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Polyphenols interaction with other food components as a mean for their neurological health benefits Hugo Granda, and Sonia de Pascual-Teresa J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b02839 • Publication Date (Web): 19 Jul 2018 Downloaded from http://pubs.acs.org on July 20, 2018

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Journal of Agricultural and Food Chemistry

Polyphenols interaction with other food components as a mean for their neurological health benefits

Hugo Granda and Sonia de Pascual-Teresa*

Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), Jose Antonio Novais 10, 28040 Madrid, Spain.

*Corresponding author: Tel: +34915492300. Fax: +34915493627. E-mail address: [email protected]

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Abstract

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Over the last years there has been an increasing interest in the possible beneficial effect

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of polyphenol consumption on neurodegenerative disorders. Since there is a clear

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impact of environmental factors on the onset and evolution of neurodegenerative

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conditions, food arises as a promising factor that might be influencing this group of

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pathologies. The mechanisms by which polyphenols can affect these processes can be

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through direct interaction with redox signalling or inflammatory pathways but can also

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be explained by the interaction of dietary polyphenols with either micro- and

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macronutrients that are known to have neurological effects or by interaction with food

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contaminants or food associated toxins avoiding their neuronal toxicity.

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Keywords: polyphenols, neurodegeneration, interaction, nutrient, food component,

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mechanism

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Introduction

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Neurodegeneration is associated with aging and thus it is increasingly perceived as a

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health and social problem since there is an ageing population worldwide.

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Neurodegeneration has a high environmental component, either on its appearance or on

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its progression. Environmental factors that might be associated with neuronal

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degeneration include pollution, nutrition and life style factors including physical

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exercise or sleep cycles1. Life style factors include sleep deprivation or sedentary

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behaviour and nutritional factors include a good number of micro and macronutrients

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status.

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The interest in polyphenols has been growing in the last decades, from their

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identification and food technology implications to their healthy properties. In recent

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years there has been an increasing interest in the effect of polyphenols at the

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neurological level based on few studies proving the association of polyphenols ingestion

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and a better cognitive performance.2

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The molecular mechanisms that are involved in neurodegeneration include:

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inflammation, autophagy, redox status, proteostasis, synapsis homeostasis, glucose

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metabolism, blood-brain barrier and vascular regulation (Figure 1). Polyphenols have

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been described to regulate most of these mechanisms and thus they can sustain the

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potential neuroprotective effectof polyphenol rich foods.3 However, another alternative

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way in which polyphenols might have a positive effect on the neuronal system is

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through interaction with different food components with proven protective or

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deleterious effect on neurons (Figure 2) and thus we consider this as being an

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interesting area of study in the future.

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Macronutrients

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Glucose

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Most of the energy required to sustain normal brain function is provided by blood

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glucose. Blood-brain barrier limits and regulates glucose access to glial and neuronal

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cells. Polyphenol modulation of glucose uptake through human blood-brain barrier has

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been studied in cell culture models showing that catechin and epicatechin methylated

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metabolites are able to increase glucose uptake but not their parent compounds,

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epicatechin or catechin.4 However, sodium-dependent glucose uptake into Caco-2 cells

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is inhibited by flavonoid glycosides and non-glycosylated polyphenols. Aglycones and

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phenolic acids have no effect under sodium-dependent conditions. On the other hand,

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sodium-independent glucose uptake is inhibited by non-glycosylated polyphenols

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whereas glycosides and phenolic acids are ineffective.5

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The regulation of glycaemia improves the quality and duration of intellectual

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performance. In infants, adults and aged people, as well as in diabetic patients, poorer

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glycaemic control is associated with lower intellectual performances. In this sense, it

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has been shown that hyperglycemia is significantly decreased in diabetic rats when

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glucose is administered with quercetin compared with administration of glucose alone.6

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Acute exposure of Caco-2 cells to anthocyanin-rich berry extract significantly decreased

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both sodium dependent and independent glucose uptake. Long-term anthocyanin

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supplementation significantly reduced sodium-glucose co-transporter (SGLT) and

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glucose transporter (GLUT2) mRNA expression in Caco-2 cells. Therefore, berry

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flavonoids may modulate postprandial glycaemia by decreasing glucose transporter

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expression.7 Additionally, in diabetic volunteers it has been shown that cranberry

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polyphenols are able to improve postprandial glucose excursions8 and that cocoa, red 4 ACS Paragon Plus Environment

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wine and tea might have a big impact on the risk of type 2 diabetes. 9 Taking all this into

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account, we could hypothesize that there is a regulation of glucose metabolism by

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polyphenols and that this interaction could explain, at least partially, the improvement

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in cognitive function.

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Lipids and Polyunsaturated fatty acids (PUFAs)

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Hypercholesterolemia is an early risk factor for Alzheimer’s disease. Subjects with

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familial hypercholesterolemia present a higher incidence of mild cognitive impairment.

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The brain of hypercholesterolemic mice presented a damaged blood-brain barrier,

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cholesterol accumulation associated with inflammation in different regions of the brain

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and loss of acetylcholinesterase activity and mitochondrial dysfunction in association

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with development of cognitive impairment.

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A meta-analysis of randomized crossover trials has shown the hypo-cholesterolemic

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effect of different polyphenols subfamilies.10 In line with this effect, it has been shown

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that luteolin and quercetin decrease cholesterol absorption by downregulation of

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Niemann-Pick C1 like 1 (NPC1L1) , the enzyme regulating cholesterol absorption by

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enterocytes.11 Moreoever, other polyphenols, i.e. cucurmin, are able to down-regulate 3-

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hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-

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controlling enzyme of the mevalonate pathway conducting to cholesterol biosynthesis.12

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Endogenous synthesis of omega-3 PUFA within the brain is low. Therefore, levels are

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maintained through their intake from dietary sources in plasma. Docosahexaenoic acid

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(DHA), the most abundant omega-3 PUFA in the brain, modulates the synthesis and

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accumulation of phosphatidylserine and key biophysical properties of the neuronal

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membrane. DHA but not eicosapentaenoic acid (EPA) has a beneficial effect on neurite

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outgrowth in aged rats, a mechanism impaired in neurodegenerative processes. Both 5 ACS Paragon Plus Environment


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DHA and EPA stimulate neurite outgrowth in the developmental stages. In humans a

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higher plasma EPA has been associated with lower cognitive decline, dementia risk and

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depression in the elderly. Moreover, EPA has been postulated as a biomarker and a

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protection factor for age-related cognitive impairment.13

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In this sense, epidemiological and animal studies suggest that simultaneous dietary

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intake of flavonoids might increase the conversion of α-linolenic acid (ALA) to longer-

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chain n-3 fatty acids EPA and DHA. The key enzymes in this process are ∆5-and ∆6-

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desaturases, of which gene expression regulation involves transcription factors such as

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peroxisome proliferator-activated receptor alpha (PPARα). It has been reported that

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concomitant consumption of ALA and curcumin increases EPA and DHA content in rat

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brain due to increased activity of required enzymes.14

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Quercetin has been shown to interact with PPARα. However, quercetin supplementation

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was not found to increment EPA in serum phospholipids of individuals treated with

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ALA.15 Similarly, anthocyanins did not prove any effect on EPA or DHA levels in

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different experimental models16 but resveratrol did.17

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Polyphenols interaction with PUFA might also take place before their joint

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consumption, during food processing and storage. Flavonoids have been proposed as

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natural antioxidants preventing the oxidation of n-3 PUFA.18

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Tryptophan

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Dietary tryptophan is the precursor of the monoaminergic neurotransmitter serotonin.

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Serotonin has well-known effects on sleep, lethargy, motivation, modulation of appetite

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and satiety, and on functions such as sensitivity to pain, regulation of blood pressure,

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and the control of mood. Serotonin cannot cross the blood-brain barrier, while

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tryptophan can, although this transport decreases with ageing. Tryptophan hydroxylase 6 ACS Paragon Plus Environment

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(TPH), the rate-limiting enzyme that catalyzes the first step of the synthesis of

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serotonin, is not saturated under physiological conditions, thus a rise in tryptophan brain

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concentration results in an increase of serotonin synthesis. In vitro, it has been shown

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that some polyphenols, including phenolic acids (chlorogenic, caffeic and gallic acids)

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and flavanols (myricetin and quercetin), react with soy proteins, therefore blocking their

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lysine, tryptophan and cysteine residues through covalent linkage.19 A nutritional

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consequence of such reactions in the food systems may be the limited availability of the

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essential amino acids lysine and tryptophan.

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However, in vivo, chronic administration of silymarin, quercetin and narigenin to aged

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rats reversed age-induced deficits in monoaminergic neurotransmitters (serotonin,

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noradrenaline, and dopamine), increasing TPH and tyrosine hydroxylase (TH)

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activities.20 In humans, red wine polyphenols participate in the regulation of amino

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acids metabolism affecting the excreted levels of tyrosine and tryptophan derivatives.21

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An increase in tryptophan bioavailability due to cross reactions with dietary

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polyphenols may result in an improvement of the cognitive function caused by

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serotonin. However, this link between tryptophan interaction with dietary polyphenols

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and the improvement of the cognitive function need to be better addressed.

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Micronutrients

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Vitamin C

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In addition to its antioxidant activity, ascorbate serves as a cofactor for dopamine-beta-

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hydroxylase, thus its presence is required for the transformation of dopamine into

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noradrenaline, which is the main neurotransmitter found in the sympathetic NS and has

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a role in brain enhancing arousal and alertness. In the elderly, ingestion of vitamin C is

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Intracellular accumulation of ascorbic acid seems to occur via two separate

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mechanisms: sodium-dependent ascorbic acid transport and sodium-independent

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dehydroascorbic acid transport. Dehydroascorbic acid is transported into cell via

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glucose transporters (GLUT 1, GLUT 3 and GLUT4) and then is reduced to ascorbate

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by intracellular proteins. Flavonoids block sodium-independent glucose transporters,

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thus inhibiting dehydroascorbic acid uptake.20 Two different isoforms of sodium-

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vitamin C cotransporters (SVCT1 and SVCT2) have been identified. SVCT2 is

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expressed in the hippocampus and cortical neurons of adult brain, in the cerebellum and

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brain cortex, and in embryonal mesencephalic neuron. Quercetin and phloretin inhibit

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ascorbic acid uptake by SVCT2 expressing neurons.22

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Vitamin B1 (thiamine)

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Vitamin B1 deficiency provokes lassitude, impaired intelligence, irritability, and

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cramps. Moreover, thiamin modulates cognitive performance, especially in the elderly.

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Consumption of food with high content in tannins could cause thiamin deficiency.

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Prolonged consumption of tea reduces thiamin brain levels, daily mean urinary

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excretion and mean blood levels of thiamin diphosphate.23 However, in most cases these

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results are not conclusive, some authors found that the inhibition of thiamine absorption

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is due to alcohol in the case of wine and not to its polyphenolic contents.24 Accordingly,

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more studies are needed in order to establish the actual effect of polyphenols on

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thiamine uptake at the neuronal level.

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Folate

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During pregnancy, folate deficiency induces major anomalies during the formation of

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the NS in the infant. In the elderly, deficiency decreases intellectual capacity and

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impairs memory. Catechins from green tea inhibit the uptake of folic acid by in vitro 8 ACS Paragon Plus Environment

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Caco-2 cell monolayers. Further study shows reduction of folic acid bioavailability by

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green and black tea in vivo.25 On the other hand, in humans, quercetin-3-rutinoside and

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chlorogenic acid reduced plasma folic acid levels but black tea consumption did not

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affect folic acid plasma levels.26

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The effect of tert-butyl hydroperoxide (TBH) induced oxidative stress reduced the

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accumulation of folic acid in Caco-2 cells. This outcome was associated with a decrease

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in the mRNA steady-state levels of proton-coupled folate transporter (PCFT) and folate

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receptor alpha (FOLR) and of the efflux transporter multidrug resistance protein 2

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(MRP2). This effect was completely prevented by dietary polyphenols: resveratrol,

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quercetin and EGCG.27 Therefore, dietary polyphenols may offer protection against

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oxidative stress induced inhibition of intestinal folic acid absorption. Additionally, it has

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been shown in vitro that resveratrol could protect folic acid against UV induced

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degradation.28

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Further research must be conducted to elucidate the interaction of different polyphenols

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on the intestinal absorption of folic acid and their effects at the neuronal level.

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Vitamin B12 (cobalamin)

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Vitamin B12 deficiency induces neurological disorders and psychic disturbances,

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including dementia and psychoses. Main symptoms are memory loss, pain, and

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abnormal sensations at extremities. Deficiency of vitamin B12 during childhood retards

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myelination and causes persistent neurological damage.

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In a cell model of Alzheimer’s disease it has been shown that vitamin B12 protective

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activity is enhanced by co-treatment with EGCG and resveratrol, showing effects on Aβ

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levels, inflammatory cytokines, cell survival proteins, oxidative enzymes expression,



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and oxidative species production.29 This experimental set-up opens new projections in

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the search of combinatorial treatment for the prevention of Alzheimer’s disease.

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Black tea, quercetin-3-rutinoside and chlorogenic acid consumption did not affect

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vitamin B12 plasma levels.26 However, it has been shown that cocoa polyphenols might

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destabilize B12 in heated chocolate milk.30

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Vitamin E

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Dietary vitamin E deficiency alters brain fatty acid profile. In transgenic mice used as

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model of Alzheimer disease, early vitamin E supplementation reduces Aβ levels and

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amiloid deposition in young but not in aged individuals. Vitamin E concentration has

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also been associated with the risk of developing dementia, being significantly increased

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for the lowest vitamin E concentration compared to the highest one.

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In vitro it has long been known that polyphenols are able to prevent vitamin E oxidation

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and degradation.31 A diet fortified with quercetin, epicatechin or catechin substantially

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increased α-tocopherol plasma and liver levels in rats. All tested flavonoids protected α-

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tocopherol from oxidation in human LDL ex vivo and reduced concentrations of α-

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tocopheroxyl radicals. On the contrary, supplementation of vitamin E-deficient diet with

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crude polyphenols from cocoa liquor did not prevent the depletion in α-tocopherol

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levels in the liver, kidney, heart, brain and plasma of rats. However, oxidative stress was

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decreased when polyphenols were administered.32 Additionally, in vivo, in pigs, tea

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polyphenols have not been shown effective in protecting vitamin E from oxidation. 33

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Minerals

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Zinc plays a key role in cognitive development and it also participates in the mechanism

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of taste and smell perception. Zinc deficiency impairs whole-body accumulation of


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PUFAs; thus brain supplying could be affected. Animal experiments have shown that

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Zn deficiency (in particular during pregnancy) results in loss of neurons and a reduction

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in brain volume (Table 1).

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Red wine, red grape juice and green tea polyphenols enhanced the uptake of zinc from

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rice. Quercetin and tannic acid stimulated the uptake of zinc. All polyphenols tested

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enhanced the expression of metallothionein, a cysteine-rich protein which participates in

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intracellular regulation of zinc concentration.34

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Additionally, it has been shown that quercetin and EGCG have a ionophore action, thus

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chelating zinc cations and transporting them across the plasma membrane independently

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of plasma membrane zinc transporters.35Copper is critical for the CNS, participating in

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its development but also in its function particularly at brain synapses. When mice were

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fed high concentrations of rutin, the Fe, Zn and Cu contents suffered no significant

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changes in the brain, whereas liver content of all of them was significantly decreased.37

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In rats fed with a flavonoid mixture (quercetin, rutin and catechin) an average decrease

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in copper plasma concentration of 27%, was found whereas Cu concentration was

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increased in liver and decreased in kidney.38Iron is an essential trace element necessary

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for the functions of many enzymes and prosthetic groups. Iron deficiency is mainly

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caused by poor iron absorption from the diet, which mainly consists of non-heme iron.

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Iron uptake in the brain is mediated by endothelial transferrin receptor expression in the

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blood-brain barrier. This expression is regulated by the iron status of the CNS.

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Iron deficit acts globally on the brain reducing the efficient supply of oxygen and

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decreasing brain energy production, as the activity of cytochrome c oxidase is reduced

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in certain cerebral regions. Otherwise, iron overload provokes oxidative stress in brain

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and other tissues. Iron concentration and metabolism is tightly regulated.



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Phenolic compounds bearing catechol groups or galloyl groups have notable iron-

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binding properties. The inhibiting effect of tea on non-heme iron absorption is attributed

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to the flavonoids present in tea. Patients with iron-deficiency anemia should avoid

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consumption of tea beverages with meals.

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The metal-binding activity of flavonoids suggests that they could also be effective

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protective agents in pathological conditions caused by both extracellular and

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intracellular oxidative stress linked to metal overload. Quercetin concentrations of less

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than 1µM can facilitate chelatable iron shuttling via GLUT 1 in either direction across

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cell membrane.39 In this sense polyphenols might protect against the neuronal amyloid-

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β production and cognitive impairment associated with iron overload.Manganese is a

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cofactor to different enzymes and is essential for neurological functioning, however it

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also might be toxic in case of overabundance in the brain, where it can result in

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manganism, a neurological condition resembling Parkinson's disease. Pretreatment with

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resveratrol and quercetin protects against the manganese-induced rise in GSSG/GSH

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ratio in the rat striatum, decrease in the nucleus accumbens α-tocopherol content, and

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reduction in superoxide dismutase in frontal cortex, nucleus accumbens and

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cerebellum.39

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Other food components

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Methylxanthynes

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Caffeine and other methylxanthynes antagonize adenosine receptors resulting in

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behavioral stimulant effects. Caffeine is metabolized in the liver by cytochrome P450

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oxidase, in particular by the CYP1A2, into three different dimethylxanthines:

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paraxanthine (84%), theobromine (12%) and theophylline (4%). Afterwards, nearly

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90% of paraxanthine is metabolized to 1,7-dimethilurate by CYP2A6. 12 ACS Paragon Plus Environment

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CYP1A2 activity was decreased by 10.4% in quercetin treated healthy volunteers,

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whereas CYP2A6 activity was increased by 25.3%.40 Quercetin inhibition of caffeine

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metabolism is unrelated to CYP1A2 gene polymorphisms.341 A longer half-life of

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methylxanthynes may result in prolonged stimulant effects at the neuronal level, even if

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it can have deleterious effects in cardiovascular function, i.e. hypertension.

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Ethanol

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Ethanol is metabolized to acetaldehyde mainly by hepatic enzyme alcohol

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dehydrogenase IB (ADH1B) using NAD+. It can also be oxidized by the microsomal

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ethanol oxidizing system (MEOS) and catalase. CYP2E1, a cytochrome P450 oxidase

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involved in metabolism of xenobiotics, is the enzyme involved in the MEOS. In human

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embryos and fetuses ethanol is metabolized to acetaldehyde by the MEOS due to

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underexpression of ADH1B. Acetaldehyde is a highly toxic unstable compound

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causative of oxidative stress. Aldehyde dehydrogensase 2 (ALDH2) transforms

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acetaldehyde to acetic acid.

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Ethanol administration enhances ROS generation and lipid peroxidation in brain, and

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decreases GSH/GSSG ratio, resulting in oxidative stress. Quercetin has been shown to

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reverse ethanol-induced cognitive dysfunction in mice.42

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Moreover, isorhamnentin glycoside from Brassica juncea increased activities of

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microsomal ethanol oxidizing system and aldehyde dehydrogenase, thus alleviating

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adverse effects of ethanol ingestion.43

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Additionally, grape skin and flesh extracts reversed ethanol-induced brain alterations in

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rats44 and the treatment with fenugreek seed polyphenols and silymarin restored ADH

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and ALDH reduced activities in sub-chronically ethanol intoxicated rats.45



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In vitro studies demonstrated that quercetin inhibited the activity of CYP2E1. Further

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study with healthy humans has showed that this relation is maintained in vivo. In this

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sense some authors have concluded that quercetin could provide a therapeutic approach

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for minimizing hepatotoxicity of ethanol.46 There is still a lack of studies on the effect

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of other polyphenols, including those present in wine or other largely consumed

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products, on ethanol neurotoxicity.

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Microbiota

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It has been proven that the human diet has a dramatic influence on its microbiota

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composition and that a diet rich in fruits and vegetables can have a positive influence on

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it.48 Additionally, there is a clear influence of the microbiota on the immune system and

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the immune system on its turn contribute to neurogenesis and spatial learning.

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Polyphenols have been proved to act as prebiotics by showing to be selectively

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fermented by human microbiota and modulating its composition.49 It has been shown

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that modulation of microbiota by prebiotics or directly probiotics administration might

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alter brain signalling mechanisms, emotional behaviour and visceral nociceptive

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reflexes. Additionally, the presence of polyphenolic metabolites derived from the

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bacterial microbiota action, such as 3-hydroxybenzoic acid and 3-(3´-hydroxyphenyl)-

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propionic acid, have been detected in the brain of rats after ingestion of grape seed

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polyphenols and these microbial metabolites can interfere with the assembly of β-

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amyloid peptides into neurotoxic β-amyloid aggregates having an impact on the onset

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and/or progression of Alzheimer disease.50

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Food or environmental pollutants

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Mercury is an environmental pollutant with high toxicity and mobility in ecosystems.

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Methylmercury (MeHg) is the mercury compound primarily associated with 14 ACS Paragon Plus Environment

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neurological alterations. The mechanism of action of MeHg is believed to be related to

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its ability to increase ROS and its high affinity for sulfhydryl groups. Therefore, MeHg

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interferes with intracellular signalling of multiple neurotransmitter receptors and

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impairs the organization of microtubules. Inorganic mercury increases permeability of

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chloride channels of GABA A receptors, which is associated with neuronal

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hyperpolarization.

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Prenatal exposure to methylmercury causes cognitive deficit in children and adults.

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Pregnant women should avoid methylmercury exposure from dietary seafood in order to

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prevent permanent cognitive adverse effects on their offspring.

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Although quercetin had displayed a protective effect against MeHg-induced oxidative

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damage in vitro, mice co-exposure to quercetin and MeHg caused higher cerebellar

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oxidative damage than individual administrations. Both compounds showed synergistic

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pro-oxidative action to mice cerebellum which resulted in motor deficit.51

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However, another study stated that quercetin and quercitrin have a protective effect

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against lipid peroxidation and ROS generation induced by MeHg, whereas rutin had no

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protective effect.52 Luteolin prevented MeHg-induced oxidative stress in lobster

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cockroach as well as acetylcholinesterase inhibition and locomotor deficit in a dose-

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dependent manner.53 Further research is needed to clarify if quercetin, quercitrin and

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other polyphenols could be used as a therapeutic approach in treating MeHg toxicity.

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Cadmium competes with biologically essential metals, such as calcium and zinc. It also

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crosses the blood-brain barrier and damages the NS. Cadmium causes neuronal

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oxidative stress and inhibits degradation of acetylcholine by acetylcholinesterase.



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Flavonoids have shown protective effects against cadmium-induced damage. Apart

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from chelating reactive oxygen species, reducing DNA damage and inhibiting

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apoptosis, flavonoids chelate cadmium thus reducing its accumulation in vivo.54

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Cadmium, like zinc, is chelated by metallothionein (MT). Quercetin stimulates the

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levels of MT-1 and MT2 mRNA and protein expression.Quercetin significantly

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prevented Pb-induced neurotoxicity in a dose-dependent manner and partly restored

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PKA, Akt, NOS, CaMKII and CREB activities in brains of Pb-treated mice. Quercetin

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administration significantly decreased Pb content in blood and brain in a dose-

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dependent manner.55 Moreoever, gossypin coadministration with lead decreased blood

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lead concentration and the uptake of lead by the brain in male rats.56Exposure of

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humans to environmental toxins such as paraquat induces acute and irreversible

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parkinsonism. Paraquat has been shown to specifically damage dopaminergic neuronal

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cells in in vivo studies with D. melanogaster, rats and mice. Pure polyphenols restore

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the impaired movement activity induced by paraquat in D. melanogaster, a valid model

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of Parkinson’s disease.57

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Cyp2d22, a mouse ortholog of human CYP2D6, offers neuroprotection in maneb- and

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paraquat-induced dopaminergic neurodegeneration. It has been shown that Resveratrol

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enhances its neuroprotective credentials by influencing Cyp2d22 expression and

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paraquat accumulation in mice co-treated with paraquat and resveratrol.58

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Perspective

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In conclusion there is a number of issues in relation to polyphenols interactions with

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other food components that need to be addressed. Some of the mechanisms that might

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underline the effect of polyphenols at the NS need confirmation in humans since most

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work has been done in laboratory animals due to the limitations inherent in this kind of 16 ACS Paragon Plus Environment

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target tissue. For this same reason there is still room for many mechanistic studies that

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could be done in vitro, in cell models or in animal models. A deeper knowledge of the

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interactions that take place in food, as part of its chemistry, during processing and

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storage can also help to get to a contrasted conclusion regarding the influence of

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polyphenols interactions with food components for their neuroprotective action.

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References

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Meireles, M.; Martel, F.; Araújo, J.; Santos-Buelga, C.; Gonzalez-Manzano, S.;

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Dueñas, M.; de Freitas, V.; Mateus, N.; Calhau, C.; Faria, A. Characterization and

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Page 26 of 30

Table 1: Mineral-Polyphenol Interactions: Effect at the Neuronal and Brain Level. Mineral Zinc

Copper

Physiological role Cognitive development and mechanism for perception of taste and smell.

CNS development and brain synapses.

Iron

Enzyme cofactor

Manganese

Iron overload provokes oxidative stress. Enzyme cofactor

Mercury

Overdose can result in Parkinson’s disease-like condition. MeHg interferes with intracellular signaling and impairs microtubule organization Prenatal exposure causes cognitive deficit.

Cadmium

Lead

Competes with Ca and Zn. Provokes neuronal oxidative stress and inhibits degradation of ACh. Affects brain development and induces behavioral changes

Polyphenol RWP, tannic acid, quercitrin Rutin Quercetin and EGCG

Effect Enhance zinc uptake and metallothionein expression.

Model Caco-2 cells

Reference 35

brain Zn content non affected.

Mice

37

ionophoric activity

Hepa 1-6 cells Mice

36

decreases plasma Cu.

Rat

38

brain Fe content non affected

Mice

37

shuttles chelatable iron across cell membrane via GLUT1. protect from oxidative stress caused by Mn overdose.

MDCK cells Rat

39 40

Rat

52

Mice

51

prevents oxidative damage and locomotor deficit Cd chelation, Cd accumulation reduction and Ox reduction

Lobster cockroach Mice

53 54

Quercetin

content in blood and brain decreased PKA, Akt, NOS, CaMKII and CREB activities restored in Pb-treated brains.

Mice

55

Gossypin

decreases Pb concentration in blood and its uptake by brain

Rats

56

Rutin Quercetin and catechin Rutin

Quercetin Resveratrol and quercetin

Quercetin and quercitrin

brain Cu content non affected

protect against lipid peroxidation and ROS generation Quercetin administration increases MeHg-induced cerebellar oxidative stress

Luteolin Quercetin, apigenin, chlorogenic acid

37

546


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FIGURE CAPTIONS Figure 1: Molecular Mechanisms Involved in Neurodegeneration Figure 2: Enzymes or Pathways Likely to be Involved in the Neurological Effect Mediated by the Interaction Between Polyphenols and Other Food Components



Page 28 of 30

Figure 1

28

ACS Paragon Plus Environment

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Figure 2

29



Page 30 of 30

TABLE OF CONTENT GRAPHIC

30


Polyphenols interaction with other food components as a mean for

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