make memories with his grandchildren he would have changed his diet immediately.

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The Effects of Flavonoids
Can flavonoids have any other effects other than the memory aspect of the brain?

The essay focuses on how the memory aspect of the brain is affected by flavonoids and can hinder dementia and how flavonoids might have many other effects on our brains.

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Flavonoid, morin inhibits oxidative stress, inflammation and enhances neurotrophic support in the brain of streptozotocin-induced diabetic rats

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This article discussed how diabetes encephalopathy affects the brain and explores if there is a therapeutic drug that helps heal and protect the brain from diabetes.

This study is effective in my essay because it adds to my central question about if flavonoids have any other effects on the brain. The article brings up morin, flavonoids found in plants, that can be effective as a therapeutic drug for people who are suffering from diabetes and are receiving brain damage from it.

“Morin is considered a potential therapeutic drug to have properties including antioxidant, anti-inflammatory and neuroprotective in neurodegenerative diseases with very minimal toxicity even at higher dose usage”

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In "The Brain the Story of You" by David Eagleman, Eagleman talks about how our brain works. He brings up topics related to how we think, learn, and act with real evidence from his studies.

This book was a great source to use for me because it provided me with basic and new knowledge about the brain such as in chapter one where he talked about how our brains aren't fully developed when we are younger and we go through a process of learning throughout our lives.

"As many as two million new connections, or synapses, are formed every second in an infant’s brain".

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This is a very subjective question. Meaning it always depends on who you're asking. Because none of this has yet to be "proven" people will argue for This is a very subjective question. Meaning it always depends on who you're asking. Because none of this has yet to be "proven" people will argue for whoever's research and theories they agree with. I can give you some of my own personal (and I try really hard to be objective and steer clear of opinions, but that will always have a role so that's just my warning label of sorts, ha) but because this is such a big topic today it'd help if you were more specific... do you mean subconscious mind just basically like how we make decisions, fears, etc or do you want to go deeper meaning the abnormal subconscious mind and/or subconscious mind of trauma, etc. there are so many good out there. If you want recs let me know, but another good way to find is to do a bit of research online and/or going to a book store and looking at several books that deal with your specific questions... I hope this helps! ...more (less)

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This is a very subjective question. Meaning it always depends on who you're asking. Because none of this has yet to be "proven" people will argue for This is a very subjective question. Meaning it always depends on who you're asking.

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The article "Can Fruits and Vegetables Boost Brain Health" by Nicholas Bakalar talks about how flavonoids are being studied to help people with dementia.

I used this article to begin my main point in Essay 4. With the information I gained about flavonoids I began to research if flavonoids can affect the brain in any other way.

"A new study, one of the largest such analyses to date, has found that flavonoids, the chemicals that give plant foods their bright colors, may help curb the frustrating forgetfulness and mild confusion that older people often complain about".

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Flavonoids, the chemicals that give plant foods their bright colors, may help curb the frustrating forgetfulness and mild confusion of advancing age.

Credit... Getty Images

Eating colorful fruits and vegetables may be good for your brain.

A new study, one of the largest such analyses to date, has found that flavonoids, the chemicals that give plant foods their bright colors, may help curb the frustrating forgetfulness and mild confusion that older people often complain about with advancing age, and that sometimes can precede a diagnosis of dementia. The study was observational so cannot prove cause and effect, though its large size and long duration add to growing evidence that what we eat can affect brain health.

The scientists used data from two large continuing health studies that began in the late 1970s and early 1980s, in which participants periodically completed diet and health questionnaires over more than 20 years. The analysis included 49,693 women whose average age was 76, and 51,529 men whose average age was 73.

The scientists calculated their intake of about two dozen commonly consumed kinds of flavonoids - which include beta carotene in carrots, flavone in strawberries, anthocyanin in apples, and other types in many other fruits and vegetables. The study appears in the journal Neurology.

The degree of subjective cognitive decline was scored using "yes" or "no" answers to seven questions: Do you have trouble remembering recent events, remembering things from one second to the next, remembering a short list of items, following spoken instructions, following a group conversation, or finding your way around familiar streets, and have you noticed a recent change in your ability to remember things?

The higher the intake of flavonoids, the researchers found, the fewer "yes" answers to the questions. Compared with the one-fifth of those with the lowest intake of flavonoids, the one-fifth with the highest were 19 percent less likely to report forgetfulness or confusion.

According to the senior author, Dr. Deborah Blacker, a professor of epidemiology at the Harvard T.H. ChanSchool of Public Health, these long-term findings suggest that starting early in life with a flavonoid-rich diet may be important for brain health.

For young people and those in midlife, she said, "the message is that these things are good for you in general, and not just for cognition. Finding ways that you enjoy incorporating these things into your life is important. Think about: How do I find fresh produce and cook it in a way that's appetizing? - that's part of the message here."

The study controlled for diet apart from flavonoid intake and for physical activity, alcohol consumption, age and body mass index, among other factors that may affect the risk for dementia. Importantly, it also controlled for depression, whose symptoms in older people can easily be mistaken for dementia.

The researchers looked not only at total flavonoid consumption, but also at about three dozen specific flavonoid-containing foods. Higher intakes of brussels sprouts, strawberries, winter squash and raw spinach were most highly associated with better scores on the test of subjective cognitive decline. The associations with consumption of onions, apple juice and grapes were significant, but weaker.

"These are the foods you should be eating for brain health," said Dr. Thomas M. Holland, a researcher at the Rush Institute for Healthy Aging who was not involved in the study. "There's some really good data here with 20 years of follow-up." Still, he added, further follow-up would be needed to determine whether foods might affect the risk of developing dementia.

Paul F. Jacques, a senior scientist at the Jean Mayer United States Agriculture Department Human Nutrition Research Center on Aging at Tufts University who had no part in the research, said: "In terms of scientific advance, this adds to the literature, and it's a really well done study. It's a medium sized step, not a large step, going in the direction of helping us to identify the early period in which we can intervene successfully" to reduce the risk for Alzheimer's disease.

Dr. Blacker pointed to broader policy issues. "If we can make a world in which everyone has access to fresh fruits and vegetables," she said, "that should help improve many health issues, and lengthen life span."

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Can Fruits and Vegetables Boost Brain Health?

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Flavonoids, the chemicals that give plant foods their bright colors, may help curb the frustrating forgetfulness and mild confusion of advancing age. Eating colorful fruits and vegetables may be good for your brain.