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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
4
impact of environmental factors on the onset and evolution of neurodegenerative
5
conditions, food arises as a promising factor that might be influencing this group of
6
pathologies. The mechanisms by which polyphenols can affect these processes can be
7
through direct interaction with redox signalling or inflammatory pathways but can also
8
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.
11
12
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
19
its progression. Environmental factors that might be associated with neuronal
20
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
23
status.
24
The interest in polyphenols has been growing in the last decades, from their
25
identification and food technology implications to their healthy properties. In recent
26
years there has been an increasing interest in the effect of polyphenols at the
27
neurological level based on few studies proving the association of polyphenols ingestion
28
and a better cognitive performance.2
29
The molecular mechanisms that are involved in neurodegeneration include:
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inflammation, autophagy, redox status, proteostasis, synapsis homeostasis, glucose
31
metabolism, blood-brain barrier and vascular regulation (Figure 1). Polyphenols have
32
been described to regulate most of these mechanisms and thus they can sustain the
33
potential neuroprotective effectof polyphenol rich foods.3 However, another alternative
34
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
36
deleterious effect on neurons (Figure 2) and thus we consider this as being an
37
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
43
cells. Polyphenol modulation of glucose uptake through human blood-brain barrier has
44
been studied in cell culture models showing that catechin and epicatechin methylated
45
metabolites are able to increase glucose uptake but not their parent compounds,
46
epicatechin or catechin.4 However, sodium-dependent glucose uptake into Caco-2 cells
47
is inhibited by flavonoid glycosides and non-glycosylated polyphenols. Aglycones and
48
phenolic acids have no effect under sodium-dependent conditions. On the other hand,
49
sodium-independent glucose uptake is inhibited by non-glycosylated polyphenols
50
whereas glycosides and phenolic acids are ineffective.5
51
The regulation of glycaemia improves the quality and duration of intellectual
52
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
55
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
58
supplementation significantly reduced sodium-glucose co-transporter (SGLT) and
59
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
69
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
73
with development of cognitive impairment.
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A meta-analysis of randomized crossover trials has shown the hypo-cholesterolemic
75
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-
79
hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-
80
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
83
(DHA), the most abundant omega-3 PUFA in the brain, modulates the synthesis and
84
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-
94
desaturases, of which gene expression regulation involves transcription factors such as
95
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
144
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
150
excretion and mean blood levels of thiamin diphosphate.23 However, in most cases these
151
results are not conclusive, some authors found that the inhibition of thiamine absorption
152
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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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
162
affect folic acid plasma levels.26
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The effect of tert-butyl hydroperoxide (TBH) induced oxidative stress reduced the
164
accumulation of folic acid in Caco-2 cells. This outcome was associated with a decrease
165
in the mRNA steady-state levels of proton-coupled folate transporter (PCFT) and folate
166
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,
168
quercetin and EGCG.27 Therefore, dietary polyphenols may offer protection against
169
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
171
degradation.28
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Further research must be conducted to elucidate the interaction of different polyphenols
173
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
180
activity is enhanced by co-treatment with EGCG and resveratrol, showing effects on Aβ
181
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
188
Dietary vitamin E deficiency alters brain fatty acid profile. In transgenic mice used as
189
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
191
also been associated with the risk of developing dementia, being significantly increased
192
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
194
and degradation.31 A diet fortified with quercetin, epicatechin or catechin substantially
195
increased α-tocopherol plasma and liver levels in rats. All tested flavonoids protected α-
196
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
198
crude polyphenols from cocoa liquor did not prevent the depletion in α-tocopherol
199
levels in the liver, kidney, heart, brain and plasma of rats. However, oxidative stress was
200
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
215
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
217
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
219
in copper plasma concentration of 27%, was found whereas Cu concentration was
220
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
222
caused by poor iron absorption from the diet, which mainly consists of non-heme iron.
223
Iron uptake in the brain is mediated by endothelial transferrin receptor expression in the
224
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
226
decreasing brain energy production, as the activity of cytochrome c oxidase is reduced
227
in certain cerebral regions. Otherwise, iron overload provokes oxidative stress in brain
228
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
234
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
236
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-
238
β production and cognitive impairment associated with iron overload.Manganese is a
239
cofactor to different enzymes and is essential for neurological functioning, however it
240
also might be toxic in case of overabundance in the brain, where it can result in
241
manganism, a neurological condition resembling Parkinson's disease. Pretreatment with
242
resveratrol and quercetin protects against the manganese-induced rise in GSSG/GSH
243
ratio in the rat striatum, decrease in the nucleus accumbens α-tocopherol content, and
244
reduction in superoxide dismutase in frontal cortex, nucleus accumbens and
245
cerebellum.39
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Other food components
247
Methylxanthynes
248
Caffeine and other methylxanthynes antagonize adenosine receptors resulting in
249
behavioral stimulant effects. Caffeine is metabolized in the liver by cytochrome P450
250
oxidase, in particular by the CYP1A2, into three different dimethylxanthines:
251
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
255
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.
258
Ethanol
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Ethanol is metabolized to acetaldehyde mainly by hepatic enzyme alcohol
260
dehydrogenase IB (ADH1B) using NAD+. It can also be oxidized by the microsomal
261
ethanol oxidizing system (MEOS) and catalase. CYP2E1, a cytochrome P450 oxidase
262
involved in metabolism of xenobiotics, is the enzyme involved in the MEOS. In human
263
embryos and fetuses ethanol is metabolized to acetaldehyde by the MEOS due to
264
underexpression of ADH1B. Acetaldehyde is a highly toxic unstable compound
265
causative of oxidative stress. Aldehyde dehydrogensase 2 (ALDH2) transforms
266
acetaldehyde to acetic acid.
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Ethanol administration enhances ROS generation and lipid peroxidation in brain, and
268
decreases GSH/GSSG ratio, resulting in oxidative stress. Quercetin has been shown to
269
reverse ethanol-induced cognitive dysfunction in mice.42
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Moreover, isorhamnentin glycoside from Brassica juncea increased activities of
271
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
274
rats44 and the treatment with fenugreek seed polyphenols and silymarin restored ADH
275
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
279
for minimizing hepatotoxicity of ethanol.46 There is still a lack of studies on the effect
280
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
285
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
289
that modulation of microbiota by prebiotics or directly probiotics administration might
290
alter brain signalling mechanisms, emotional behaviour and visceral nociceptive
291
reflexes. Additionally, the presence of polyphenolic metabolites derived from the
292
bacterial microbiota action, such as 3-hydroxybenzoic acid and 3-(3´-hydroxyphenyl)-
293
propionic acid, have been detected in the brain of rats after ingestion of grape seed
294
polyphenols and these microbial metabolites can interfere with the assembly of β-
295
amyloid peptides into neurotoxic β-amyloid aggregates having an impact on the onset
296
and/or progression of Alzheimer disease.50
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Food or environmental pollutants
298
Mercury is an environmental pollutant with high toxicity and mobility in ecosystems.
299
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
302
interferes with intracellular signalling of multiple neurotransmitter receptors and
303
impairs the organization of microtubules. Inorganic mercury increases permeability of
304
chloride channels of GABA A receptors, which is associated with neuronal
305
hyperpolarization.
306
Prenatal exposure to methylmercury causes cognitive deficit in children and adults.
307
Pregnant women should avoid methylmercury exposure from dietary seafood in order to
308
prevent permanent cognitive adverse effects on their offspring.
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Although quercetin had displayed a protective effect against MeHg-induced oxidative
310
damage in vitro, mice co-exposure to quercetin and MeHg caused higher cerebellar
311
oxidative damage than individual administrations. Both compounds showed synergistic
312
pro-oxidative action to mice cerebellum which resulted in motor deficit.51
313
However, another study stated that quercetin and quercitrin have a protective effect
314
against lipid peroxidation and ROS generation induced by MeHg, whereas rutin had no
315
protective effect.52 Luteolin prevented MeHg-induced oxidative stress in lobster
316
cockroach as well as acetylcholinesterase inhibition and locomotor deficit in a dose-
317
dependent manner.53 Further research is needed to clarify if quercetin, quercitrin and
318
other polyphenols could be used as a therapeutic approach in treating MeHg toxicity.
319
Cadmium competes with biologically essential metals, such as calcium and zinc. It also
320
crosses the blood-brain barrier and damages the NS. Cadmium causes neuronal
321
oxidative stress and inhibits degradation of acetylcholine by acetylcholinesterase.
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Flavonoids have shown protective effects against cadmium-induced damage. Apart
323
from chelating reactive oxygen species, reducing DNA damage and inhibiting
324
apoptosis, flavonoids chelate cadmium thus reducing its accumulation in vivo.54
325
Cadmium, like zinc, is chelated by metallothionein (MT). Quercetin stimulates the
326
levels of MT-1 and MT2 mRNA and protein expression.Quercetin significantly
327
prevented Pb-induced neurotoxicity in a dose-dependent manner and partly restored
328
PKA, Akt, NOS, CaMKII and CREB activities in brains of Pb-treated mice. Quercetin
329
administration significantly decreased Pb content in blood and brain in a dose-
330
dependent manner.55 Moreoever, gossypin coadministration with lead decreased blood
331
lead concentration and the uptake of lead by the brain in male rats.56Exposure of
332
humans to environmental toxins such as paraquat induces acute and irreversible
333
parkinsonism. Paraquat has been shown to specifically damage dopaminergic neuronal
334
cells in in vivo studies with D. melanogaster, rats and mice. Pure polyphenols restore
335
the impaired movement activity induced by paraquat in D. melanogaster, a valid model
336
of Parkinson’s disease.57
337
Cyp2d22, a mouse ortholog of human CYP2D6, offers neuroprotection in maneb- and
338
paraquat-induced dopaminergic neurodegeneration. It has been shown that Resveratrol
339
enhances its neuroprotective credentials by influencing Cyp2d22 expression and
340
paraquat accumulation in mice co-treated with paraquat and resveratrol.58
341
Perspective
342
In conclusion there is a number of issues in relation to polyphenols interactions with
343
other food components that need to be addressed. Some of the mechanisms that might
344
underline the effect of polyphenols at the NS need confirmation in humans since most
345
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
347
could be done in vitro, in cell models or in animal models. A deeper knowledge of the
348
interactions that take place in food, as part of its chemistry, during processing and
349
storage can also help to get to a contrasted conclusion regarding the influence of
350
polyphenols interactions with food components for their neuroprotective action.
351
References
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Musiek, E. S.; Holtzman, D. M. Mechanisms linking circadian clocks, sleep, and
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Spencer J. P.; Rice-Evans, C.; Williams, R. J. Modulation of pro-survival
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Akt/protein kinase B and ERK1/2 signaling cascades by quercetin and its in vivo
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metabolites underlie their action on neuronal viability. J Biol Chem. 2003, 278,
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34783–34793.
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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
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Figure 1
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Figure 2
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TABLE OF CONTENT GRAPHIC
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