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Interaction of Polyphenols with Other Food Components as a Means for Their Neurological Health Benefits Hugo Granda and Sonia de Pascual-Teresa*
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Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN), Spanish National Research Council (CSIC), Jose Antonio Novais 10, 28040 Madrid, Spain ABSTRACT: Over the last few years, there has been increasing interest in the possible beneficial effect of polyphenol consumption on neurodegenerative disorders. Because there is a clear impact of environmental factors on the onset and evolution of neurodegenerative conditions, food arises as a promising factor that might be influencing this group of pathologies. The mechanisms by which polyphenols can affect these processes can be through direct interaction with redox signaling or inflammatory pathways but can also be explained by the interaction of dietary polyphenols with either micro- and macronutrients that are known to have neurological effects or interaction with food contaminants or food-associated toxins, avoiding their neuronal toxicity. KEYWORDS: polyphenols, neurodegeneration, interaction, nutrient, food component, mechanism
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INTRODUCTION Neurodegeneration is associated with aging, and thus, it is increasingly perceived as a health and social problem because there is an aging population worldwide. Neurodegeneration has a high environmental component, on either its appearance or its progression. Environmental factors that might be associated with neuronal degeneration include pollution, nutrition, and lifestyle factors, including physical exercise or sleep cycles.1 Lifestyle factors include sleep deprivation or sedentary behavior, and nutritional factors include a good number of micro- and macronutrient statuses. The interest in polyphenols has been growing in the last few decades, from their identification and food technology implications to their healthy properties. In recent years, there has been increasing interest in the effect of polyphenols at the neurological level based on a few studies proving the association of polyphenol ingestion and a better cognitive performance.2 The molecular mechanisms that are involved in neurodegeneration include inflammation, autophagy, redox status, proteostasis, synapsis homeostasis, glucose metabolism, blood−brain barrier, and vascular regulation (Figure 1). Polyphenols have been described to regulate most of these mechanisms, and thus, they can sustain the potential neuroprotective effect of polyphenol-rich foods.3 However, another alternative way in which polyphenols might have a positive effect on the neuronal system is through interaction with different food components with a proven protective or deleterious effect on neurons (Figure 2), and thus, we consider this as being an interesting area of study in the future.
Figure 1. Molecular mechanisms involved in neurodegeneration.
models showing that catechin- and epicatechin-methylated metabolites are able to increase glucose uptake but not their parent compounds, epicatechin or catechin.4 However, sodium-dependent glucose uptake into Caco-2 cells is inhibited by flavonoid glycosides and non-glycosylated polyphenols. Aglycones and phenolic acids have no effect under sodium-dependent conditions. On the other hand, sodium-independent glucose uptake is inhibited by nonglycosylated polyphenols, whereas glycosides and phenolic acids are ineffective.5 The regulation of glycaemia improves the quality and duration of intellectual performance. In infants, adults, and aged people as well as in diabetic patients, poorer glycaemic control is associated with lower intellectual performances. In this sense, it has been shown that hyperglycemia is significantly
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MACRONUTRIENTS Glucose. Most of the energy required to sustain normal brain function is provided by blood glucose. The blood−brain barrier limits and regulates glucose access to glial and neuronal cells. Polyphenol modulation of glucose uptake through a human blood−brain barrier has been studied in cell culture © 2018 American Chemical Society
Received: Revised: Accepted: Published: 8224
May 30, 2018 July 18, 2018 July 19, 2018 July 19, 2018 DOI: 10.1021/acs.jafc.8b02839 J. Agric. Food Chem. 2018, 66, 8224−8230
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Journal of Agricultural and Food Chemistry
neurite outgrowth in aged rats, a mechanism impaired in neurodegenerative processes. Both DHA and EPA stimulate neurite outgrowth in the developmental stages. In humans, a higher plasma EPA has been associated with lower cognitive decline, dementia risk, and depression in the elderly. Moreover, EPA has been postulated as a biomarker and protection factor for age-related cognitive impairment.13 In this sense, epidemiological and animal studies suggest that simultaneous dietary intake of flavonoids might increase the conversion of α-linolenic acid (ALA) to longer chain ω-3 fatty acids EPA and DHA. The key enzymes in this process are Δ5- and Δ6-desaturases, of which gene expression regulation involves transcription factors, such as peroxisome proliferatoractivated receptor α (PPARα). It has been reported that concomitant consumption of ALA and curcumin increases EPA and DHA content in a rat brain as a result of increased activity of required enzymes.14 Quercetin has been shown to interact with PPARα. However, quercetin supplementation was not found to increment EPA in serum phospholipids of individuals treated with ALA.15 Similarly, anthocyanins did not prove any effect on EPA or DHA levels in different experimental models,16 but resveratrol did.17 Polyphenol interaction with PUFA might also take place before their joint consumption, during food processing and storage. Flavonoids have been proposed as natural antioxidants, preventing the oxidation of ω-3 PUFA.18 Tryptophan. Dietary tryptophan is the precursor of the monoaminergic neurotransmitter serotonin. Serotonin has well-known effects on sleep, lethargy, motivation, modulation of appetite and satiety, and functions such as sensitivity to pain, regulation of blood pressure, and mood control. Serotonin cannot cross the blood−brain barrier, while tryptophan can, although this transport decreases with aging. Tryptophan hydroxylase (TPH), the rate-limiting enzyme that catalyzes the first step of the synthesis of serotonin, is not saturated under physiological conditions; thus, a rise in the tryptophan brain concentration results in an increase of serotonin synthesis. In vitro, it has been shown that some polyphenols, including phenolic acids (chlorogenic, caffeic, and gallic acids) and flavanols (myricetin and quercetin), react with soy proteins, therefore blocking their lysine, tryptophan, and cysteine residues through covalent linkage.19 A nutritional consequence of such reactions in the food systems may be the limited availability of the essential amino acids lysine and tryptophan. However, in vivo, chronic administration of silymarin, quercetin, and narigenin to aged rats reversed age-induced deficits in monoaminergic neurotransmitters (serotonin, noradrenaline, and dopamine), increasing TPH and tyrosine hydroxylase (TH) activities.20 In humans, red wine polyphenols participate in the regulation of amino acid metabolism, affecting the excreted levels of tyrosine and tryptophan derivatives.21 An increase in tryptophan bioavailability as a result of cross reactions with dietary polyphenols may result in an improvement of the cognitive function caused by serotonin. However, this link between tryptophan interaction with dietary polyphenols and the improvement of the cognitive function needs to be better addressed.
Figure 2. Enzymes or pathways likely to be involved in the neurological effect mediated by the interaction between polyphenols and other food components.
decreased in diabetic rats when glucose is administered with quercetin compared to administration of glucose alone.6 Acute exposure of Caco-2 cells to anthocyanin-rich berry extract significantly decreased both sodium-dependent and -independent glucose uptake. Long-term anthocyanin supplementation significantly reduced sodium−glucose cotransporter (SGLT) and glucose transporter (GLUT2) mRNA expression in Caco-2 cells. Therefore, berry flavonoids may modulate postprandial glycaemia by decreasing glucose transporter expression.7 Additionally, in diabetic volunteers, it has been shown that cranberry polyphenols are able to improve postprandial glucose excursions8 and that cocoa, red wine, and tea might have a big impact on the risk of type 2 diabetes.9 Taking all this into account, we could hypothesize that there is a regulation of glucose metabolism by polyphenols and that this interaction could explain, at least partially, the improvement in cognitive function. Lipids and Polyunsaturated Fatty Acids (PUFAs). Hypercholesterolemia is an early risk factor for Alzheimer’s disease. Subjects with familial hypercholesterolemia present a higher incidence of mild cognitive impairment. The brain of hypercholesterolemic mice presented a damaged blood−brain barrier, cholesterol accumulation associated with inflammation in different regions of the brain, and loss of acetylcholinesterase activity and mitochondrial dysfunction in association with development of cognitive impairment. A meta-analysis of randomized crossover trials has shown the hypocholesterolemic effect of different polyphenol subfamilies.10 In line with this effect, it has been shown that luteolin and quercetin decrease cholesterol absorption by downregulation of Niemann−Pick C1-like 1 (NPC1L1), the enzyme regulating cholesterol absorption by enterocytes.11 Moreoever, other polyphenols, i.e., cucurmin, are able to downregulate 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-controlling enzyme of the mevalonate pathway conducting cholesterol biosynthesis.12 Endogenous synthesis of ω-3 PUFA within the brain is low. Therefore, levels are maintained through their intake from dietary sources in plasma. Docosahexaenoic acid (DHA), the most abundant ω-3 PUFA in the brain, modulates the synthesis and accumulation of phosphatidylserine and key biophysical properties of the neuronal membrane. DHA but not eicosapentaenoic acid (EPA) has a beneficial effect on
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MICRONUTRIENTS Vitamin C. In addition to its antioxidant activity, ascorbate serves as a cofactor for dopamine-β-hydroxylase; thus, its presence is required for the transformation of dopamine into
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Journal of Agricultural and Food Chemistry Table 1. Mineral−Polyphenol Interactions: Effect at the Neuronal and Brain Level mineral zinc
physiological role cognitive development and mechanism for perception of taste and smell
polyphenol
effect
RWP, tannic acid, and quercitrin rutin quercetin and EGCG
copper
CNS development and brain synapses
rutin quercetin and catechin rutin quercetin
iron
enzyme cofactor iron overload provokes oxidative stress
manganese
enzyme cofactor
mercury
overdose can result in Parkinson’s disease-like conditions MeHg interferes with intracellular signaling and quercetin and quercitrin impairs microtubule organization prenatal exposure causes cognitive deficit
resveratrol and quercetin
luteolin cadmium
lead
competes with Ca and Zn provokes neuronal oxidative stress and inhibits degradation of ACh affects brain development and induces behavioral changes
quercetin, apigenin, and chlorogenic acid
quercetin
model
enhance zinc uptake and metallothionein expression brain Zn content not affected ionophoric activity
Caco-2 cells mice Hepa 1−6 cells brain Cu content not affected mice decreases plasma Cu rats brain Fe content not affected mice shuttles chelatable iron across the cell MDCK membrane via GLUT1 cells protects from oxidative stress caused by Mn rats overdose
protects against lipid peroxidation and ROS generation quercetin administration increases MeHg-induced cerebellar oxidative stress prevents oxidative damage and locomotor deficit Cd chelation, Cd accumulation reduction, and Ox reduction
content in blood and brain decreased PKA, Akt, NOS, CaMKII, and CREB activities restored in Pb-treated brains decreases Pb concentration in blood and its uptake by the brain
gossypin
reference 35 37 36 37 38 37 39 40
rats
52
mice
51
lobster cockroach mice
53
mice
55
rats
56
54
Folate. During pregnancy, folate deficiency induces major anomalies during the formation of the nervous system in the infant. In the elderly, deficiency decreases intellectual capacity and impairs memory. Catechins from green tea inhibit the uptake of folic acid by in vitro Caco-2 cell monolayers. Further study shows reduction of folic acid bioavailability by green and black tea in vivo.25 On the other hand, in humans, quercetin-3rutinoside and chlorogenic acid reduced plasma folic acid levels but black tea consumption did not affect folic acid plasma levels.26 The effect of tert-butyl hydroperoxide (TBH)-induced oxidative stress reduced the accumulation of folic acid in Caco-2 cells. This outcome was associated with a decrease in the mRNA steady-state levels of proton-coupled folate transporter (PCFT) and folate receptor α (FOLR) and the efflux transporter multidrug resistance protein 2 (MRP2). This effect was completely prevented by dietary polyphenols: resveratrol, quercetin, and epigallocatechin gallate (EGCG).27 Therefore, dietary polyphenols may offer protection against oxidative-stress-induced inhibition of intestinal folic acid absorption. Additionally, it has been shown in vitro that resveratrol could protect folic acid against ultraviolet (UV)induced degradation.28 Further research must be conducted to elucidate the interaction of different polyphenols on the intestinal absorption of folic acid and their effects at the neuronal level. Vitamin B12 (Cobalamin). Vitamin B12 deficiency induces neurological disorders and psychic disturbances, including dementia and psychoses. Main symptoms are memory loss, pain, and abnormal sensations at extremities. Deficiency of vitamin B12 during childhood retards myelination and causes persistent neurological damage.
noradrenaline, which is the main neurotransmitter found in the sympathetic nervous system and has a role in brain-enhancing arousal and alertness. In the elderly, ingestion of vitamin C is associated with a lower incidence of major alterations in cognitive performance. Intracellular accumulation of ascorbic acid seems to occur via two separate mechanisms: sodium-dependent ascorbic acid transport and sodium-independent dehydroascorbic acid transport. Dehydroascorbic acid is transported into the cell via glucose transporters (GLUT1, GLUT3, and GLUT4) and then reduced to ascorbate by intracellular proteins. Flavonoids block sodium-independent glucose transporters, thus inhibiting dehydroascorbic acid uptake.20 Two different isoforms of sodium−vitamin C cotransporters (SVCT1 and SVCT2) have been identified. SVCT2 is expressed in the hippocampus and cortical neurons of the adult brain, in the cerebellum and brain cortex, and in the embryonal mesencephalic neuron. Quercetin and phloretin inhibit ascorbic acid uptake by SVCT2expressing neurons.22 Vitamin B1 (Thiamine). Vitamin B1 deficiency provokes lassitude, impaired intelligence, irritability, and cramps. Moreover, thiamin modulates cognitive performance, especially in the elderly. Consumption of food with a high content in tannins could cause thiamin deficiency. Prolonged consumption of tea reduces thiamin brain levels, daily mean urinary excretion, and mean blood levels of thiamin diphosphate.23 However, in most cases, these results are not conclusive; some authors found that the inhibition of thiamine absorption is due to alcohol in the case of wine and not its polyphenolic contents.24 Accordingly, more studies are needed to establish the actual effect of polyphenols on thiamine uptake at the neuronal level. 8226
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consists of non-heme iron. Iron uptake in the brain is mediated by endothelial transferrin receptor expression in the blood− brain barrier. This expression is regulated by the iron status of the CNS. An iron deficit acts globally on the brain, reducing the efficient supply of oxygen and decreasing brain energy production, because the activity of cytochrome c oxidase is reduced in certain cerebral regions. Otherwise, iron overload provokes oxidative stress in the brain and other tissues. The iron concentration and metabolism are tightly regulated. Phenolic compounds bearing catechol groups or galloyl groups have notable iron-binding properties. The inhibiting effect of tea on non-heme iron absorption is attributed to the flavonoids present in tea. Patients with iron-deficiency anemia should avoid consumption of tea beverages with meals. The metal-binding activity of flavonoids suggests that they could also be effective protective agents in pathological conditions caused by both extracellular and intracellular oxidative stress linked to metal overload. Quercetin concentrations of less than 1 μM can facilitate chelatable iron shuttling via GLUT1 in either direction across the cell membrane.39 In this sense, polyphenols might protect against the neuronal amyloid-β production and cognitive impairment associated with iron overload. Manganese is a cofactor to different enzymes and is essential for neurological functioning; however, it might also be toxic in the case of overabundance in the brain, where it can result in manganism, a neurological condition resembling Parkinson’s disease. Pretreatment with resveratrol and quercetin protects against the manganeseinduced rise in the glutathione disulfide (GSSG)/glutathione (GSH) ratio in the rat striatum, the decrease in the nucleus accumbens α-tocopherol content, and the reduction in superoxide dismutase in the frontal cortex, nucleus accumbens, and cerebellum.39
In a cell model of Alzheimer’s disease, it has been shown that vitamin B12 protective activity is enhanced by co-treatment with EGCG and resveratrol, showing effects on Aβ levels, inflammatory cytokines, cell survival proteins, oxidative enzyme expression, and oxidative species production.29 This experimental setup opens new projections in the search of combinatorial treatment for the prevention of Alzheimer’s disease. Black tea, quercetin-3-rutinoside, and chlorogenic acid consumption did not affect vitamin B12 plasma levels.26 However, it has been shown that cocoa polyphenols might destabilize B12 in heated chocolate milk.30 Vitamin E. Dietary vitamin E deficiency alters the brain fatty acid profile. In transgenic mice used as a model of Alzheimer’s disease, early vitamin E supplementation reduces Aβ levels and amiloid deposition in the young but not in aged individuals. The vitamin E concentration has also been associated with the risk of developing dementia, being significantly increased for the lowest vitamin E concentration compared to the highest vitamin E concentration. In vitro, it has long been known that polyphenols are able to prevent vitamin E oxidation and degradation.31 A diet fortified with quercetin, epicatechin, or catechin substantially increased α-tocopherol plasma and liver levels in rats. All tested flavonoids protected α-tocopherol from oxidation in human low-density lipoprotein (LDL) ex vivo and reduced concentrations of α-tocopheroxyl radicals. On the contrary, supplementation of a vitamin-E-deficient diet with crude polyphenols from cocoa liquor did not prevent the depletion in α-tocopherol levels in the liver, kidney, heart, brain, and plasma of rats. However, oxidative stress was decreased when polyphenols were administered.32 Additionally, in vivo, in pigs, tea polyphenols have not been shown effective in protecting vitamin E from oxidation.33 Minerals. Zinc plays a key role in cognitive development and also participates in the mechanism of taste and smell perception. Zinc deficiency impairs whole-body accumulation of PUFAs; thus, the brain supply could be affected. Animal experiments have shown that Zn deficiency (in particular, during pregnancy) results in loss of neurons and a reduction in brain volume (Table 1). Red wine, red grape juice, and green tea polyphenols enhanced the uptake of zinc from rice. Quercetin and tannic acid stimulated the uptake of zinc. All polyphenols tested enhanced the expression of metallothionein, a cysteine-rich protein, which participates in intracellular regulation of the zinc concentration.34 Additionally, it has been shown that quercetin and EGCG have a ionophore action, thus chelating zinc cations and transporting them across the plasma membrane independently of plasma membrane zinc transporters.35 Copper is critical for the central nervous system (CNS), participating in its development but also in its function, particularly at brain synapses. When mice were fed high concentrations of rutin, the Fe, Zn, and Cu contents suffered no significant changes in the brain, whereas the liver content of all of them was significantly decreased.37 In rats fed with a flavonoid mixture (quercetin, rutin, and catechin), an average decrease in the copper plasma concentration of 27%, was found, whereas the Cu concentration was increased in the liver and decreased in the kidney.38 Iron is an essential trace element necessary for the functions of many enzymes and prosthetic groups. Iron deficiency is mainly caused by poor iron absorption from the diet, which mainly
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OTHER FOOD COMPONENTS Methylxanthynes. Caffeine and other methylxanthynes antagonize adenosine receptors, resulting in behavioral stimulant effects. Caffeine is metabolized in the liver by cytochrome P450 oxidase, in particular by CYP1A2, into three different dimethylxanthines: paraxanthine (84%), theobromine (12%), and theophylline (4%). Afterward, nearly 90% of paraxanthine is metabolized to 1,7-dimethilurate by CYP2A6. CYP1A2 activity was decreased by 10.4% in quercetintreated healthy volunteers, whereas CYP2A6 activity was increased by 25.3%.40 Quercetin inhibition of caffeine metabolism is unrelated to CYP1A2 gene polymorphisms.41 A longer half-life of methylxanthynes may result in prolonged stimulant effects at the neuronal level, even if it can have deleterious effects in cardiovascular function, i.e., hypertension. Ethanol. Ethanol is metabolized to acetaldehyde mainly by hepatic enzyme alcohol dehydrogenase IB (ADH1B) using NAD+. It can also be oxidized by the microsomal ethanoloxidizing system (MEOS) and catalase. CYP2E1, a cytochrome P450 oxidase involved in metabolism of xenobiotics, is the enzyme involved in the MEOS. In human embryos and fetuses, ethanol is metabolized to acetaldehyde by the MEOS as a result of underexpression of ADH1B. Acetaldehyde is a highly toxic unstable compound causative of oxidative stress. Aldehyde dehydrogensase 2 (ALDH2) transforms acetaldehyde to acetic acid. Ethanol administration enhances reactive oxygen species (ROS) generation and lipid peroxidation in the brain and 8227
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damage than individual administrations. Both compounds showed synergistic pro-oxidative action to mice cerebellum, which resulted in a motor deficit.51 However, another study stated that quercetin and quercitrin have a protective effect against lipid peroxidation and ROS generation induced by MeHg, whereas rutin had no protective effect.52 Luteolin prevented MeHg-induced oxidative stress in lobster cockroach as well as acetylcholinesterase inhibition and locomotor deficit in a dose-dependent manner.53 Further research is needed to clarify if quercetin, quercitrin, and other polyphenols could be used as a therapeutic approach in treating MeHg toxicity. Cadmium competes with biologically essential metals, such as calcium and zinc. It also crosses the blood−brain barrier and damages the nervous system. Cadmium causes neuronal oxidative stress and inhibits degradation of acetylcholine by acetylcholinesterase. Flavonoids have shown protective effects against cadmiuminduced damage. Apart from chelating reactive oxygen species, reducing DNA damage, and inhibiting apoptosis, flavonoids chelate cadmium, thus reducing its accumulation in vivo.54 Cadmium, like zinc, is chelated by metallothionein (MT). Quercetin stimulates the levels of MT1 and MT2 mRNA and protein expression. Quercetin significantly prevented Pbinduced neurotoxicity in a dose-dependent manner and partly restored protein kinase A (PKA), protein kinase B (Akt), nitric oxide synthase (NOS), calmodulin-dependent protein kinase II (CaMKII), and cAMP response element binding protein (CREB) activities in brains of Pb-treated mice. Quercetin administration significantly decreased the Pb content in blood and the brain in a dose-dependent manner.55 Moreoever, gossypin co-administration with lead decreased the blood lead concentration and the uptake of lead by the brain in male rats.56 Exposure of humans to environmental toxins, such as paraquat, induces acute and irreversible parkinsonism. Paraquat has been shown to specifically damage dopaminergic neuronal cells in in vivo studies with Drosophila melanogaster, rats, and mice. Pure polyphenols restore the impaired movement activity induced by paraquat in D. melanogaster, a valid model of Parkinson’s disease.57 Cyp2d22, a mouse orthologue of human CYP2D6, offers neuroprotection in maneb- and paraquat-induced dopaminergic neurodegeneration. It has been shown that resveratrol enhances its neuroprotective credentials by influencing Cyp2d22 expression and paraquat accumulation in mice cotreated with paraquat and resveratrol.58
decreases the GSH/GSSG ratio, resulting in oxidative stress. Quercetin has been shown to reverse ethanol-induced cognitive dysfunction in mice.42 Moreover, isorhamnentin glycoside from Brassica juncea increased activities of MEOS and aldehyde dehydrogenase, thus alleviating adverse effects of ethanol ingestion.43 Additionally, grape skin and flesh extracts reversed ethanolinduced brain alterations in rats,44 and the treatment with fenugreek seed polyphenols and silymarin restored alcohol dehydrogenase (ADH)- and aldehyde dehydrogensase (ALDH)-reduced activities in subchronically ethanol-intoxicated rats.45 In vitro studies demonstrated that quercetin inhibited the activity of CYP2E1. Further studies with healthy humans has shown that this relation is maintained in vivo. In this sense, some authors have concluded that quercetin could provide a therapeutic approach for minimizing hepatotoxicity of ethanol.46,47 There is still a lack of studies on the effect of other polyphenols, including those present in wine or other largely consumed products, on ethanol neurotoxicity.
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MICROBIOTA It has been proven that the human diet has a dramatic influence on its microbiota composition and that a diet rich in fruits and vegetables can have a positive influence on it.48 Additionally, there is a clear influence of the microbiota on the immune system, and the immune system on its turn contributes to neurogenesis and spatial learning. Polyphenols have been proven to act as prebiotics by showing to be selectively fermented by human microbiota and modulating its composition.49 It has been shown that modulation of microbiota by prebiotics or directly probiotic administration might alter brain-signaling mechanisms, emotional behavior, and visceral nociceptive reflexes. Additionally, the presence of polyphenolic metabolites derived from the bacterial microbiota action, such as 3-hydroxybenzoic acid and 3-(3′-hydroxyphenyl)-propionic acid, have been detected in the brain of rats after ingestion of grape seed polyphenols, and these microbial metabolites can interfere with the assembly of β-amyloid peptides into neurotoxic β-amyloid aggregates, having an impact on the onset and/or progression of Alzheimer’s disease.50
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FOOD OR ENVIRONMENTAL POLLUTANTS Mercury is an environmental pollutant with high toxicity and mobility in ecosystems. Methylmercury (MeHg) is the mercury compound primarily associated with neurological alterations. The mechanism of action of MeHg is believed to be related to its ability to increase ROS and its high affinity for sulfhydryl groups. Therefore, MeHg interferes with intracellular signaling of multiple neurotransmitter receptors and impairs the organization of microtubules. Inorganic mercury increases permeability of chloride channels of γ-aminobutyric acid (GABA) A receptors, which is associated with neuronal hyperpolarization. Prenatal exposure to MeHg causes a cognitive deficit in children and adults. Pregnant women should avoid MeHg exposure from dietary seafood to prevent permanent cognitive adverse effects on their offspring. Although quercetin had displayed a protective effect against MeHg-induced oxidative damage in vitro, mice co-exposure to quercetin and MeHg caused higher cerebellar oxidative
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PERSPECTIVE In conclusion, there is a number of issues in relation to polyphenol interactions with other food components that need to be addressed. Some of the mechanisms that might underline the effect of polyphenols at the nervous system need confirmation in humans because most work has been performed in laboratory animals as a result of the limitations inherent in this kind of target tissue. For this same reason, there is still room for many mechanistic studies that could be performed in vitro, in cell models, or in animal models. A deeper knowledge of the interactions that take place in food, as part of its chemistry, during processing and storage can also help to obtain a contrasted conclusion regarding the influence of interactions of polyphenols with food components for their neuroprotective action. 8228
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prevention of anxiety disorders. Biochim. Biophys. Acta, Mol. Basis Dis. 2015, 1852, 951−961. (15) Burak, C.; Wolffram, S.; Zur, B.; Langguth, P.; Fimmers, R.; Alteheld, B.; Stehle, P.; Egert, S. Effects of the flavonol quercetin and α-linolenic acid on n-3 PUFA status in metabolically healthy men and women: A randomised, double-blinded, placebo-controlled, crossover trial. Br. J. Nutr. 2017, 117, 698−711. (16) Vauzour, D.; Tejera, N.; O’Neill, C.; Booz, V.; Jude, B.; Wolf, I. M.; Rigby, N.; Silvan, J. M.; Curtis, P. J.; Cassidy, A.; de PascualTeresa, S.; Rimbach, G.; Minihane, A. M. Anthocyanins do not influence long-chain n-3 fatty acid status: Studies in cells, rodents and humans. J. Nutr. Biochem. 2015, 26, 211−218. (17) Torno, C.; Staats, S.; de Pascual-Teresa, S.; Rimbach, G.; Schulz, C. Fatty acid profile is modulated by dietary resveratrol in rainbow trout (Oncorhynchus mykiss). Mar. Drugs 2017, 15, 252. (18) Vaisali, C.; Belur, P. D.; Iyyaswami, R. Effectiveness of rutin and its lipophilic ester in improving oxidative stability of sardine oil containing trace water. Int. J. Food Sci. Technol. 2018, 53, 541−548. (19) Rawel, H. M.; Czajka, D.; Rohn, S.; Kroll, J. Interactions of different phenolic acids and flavonoids with soy proteins. Int. J. Biol. Macromol. 2002, 30, 137−150. (20) Sarubbo, F.; Ramis, M. R.; Kienzer, C.; Aparicio, S.; Esteban, S.; Miralles, A.; Moranta, D. Chronic silymarin, quercetin and naringenin treatments increase monoamines synthesis and hippocampal Sirt1 levels improving cognition in aged rats. J. of Neuroimmune Pharmacol. 2018, 13, 24−38. (21) Jacobs, D. M.; Fuhrmann, J. C.; van Dorsten, F. A.; Rein, D.; Peters, S.; van Velzen, E. J.; Hollebrands, B.; Draijer, R.; van Duynhoven, J.; Garczarek, U. Impact of short-term intake of red wine and grape polyphenol extract on the human metabolome. J. Agric. Food Chem. 2012, 60, 3078−3085. (22) Park, J. B.; Levine, M. Intracellular accumulation of ascorbic acid is inhibited by flavonoids via blocking of dehydroascorbic acid and ascorbic acid uptakes in HL- 60, U937 and Jurkat cells. J. Nutr. 2000, 130, 1297−1302. (23) Caprile, T.; Salazar, K.; Astuya, A.; Cisternas, P.; Silva-Alvarez, C.; Montecinos, H.; Millán, C.; García, M. A.; Nualart, F. The Na +-dependent L-ascorbic acid transporter SVCT2 expressed in brainstem cells, neurons, and neuroblastoma cells is inhibited by flavonoids. J. Neurochem. 2009, 108, 563−577. (24) Wang, R. S.; Kies, C. Niacin, thiamin, iron and protein status of humans as affected by the consumption of tea (Camellia sinensis) infusions. Plant Foods Hum. Nutr. 1991, 41, 337−353. (25) Lemos, C.; Azevedo, I.; Martel, F. Effect of red wine on the intestinal absorption of thiamine and folate in the rat: Comparison with the effect of ethanol alone. Alcohol.: Clin. Exp. Res. 2005, 29, 664−671. (26) Alemdaroglu, N. C.; Dietz, U.; Wolffram, S.; Spahn-Langguth, H.; Langguth, P. Influence of green and black tea on folic acid pharmacokinetics in healthy volunteers: Potential risk of diminished folic acid bioavailability. Biopharm. Drug Dispos. 2008, 29, 335−348. (27) Olthof, M. R.; Hollman, P. C.; Zock, P. L.; Katan, M. B. Consumption of high doses of chlorogenic acid, present in coffee, or of black tea increases plasma total homocysteine concentrations in humans. Am. J. Clin. Nutr. 2001, 73, 532−538. (28) Couto, M. R.; Gonçalves, P.; Catarino, T.; Araújo, J. R.; Correia-Branco, A.; Martel, F. The effect of oxidative stress upon the intestinal uptake of folic acid: In vitro studies with Caco-2 cells. Cell Biol. Toxicol. 2012, 28, 369−381. (29) Wusigale; Fang, Z.; Hu, L.; Gao, Y.; Li, J.; Liang, L. Protection of resveratrol against the photodecomposition of folic acid and photodecomposition-induced structural change of β-lactoglobulin. Food Res. Int. 2017, 102, 435−444. (30) Beesley, S.; Olcese, J.; Saunders, C.; Bienkiewicz, E. A. Combinatorial treatment effects in a cell culture model of Alzheimer’s disease. J. Alzheimer's Dis. 2017, 55, 1155−1166. (31) Johns, P. W.; Das, A.; Kuil, E. M.; Jacobs, W. A.; Schimpf, K. J.; Schmitz, D. J. Cocoa polyphenols accelerate vitamin B12 degradation in heated chocolate milk. Int. J. Food Sci. Technol. 2015, 50, 421−430.
AUTHOR INFORMATION
Corresponding Author
*Telephone: +34915492300. Fax: +34915493627. E-mail: s.
[email protected]. ORCID
Sonia de Pascual-Teresa: 0000-0001-6490-6934 Funding
Authors wish to thank the Spanish Comisión Interministerial de Ciencia y Tecnologı ́a (CICYT) for funding throw project AGL2016-76832. Notes
The authors declare no competing financial interest.
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