Over the last two decades, the increase in the incidence of neurodegenerative diseases due to the increasingly ageing population has resulted in a major social and economic burden. At present, a large body of literature supports the potential use of functional nutrients, which exhibit potential neuroprotective properties to mitigate these diseases. Among the most studied dietary molecules, polyphenols stand out because of their multiple and often overlapping reported modes of action. However, ambiguity still exists as to the significance of their influence on human health. This review discusses the characteristics and functions of polyphenols that shape their potential therapeutic actions in neurodegenerative diseases while the less-explored gaps in knowledge of these nutrients will also be highlighted.
It is widely acknowledged that nutrition plays a key role in the occurrence and progression of non-communicable diseases. A body of epidemiological evidence shows that a diet rich in fruit and vegetables reduces the incidence of cardiovascular diseases [1,2,3,4], type 2 diabetes [5,6], stroke [7,8] and numerous cancers [9,10,11]. Other studies find an inverse association between the consumption of green tea and cognitive decline [12,13]. These observed health benefits are thought to be at least partly attributable to a class of non-essential nutrients named polyphenols, found abundantly in fruits and vegetables [14,15].
Together with cancer and cardiovascular diseases, neurodegenerative disorders constitute a potential application for the benefits of polyphenols [16,17]. This includes Parkinson’s and Alzheimer’s diseases which lack clear etiopathogenetic origins and arise from the interaction between aging, environment and genetic risk factors. The etiology of these diseases is further complicated by a number of proposed causative mechanisms, including oxidative stress, neuroinflammation, protein aggregation, iron toxicity and mitochondrial dysfunction. Polyphenols are reported to improve many of these factors at a cellular level, which makes their use in complex neurodegenerative disorders compelling. In this review, the properties that may influence the functionality and bioavailability of dietary polyphenols in the central nervous system (CNS) are discussed with a particular focus on therapeutic applications and limitations.
2. Chemico-Structural Characteristics
Plant polyphenols were originally classified in the early literature as “vegetable tannins” owing to their tanning action on animal skins . The first comprehensive description, referred to as the White–Bate-Smith–Swain–Haslam (WBSSH) definition, recommended that the term polyphenol be exclusively used to describe water-soluble phenolic compounds having a molecular mass ranging between 500 to 4000 Da, possessing at least 12 phenolic hydroxyl groups and 5 to 7 aromatic rings per 1000 Da . A less restrictive interpretation was proposed offering a broader view of the WBSSH definition to include simpler phenolic compounds with potential biological activities others than tanning :
“The term “polyphenol” should be used to define compounds exclusively derived from the shikimate/phenylpropanoid and/or the polyketide pathway, featuring more than one phenolic unit and deprived of nitrogen-based functions. This definition lets out all monophenolic structures as well as all their naturally occurring derivatives such as phenyl esters, methyl phenyl ethers and O-phenyl glycosides.”
A majority of plant polyphenols originate from phenylalanine which is deaminated to cinnamic acid, which then enters the phenylpropanoid pathway . Plant metabolism utilizes the phenylpropanoid unit C6-C3, a phenol ring with a 3-carbon side chain, as a building block to construct polyphenols. Classification of the resulting molecules is dictated by the number of phenol rings (C6) they contain and the structural elements binding these rings to one another. The main subclasses, varying in complexity, are phenolic acids (C6-C3 and C6-C1), flavonoids (C6-C3-C6), stilbenes (C6-C2-C6) and lignans (C6-C3-C3-C6). Within these subclasses, hydroxylations and O-glycosylations at various positions as well as cis-trans isomerization give rise to the thousands of polyphenols (estimated to be >8000) identified to date, resulting in a complex range of molecules with potential pharmacological values. Details of these polyphenols alongside their occurrence in various food products are available on databases such as Phenol-Explorer managed by the Institut National de la Recherche Agronomique (www.phenol-explorer.eu).
2.2. Structure versus Biofunctionality in Neuroprotection
The structural properties shared by polyphenols are important to their potential therapeutic applications, particularly in neuroprotection. These include the presence of phenol rings, variable hydroxylation patterns and conjugated double bonds all of which grant polyphenols metal-chelating, fibril-destabilizing, estrogen-like, enzyme-binding and antioxidative properties. These modes of action allow polyphenols to provide a defense against many pathophysiological aspects of neurodegenerative diseases, namely oxidative stress, neuroinflammation, protein aggregation, iron toxicity and mitochondrial dysfunction. These are detailed below:
The redox properties of divalent metals, such as copper, zinc and iron, are essential for cellular homeostasis. When in excess, however, these metals generate surplus reactive oxygen species. This excess can be reversed by chelation with polyphenols that possess at least one galloyl or catechol group (hydroxyl groups in the ortho-position) which are powerful bidentate chelators of divalent metals , whereas polyphenols having only a phenol substitution (one hydroxyl function) or possessing a resorcinol group (meta-position hydroxyl pair) are less potent monodentate chelators [23,24]. For chelation to occur, a deprotonation step of the phenolic group is necessary and has been shown to be possible at physiological pH .
Self-assembly of amyloidogenic fibrils including tau, beta amyloid (Aβ) and α-synuclein all neuropathologically relevant proteins involves interactions between aromatic residues . Using similar aromatic interactions, as described above, phenol moieties in polyphenols can interfere with fibril assembly , possibly by weakening cross-β structures. This interference seems to arise from hydrophobic and π stacking interactions , although the formation of covalent bonds through Schiff base reactions has also been proposed for the green tea polyphenol epigallocatechin-3-gallate (EGCG) [28,29]. Analysis of binding energies between polyphenols and protein fibrils has also shown favorable entropic and enthalpic dynamics that suggest the stabilization of H-bonds .
Polyphenols, referred to as phytoestrogens, have the ability to bind estrogen receptors (ERs), usually with a greater affinity for ERβ [31,32]. Depending on structure, dose, cell type and estrogen response element (ERE) sequence, different polyphenols have a weak or strong antagonistic or agonistic effect on ERs, resulting in a wide spectrum of activities in cells [33,34,35,36]. To enable binding to ERs, a structure should be composed of a phenolic ring with a configuration resembling that of estradiol, as found in flavonoid isoflavones or the stilbene resveratrol, for instance. Also, a specific hydroxylation pattern and an adequate distance between substituted hydroxyl groups are necessary to bind ERs.
Polyphenols can also share structural similarities with endogenous ligands, such as cyclic adenosine monophosphate (cAMP) or nucleoside triphosphates, endowing them with the aptitude to activate or inhibit key enzymes [37,38]. To date, the modulatory effects of several polyphenols on enzymes have been confirmed in cellular or animal models, these include resveratrol on cAMP phosphodiesterases , theaflavins on the adenosine triphosphate (ATP) synthase and respiratory chain  and curcumin on glyoxalase 1 . The presence of appropriately spaced ketone and hydroxyl groups in a planar configuration, bestow some polyphenols, such as curcumin, with the ability to mimic an enediolate intermediate in physiological conditions  is an example of structural elements that make enzyme binding possible.
Apart from the functions described above which result from the unique chemical structures of polyphenols, the most vastly studied characteristic of this class of chemicals is their antioxidative action. Polyphenols are thought to exert their antioxidative action directly, by scavenging free radical species firsthand, and/or indirectly, by activating endogenous antioxidative pathways. Direct antioxidative effects usually occur through H-atom transfer from polyphenols’ (ArOH) hydroxyl (OH) groups to the free radicals (R•):
ArOH + R• → ArO• + RH
The existence of multiple conjugated double bonds in polyphenols allows unpaired electron to be delocalized over the aromatic ring, yielding a much more stable and much less reactive, polyphenolic radical (ArO•) (Equation (1)). Some polyphenols also exert indirect antioxidative effects through the Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2/antioxidant response elements (Keap1/Nrf2/ARE) regulatory pathway made possible by the presence of electrophilic functions (α,β-unsaturated carbonyl group, 1,2- and 1,4-quinones or other groups) that alkylate thiol sensors in the cysteine pocket of Keap1 [43,44]. Others, like stilbenes, engage their resorcinol hydroxyl functions in hydrogen bonds with the Kelch pocket of Keap1 . Both these events lead to the disruption of the Keap1/Nrf2 complex, allowing Nrf2 to translocate to the nucleus where it can trigger the expression of antioxidant proteins like heme oxygenase-1 via binding of adenylate and uridylate (AU)-rich elements (AREs). This cysteine-modifying function of polyphenols may also have implications for the activity of various other enzymes .
3. Factors Influencing Pharmacokinetics and Bioavailability
To be effective in the prevention or amelioration of neurodegenerative diseases, polyphenols must be bioavailable. Extensive reports on the bioavailability of the most common dietary polyphenols can be found elsewhere [46,47,48]. In this review, we will first discuss the obstacles that hinder polyphenol bioavailability and address CNS permeability in particular.
3.1. Food Matrix or Vehicle
Oral administration is the most usual route if polyphenols are given pharmacologically but this often conflicts with bioavailability. Particular factors include interaction with vehicle, transformations by digestive and microbial enzymes and absorption by the gastrointestinal tract .
Food matrices are central to the efficacy of polyphenols . Few studies have been conducted and inconsistent results have been obtained, demonstrating either a negligible [51,52] or a significant [53,54,55,56] contribution of the food matrix to polyphenol absorption. Indeed, peculiar factors such as the type of lipid matrix used may mediate in the release of polyphenols in the gastrointestinal tract [57,58]. Ethanol may also play a role in polyphenols absorption with studies showing improved bioavailability of quercetin in rats when administered in 30% ethanol, an alcohol content that is unsustainable in the diet . In humans administered normal or dealcoholized red wine there was no differences in plasma levels of catechin but increased catechin excretion with red wine probably due to a diuretic effect of alcohol . However, matrix effects are too peculiar to be fully reviewed here.
3.2. Gastrointestinal Transformations and Absorption
Absorption and metabolism of polyphenols have extensively studied (see for review, References [61,62]). Whereas aglycones are normally well absorbed by the small intestine, nutritional polyphenols are more commonly present as glycosides, esters and polymers, which cannot be efficiently assimilated in the upper portion of the gut.
Molecules not absorbed in the upper gastrointestinal tract continue to the colon to become substrates for the gut microbiota, responsible for a very wide array of reactions, some of which yield monomers or aglycones from glycosylated polyphenols (see for review ). Smaller, better-absorbed phenolic acids may also be produced by the gut microbiota. For example, microbiotic degradation of quercetin mainly generates 3,4-dihydroxyphenylacetic, 3-methoxy-4-hydroxyphenylacetic (homovanillic acid) and 3-hydroxyphenylacetic acid . In volunteers challenged with 75 mg of rutin, a quercetin glycoside, the total urinary excretion of microbial metabolites accounted for as much as 50% of the ingested dose . Importantly, the sum of these gastrointestinal transformations and food matrix interactions can either increase or decrease the absorption of the resulting metabolites in the bloodstream.
3.3. Plasma Bioavailability, Transformations and Cellular Uptake
Once in the blood stream, enzymes in the liver and kidneys further modify polyphenols into various conjugated forms, a process that serves to detoxify potentially harmful substances. Molecules are rendered more hydrophilic in order to facilitate their urinary elimination, which usually lowers bioavailability [66,67]. While metabolites usually constitute the greatest fraction of circulating polyphenolic species, some forms undergo enterohepatic recirculation via biliary secretion, followed by deconjugation into free polyphenols by the gut microbiota and reabsorption in the colon [68,69,70]. Additional hepatic reactions may also occur which revert circulating metabolites back to the free form [71,72,73], as is the case for the conversion of resveratrol sulphate to bioactive resveratrol by sulphatases in humans . Moreover, glucuronide and sulphate metabolites retain some of their beneficial effects in vitro [74,75]. Thus, chronic administration of polyphenols may be an efficient strategy to increase plasma bioavailability in humans, as reported for epigallocatechin-3-gallate (EGCG) .
The final step in the action of polyphenols is cellular uptake, which depends not only on how they have been metabolized but also on their interaction with circulating proteins, fatty acids and lipoproteins  with the bioefficacy of therapeutic agents heavily relying on binding to such serum transporters . Resveratrol for example, is lipophilic which requires transformation into a more hydrophilic form, by sulphation, glucuronidation or binding to proteins enabling circulation in appropriate concentrations . The formation of complexes between resveratrol and transporter proteins, principally albumin [80,81,82] and lipoproteins [83,84,85,86], impedes its uptake by cells . Fatty acids are also known to improve the ability of resveratrol to bind transporter proteins .
While the binding by transporter proteins diminishes the availability of the free form of the polyphenol, it is thought to provide a polyphenol reservoir, important in the systemic distribution of bound species . Some studies have proposed that these complexes are retained at the cell membrane by albumin and lipoprotein receptors, offering a carrier-mediated mechanism by which polyphenols may gain entry to cells  in addition to passive diffusion . There is also the possibility that polyphenols need not enter cells to have an effect, as when free resveratrol binds integrin αVβ3  to produce an angiosuppressive effect (Belleri et al., 2008) and when it triggers p53-dependent apoptosis of breast cancer cells .
3.4. Accumulation in the Brain Parenchyma
Drugs targeting the brain must ultimately be able to accumulate in the brain parenchyma, in a biologically active form and in sufficient concentrations. Three important obstacles stand in the way of this: the blood-brain barrier (BBB), efflux transporters and multidrug resistance-associated proteins [90,91]. Youdim and colleagues were the first to demonstrate polyphenols crossing the BBB in an in vitro model, describing superior penetration of lipophilic (methylated conjugates) in comparison to hydrophilic molecules (sulphated or glucuronidated) [92,93]. Another study identified a stereoselective process in the passage of flavonoid catechins across the BBB . Yet, the exact mechanisms polyphenols use by to traverse the BBB in vivo, either via diffusion or via transporters, remains to be elucidated.
Although information on transport of polyphenols into the brain is limited compared to the measurement of plasma levels, an increasing number of studies have measured polyphenols and metabolites in the brains of rodents and pigs , as reviewed elsewhere [90,96,97]. Entry into the CNS of the most commonly studied polyphenols has been reported several times, for resveratrol [67,98,99,100,101], EGCG [102,103] and quercetin [93,104,105,106].
However, differences in uptake are reported depending on the route of administration and the methods used for measurement. For example, in one study, orally administered tritiated resveratrol in rats (50 mg/kg b.w.) was reported to reach 1.7% of the ingested dose in the plasma and below 0.1% in the brain after 2 h . Interestingly, 18 h after administration, the CNS retained 43% of the resveratrol measured at 2 h, mainly in the free form. Despite this retention in the brain, resveratrol levels, measured by high-performance liquid chromatography (HPLC) are lower than in the liver, kidney, testes and lungs . However, another study was unable to detect brain resveratrol or metabolites in rats fed a 0.2% resveratrol diet for 45 days using HPLC with a detection limit of 0.5 pmol/mL/mg . Other studies have also used chromatographic methods to measure resveratrol in rat brains using different protocols. In one study, 15 mg/kg b.w. of resveratrol were administered intravenously (i.v.), a relatively high dose, with brain tissue concentrations reaching ~0.17 nmol/g after 90 min . Another study administered escalating oral doses of resveratrol (100–400 mg/kg b.w.) for 3 days and detected ~1.7 nmol/g in the brain by liquid chromatography-mass spectrometry .
Some polyphenols are extensively transformed before they reach the brain, which may dampen their bioavailability, as discussed above. As an example, curcumin is highly lipophilic and, in theory, should easily gain entry to the brain . However, before reaching the BBB, the free form of curcumin is rapidly conjugated, rendering it only sparingly bioavailable to the CNS . Conversely, catechins efficiently cross the BBB after oral administration but are found in glucuronidated and 3′-O-methyl glucuronidated forms in the brain [102,110]. To date, it remains unclear whether conjugation occurs before or after entry into the brain. Nevertheless, strategies exist to boost CNS concentrations of the aglycone form, for example by continuous administration aimed at promoting tissue accumulation . Following 24 h of continuous intragastric administration, EGCG levels in the CNS reached 5–10% of concentrations measured in the plasma . These results imply, however, that a very high plasma concentration is needed for EGCG to accumulate in therapeutically reasonable concentrations in the brain. The necessity of maintaining high circulating concentrations may raise questions regarding the safety and tolerability of polyphenols.
3.5. Synergistic Effects
Some polyphenols interact beneficially when administered in combination. Synergistic pharmacokinetics are at the basis of emerging multi-drug therapies [111,112,113] developed to surmount problems of low efficacy, acquired resistance and undesirable side effects in standalone treatments. Polyphenols synergize via multiple mechanisms, extensively reviewed elsewhere [114,115,116]. Although synergistic chemosensitization properties of polyphenols are well known, for example EGCG-induced downregulation of endoplasmic reticulum stress response elements rendering temozolomide treatments more efficient in a mouse model of glioma , what follows will concentrate solely on neuroprotective mechanisms.
Underlying the efficacy of herb and plant extracts, different polyphenols may concurrently regulate the same or separate targets in cells, resulting in a concerted agonistic effect. For instance, combinations of resveratrol and quercetin [118,119] or epicatechin and quercetin  synergize to protect against amyloid-like aggregation, oxidative stress and oxygen-glucose deprivation in vitro. An earlier report of synergy between polyphenols showed that treatment of neuronal PC12 cells with suboptimal doses of resveratrol in combination with catechin conferred greater protection against Aβ toxicity than the sum of their individual actions . However, when measuring their free radical scavenging activities, the authors found their combined antioxidative effect to be merely additive, suggesting that their synergistic neuroprotective competences at combined subliminal doses may depend on other cellular mechanisms . Very few studies have addressed neuroprotective synergy in vivo though a combination of polyphenols was found to synergistically rescue photoreceptors in an animal model of retinal degeneration .
Synergy can also occur between polyphenols, drugs and hormones. Many in vitro reports support this, as is the case for the potentiation of neurite outgrowth by a subeffective dose of brain-derived neurotrophic factor (BDNF) in conjunction with green tea catechins [123,124], as well as the protection of primary neurons and astrocytes by a cocktail of suboptimal doses of resveratrol and melatonin via upregulation of heme oxygenase-1 . One of the first reports of polyphenol-drug synergy in rodents showed EGCG favorably interacting with rasagiline, an irreversible inhibitor of dopamine-metabolizing monoamine oxidase B (MAO-B) for the treatment of Parkinson’s disease [126,127]. When administered alone in suboptimal doses, neither EGCG nor rasagiline were capable of rescuing nigrostriatal neurons in a 1,2,3,6-tetrahydropyridine (MPTP)-injured mouse model of Parkinson’s disease . However, in combination these agents in low doses promoted the survival of the dopaminergic nigrostriatal pathway, demonstrating their synergistic effect. Interestingly, the ability of rasagiline to promote the expression of BDNF in concert with EGCG-induced induction of protein kinase C produced a sum agonistic effect converging at their downstream effector Akt/protein kinase B, thought to account for their neuroprotective action. Other examples of polyphenol-drug synergies exist for valproate and resveratrol in ischemic stroke  as well as for glatiramer acetate and EGCG in experimental autoimmune encephalomyelitis .
Many polyphenols readily regulate absorption in the gastrointestinal tract, clearance at the level of the kidneys and detoxification in the liver by modulating the activity of transport proteins or metabolic enzymes, which may improve their own oral availability. This property has potential for use in Parkinson’s disease by minimizing levodopa methylation in the liver by inhibiting human catechol-O-methyl transferase (COMT), thereby enhancing bioavailability of the drug . Flavonoids are also known to be potent inhibitors of cytochrome P450 (CYP) enzymes [132,133] whose activity reduces polyphenol bioavailability. This potential to enhance bioavailability of metabolism-sensitive drugs constitutes a clear example of polyphenol synergy that may be relevant in human treatment.
4. Safety and Tolerability
In addition to favorable pharmacokinetics, polyphenols must be safe and well-tolerated in humans. Several investigations have already addressed safety and tolerability issues (see for review [134,135,136,137]). What follows is a summary of these findings.
4.1. Side Effects from Dosage and Chronicity
Virtually all investigations performed in humans using a wide array of polyphenol preparations found that they are safe and tolerable in the short- [138,139], medium- [46,140] and long-term [141,142,143]. Generally, side effects are uncommon and are mild and transient and include minor gastrointestinal problems and, more rarely, headaches, dizziness and rashes. In a phase II trial, 24 Alzheimer’s patients were administered 2 or 4 g of curcuminoids daily for 48 weeks and 3 withdrew due to minor gastrointestinal issues . A study using a single 5 g/70 kg b.w. intake of resveratrol, representing 1/40 of the nephrotoxic dose and 1/4 of the highest dose reported to be safe in rats , did not show any serious adverse effects . A great number of investigations have also addressed the safety of specific diets enriched in polyphenol-rich foods. Of particular interest, black cohosh, soy and red clover regimens aimed at reducing menopausal symptoms in women have proven to be safe, with occasional mild gastrointestinal issues, musculoskeletal and connective tissue troubles, as well as weight gain (see for review, Reference ).
4.2. Adverse Pharmacological Interactions
While a consensus has been reached on the safety and tolerability of polyphenols in most individuals, certain contexts preclude their use. Grapefruit juice is an example of the possible effects of polyphenols under specific conditions. Apigenin, naringenin, nobiletin and hesperetin in grapefruit juice potently inhibit the detoxifying enzymes, members of the CYP family, responsible for the metabolism of several prescription drugs [132,145,146,147,148]. Interestingly, enzymatic inhibition is apparently irreversible following the ingestion of 200–300 mL of juice, leading to increased drug bioavailability and toxicity for up to 24 h after intake. Medical professionals are now mindful of the risks of consuming grapefruit juice in individuals already taking antidepressants such as buspirone (Buspar) and sertraline (Zoloft), beta-blockers, anti-cancer agents, fexofenadine (Allegra) or certain statins (atorvastatin) among other drugs [149,150,151,152]. Several other adverse interactions exist between polyphenols and drugs [153,154] and have been extensively discussed elsewhere .
As previously discussed, certain polyphenols, termed phytoestrogens, are biofunctional due to their resemblance to steroid hormones. Members of the flavonoid and stilbene subclasses indeed possess the capacity to bind ERs  and testosterone receptors , albeit with much lower affinities than endogenous ligands. Many studies find phytoestrogens to be safe with respect to incidences of cancers [157,158] and support their role in inhibiting aberrant cell proliferation [159,160,161,162,163,164,165]. Nevertheless, a few publications draw attention to the possible carcinogenic actions of some phytoestrogens that should not be ignored . In particular, soy genistein and daidzein (0.001–10 µM) may stimulate the growth of malignant breast tumors, both in vitro and in vivo [166,167].
In the case of the stilbene resveratrol, studies confirm its ability to bind both ERs , however with 7000 times less affinity than estradiol . Interestingly, its effects are apparent for select EREs regulated by ERα but not for EREs dependent on ERβ activation. Unlike other ERα agonists, resveratrol does not appear to provoke mammary or uterine tissue proliferation in rats  and even promotes neuronal differentiation in vitro . In light of this, resveratrol’s favorable effects may in fact partially hinge on tissue-specific expression profiles of ERα and ERβ . More recently, a study delineated the discriminatory ability of resveratrol to impede inflammation without promoting cell proliferation through pathway-selective ERα activation . Crystallographic studies of the ligand-binding domain revealed resveratrol to bind in the opposite orientation to estradiol, which may be at the core of its pathway selectivity and its proven safety in humans , particularly with regard to carcinogenesis.
5. Clinical Progress
The therapeutic potential of polyphenols is clear from the overwhelming body of literature supporting their beneficial effects in countless preclinical disease settings (see for review [16,17]). Notwithstanding the weight of epidemiological, anecdotal and fundamental evidence, translation from bench-to-bedside has proven challenging despite relentless efforts to test polyphenols in human trials (see  for a review). Currently, only a single trial looking at polyphenols in neurodegenerative disease has reached phase III clinical testing . In this randomized, double-blind, placebo-controlled parallel group study, disease progression will be assessed after 48 weeks of daily oral EGCG treatments in multiple system atrophy patients.
The example of a standardized Ginkgo biloba extract, rich in flavonoids, yielded particularly disappointing results with numerous failed phase I trials [106,174,175,176]. These studies addressed dementia prevention in large cohorts of healthy or mildly cognitively impaired elderly individuals administered oral Ginkgo biloba twice daily for several years  but no reduction in the incidence of cognitive decline or Alzheimer’s disease was found [178,179,180,181,182]. Other phase I and II clinical attempts have also been unsuccessful in confirming the putative positive effects of curcumin in Alzheimer’s disease patients [143,183]. The reasons behind these results may be due to preclinical models failing to fulfill their predictive purpose or clinical trials may simply be incapable of detecting the beneficial effects of polyphenols due to a flawed approach. What is important to keep in mind is that successful clinical trials are not common, on account of the inherent difficulty of translating applications between rodents and humans.
To address this, the required recruitment profile for testing Ginkgo biloba extracts was re-evaluated, yielding positive results in a new round of clinical trials, this time performed in full-blown Alzheimer’s disease and vascular dementia. These trials successfully uncovered the benefits of several months of a daily Ginkgo biloba treatment on cognition and neuropsychiatric symptoms [141,142]. Changing the endpoints and focusing on prefrontal dopaminergic functions in elderly humans with self-reported mild cognitive decline was another fruitful strategy to reveal the beneficial effects of Ginkgo biloba . Nevertheless, the cholinesterase inhibitor rivastigmine, commercially known as Exelon, has been shown to be more efficient than Ginkgo biloba in treating Alzheimer’s disease and remains the drug of choice to ameliorate cognitive impairment in mild to moderate forms of the disease .
Several other phase I trials have been successful in confirming small positive effects in healthy individuals. A variety of polyphenols, including resveratrol, were found to increase cerebral blood flow without, however, improving cognitive performances in young adults, whether administered in a single dose [186,187,188] or chronically over 28 days . However, other groups found that longer chronic interventions in elderly humans using either cocoa flavanols or resveratrol enhanced dentate gyrus-related cognitive functions  and hippocampal-related memory functions , respectively. In Alzheimer’s disease patients, resveratrol reached phase II trials on the basis of its modulatory role on neuroinflammation, cognitive decline and cerebrospinal fluid (CSF) levels of Aβ40 [192,193]. Following a twice-daily oral regime for one year, resveratrol and its metabolites were present in the CSF, validating its ability to cross the BBB in humans . Despite its relatively low bioavailability, resveratrol remains a candidate for potential use in human neurodegenerative diseases.
6. Future Strategies for Pharmaceutical Development for Neuroprotection
Polyphenols have interesting properties that justify efforts to translate their potential neuroprotective effects into treatment for human neurodegenerative diseases. However, their questionable bioavailability, modest effects in humans and the impossibility of applying patent protection on natural molecules detracts from the appeal of polyphenols for pharmaceutical use. Nevertheless, several strategies have been used by drug development in recent years to tackle these issues.
6.1. Alternative Preparations and Prodrug Approches
The engineering of novel structural analogues inspired by existing polyphenols or formulating specific preparations of polyphenols, such as the well-defined Ginkgo Biloba extract 761, may be patentable options. Among the latest innovations, chemical engineering of pro-drug polyphenolic structures has shown promising results. For instance, acetylation of EGCG or resveratrol via esterification of their hydroxyl moieties yields stable pro-drugs in vivo whose acetyl groups can be hydrolyzed intracellularly by esterases to release the free polyphenol within the cell [194,195,196]. This strategy minimizes polyphenol auto-oxidation and allows better lipophilicity-dependent cellular uptake [197,198,199]. Production of conjugates with improved bioefficacy has also been a good approach to promote polyphenols absorption and activity. For example, the glutamoyl diester of curcumin is a more potent neuroprotective agent than curcumin  and similar approaches have been deployed for resveratrol [201,202]. More importantly, prodrugs of resveratrol are promising as recently reviewed in Biasutto et al. , for delivery to the brain parenchyma.
6.2. Alternative Drug Delivery Systems
Another favorable approach is the development of novel encapsulation technologies. Progress in vehicle formulation has allowed polyphenols to be contained in lipid nanocapsules [204,205,206], nanoparticles [206,207], exosomes , nanocomposites , emulsified formulations [206,210,211] or in gel form . Several reports demonstrate increased bioavailability for encapsulated polyphenols in rodents [213,214]. Another unusual approach is the administration of biologically compatible carbon nanotubes  grafted with polyphenols, such as gallic acid . This method was shown to enhance the antioxidative properties of grafted agents  and to improve their ability to traverse biological barriers [215,217], although the application of such conjugates is still not common, and the outcomes have not been sufficiently addressed. Possible health concerns of using carbon nanotubes also warrant further investigations [215,218]. Another simple tactic consists in improving solubility of polyphenols in circulation, such as for the lipophilic resveratrol , via coupling to cyclodextrins, which have the capacity to form inclusion complexes and this approach has already been exploited in other drug delivery strategies . Overall, each of these methods has advantages and disadvantages but brain accessibility is generally augmented owing to improved BBB infiltration by lipophilic vehicles, brain targeting by encapsulation and blocking the metabolism of polyphenols .
6.3. Alternative Administration Routes
In order to target the human brain more efficiently, the route of administration is another variable that can be altered. The most promising of these is intranasal administration, usually paired with one of the previously described encapsulation techniques, which has proved successful for brain-targeted drugs in humans, at least for increased bioavailability and the avoidance peripheral side effects [222,223]. Notable examples are the administration of insulin for the treatment of Alzheimer’s disease  and apomorphine for the treatment of Parkinson’s disease . The mechanisms by which drugs can be delivered to the brain parenchyma are only beginning to be explored. It would appear that drugs administered nasally either enter the brain through retrograde axonal transport at the level of the olfactory sensory cells or by penetration into the CSF across the nasal epithelium . Although studies with polyphenols are scarce in preclinical models [227,228,229], intranasal curcumin administration has gained attention (see for review ) due to its very poor oral bioavailability  but promising neuroprotective actions. Curcumin is highly lipophilic and may easily cross the BBB  if it is delivered into the bloodstream and protected from enzymatic modifications . While it is generally recognized as a safe route, intranasal administration sometimes leads to minor adverse effects, principally nasal irritation, constituting a potential problem in the development of intranasal polyphenol administration [225,233]. More unusual administration systems for polyphenols include rectal suppositories for efficient systemic distribution, bone-marrow administration for immunomodulatory effects and controlled-release implant strategies for targeting tumors. Intrathecal administration for direct distribution in the CSF of curcumin remains a favorable yet invasive option for brain targeting (see for review, Reference ).
7. On the Topic of Dose-Response
To prove that polyphenols can accumulate in high-enough concentrations in target tissues as the brain is linked to the antioxidative properties of polyphenols in vitro [234,235].
More recently, the physiological significance of the direct antioxidative actions of polyphenols is met with skepticism, particularly with regard to the action in the brain, due to limited gastrointestinal absorption, propensity to undergo biotransformation and rapid excretion by the kidneys [97,236]. On the one hand, H-atom transfer must always occur faster than at least one of the reactions of free-radical-production cascades (e.g., the limiting step in lipid peroxidation) and this is improbable . On the other hand, polyphenol concentrations, which rarely exceed micromolar concentrations in plasma or tissues  are substantially inferior to those of endogenous antioxidants such as ascorbate (30–100 µM) and urate (140–200 µM) . Consequently, it is argued that their contribution to the total antioxidative capacity of the plasma never exceeds 2% and may therefore be irrelevant in a physiological context [236,240]. In fact, direct antioxidative effects of polyphenols have not been measured in the brain . Also, studies demonstrating the anti-inflammatory properties of polyphenol analogues, other than direct antioxidative actions, challenges the idea that their health effects stem from their ability to hamper oxidative stress [201,202].
Nowadays, it is acknowledged that high circulating concentrations of polyphenols may not be required to achieve certain clinical endpoints. Indeed, by interacting with various enzymatic targets, for instance Keap1, very small doses of polyphenols may benefit from the cascades of events that ensue in cells. Despite this, efforts continue to focus on enhancing bioavailability rather than on identifying an adequate dose-response framework that could predict the behavior of this class of molecules. This oversight may partly account for the apparent difficulty of translating preclinical findings into actual positive outcomes in humans. Where disappointingly modest clinical benefits have been shown, is increasing the dose always a judicious strategy? The answer may not be as obvious as once thought.
Explanations have been proposed to explain the bioefficacy of polyphenols at very low doses. One of these is that polyphenols exert their biological effects in a non-linear fashion by exhibiting a biphasic dose-response profile. One such model predicts J or inverted U dose-response curves depending on the endpoint [241,242]. The biphasic theory stipulates low-dose stimulatory and high-dose inhibitory effects [243,244]. It direct stimulatory effects at low concentrations followed by biological overcompensation at higher doses . In neuroprotection, hormesis predicts very low doses as beneficial and higher doses as potentially harmful. The application of this theory is thus intimately linked with whether polyphenols are indeed stressors that induce a defense response in cells. This has yet to be confirmed for polyphenols.
At present, the biphasic hypothesis explaining the bioefficacy of polyphenols at very low doses is gaining momentum, resveratrol constituting the best example. A wealth of reports support the hormetic action of resveratrol in various applications, ranging from cancer to neuroscience, extensively reviewed elsewhere . In some instances, resveratrol stimulates cancer cell proliferation at very low doses but inhibits carcinogenesis in higher concentrations . Other reports show resveratrol inducing atherosclerotic lesions at high doses, while it remains cardioprotective at lower concentrations . In neurons, resveratrol promotes survival at very low concentrations but is neurotoxic at higher doses [121,249]. One study performed in mice and primary cortical neurons proposed a mechanism possibly underlying the biphasic response of energy-depleted neurons to resveratrol, showing protection at low doses and toxicity at higher doses . The authors explained resveratrol’s bimodal effects via its stimulatory action on silent mating type information regulation 2 homolog 1 (SIRT1), whose low-grade activity can suppress oxidative stress . However, when stimulated by greater doses of resveratrol, SIRT1 expends too much-reduced nicotinamide adenine dinucleotide (NAD+) where neurons are already energetically depleted, causing energy failure. During an ischemic event, resveratrol administration could be either beneficial or detrimental, depending on dosage and timing and the bioenergetic status of neurons.
At present, these studies are usually performed in pre-clinical models and do not necessarily reflect what could occur in humans. The best-documented evidence of biphasic dose-responses in humans is for radiation, for instance in cancer treatments or in atomic bomb survivors [252,253]. However, reservations remain on the significance of such a dose-response relationship in the human brain, as it is highly unlikely that polyphenols could ever increase bioavailability in the parenchyma beyond low concentrations. This means that the observed bioefficacy of polyphenols may already be optimal where modest benefits are found in trials. Indeed, one distinct feature of the biphasic hypothesis provides that beneficial effects at low doses stem from cellular overcompensation mechanisms in response to the polyphenol-induced stress . Beyond the optimal concentration at which maximal benefits are seen this compensation reaction is slowly overwhelmed by the increasing stress polyphenols directly exert on the cell. Even at the optimal concentration, these beneficial effects are thus thought to be at best partial. If this theory holds true, this could explain the results of clinical trials to date, even upon increasing dosages.
8. Concluding Remarks
The chemical structure of polyphenols confers them metal-chelating, fibril-destabilizing, estrogen-like, enzyme-binding and indirect antioxidative effects supporting their usefulness in neurodegenerative diseases. Epidemiological evidence shows a strong association between polyphenol consumption and reduced occurrence of various neurodegenerative diseases. Preclinical models lend them neuroprotective properties. Some clinical trials have even been successful in revealing small but measurable improvements in human health and have confirmed their safety in various settings. Nevertheless, the limited bioavailability of polyphenols together with their apparent bioefficacy remains under-explored. Investigators must demonstrate that polyphenols exert significant health benefits. However, in neurodegenerative diseases, polyphenol trials consistently fail in early clinical testing. To overcome this, researchers must optimize the design of their trials, subjects (disease stage, participant profile, cohort age and medical history), polyphenol administration (polyphenol formulation, route, dosage, frequency and duration) and endpoints (motor symptoms, cognitive decline, neuroinflammation, neuron integrity, CNS vascular health, etc.). As reviewed here, polyphenols are sensitive to a great number of physiological conditions that impinge on their bioavailability and biofunctionality, which may account for the markedly high inter individual variation observed in clinical investigations, which cannot be explained by biphasic dose-response theories.
Despite a large amount of information from many pre-clinical disease models and applications, a working theoretical framework that could aid in predicting outcomes in humans cannot be agreed. A priority would consist of determining the maximal health benefits that could be achieved from polyphenol monotherapies as they most usually stand alone in trials. Can we really expect standalone treatments to fulfill hard-to-reach clinical endpoints? If epidemiological evidence is strong for the protective effects of consuming complex mixtures of polyphenols in food, it may be unjustified to expect single molecules to be as effective. Perhaps concentrating on the concerted effects between polyphenols with each other or with other drugs that show partial benefits, such as the MAO-B inhibitor rasagiline  or levodopa , may overcome the as yet modest effects in humans. Evaluating polyphenols in preventive clinical paradigms may also constitute a more realistic strategy.
Besides, recent nutrigenomics data show that the interaction between genes and food bioactive compounds can positively or negatively influence an individual’s health and possibly will aid with the prescription of customized diets according to an individual’s genotype. Thus, the next approaches to clinical research with polyphenols should consider that dietary bioactive compounds such as polyphenols can be attributed to epigenetic mechanisms such as the regulation of histone deacetylases (HDAC) and histone acetyltransferase (HAT) activities and acetylation of histones and non-histone chromatin proteins [255,256].
This research was funded by the Natural Sciences and Engineering Research Council (NSERC) of Canada (no. 04321) to M.-G.M. J.R. is recipient of a Vanier Graduate Scholarship from the NSERC and a Doctoral Training Scholarship from the Fonds de recherche en santé du Québec.
The authors would like to thank Lynda M. Williams (Rowett Institute, University of Aberdeen, Scotland, UK) for revising the manuscript and helpful suggestions.
Conflicts of Interest
The authors declare no conflict of interest.
uridylate (AU)-rich elements
brain-derived neurotrophic factor
central nervous system
cyclic adenosine monophosphate
estrogen receptor alpha
estrogen receptor beta
estrogen response element
high-performance liquid chromatography
Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2/antioxidant response elements
monoamine oxidase B
nicotinamide adenine dinucleotide
silent mating type information regulation 2 homolog 1
Estruch, R.; Ros, E.; Salas-Salvadó, J.; Covas, M.I.; Corella, D.; Arós, F.; Gómez-Gracia, E.; Ruiz-Gutiérrez, V.; Fiol, M.; Lapetra, J.; et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N. Engl. J. Med.2013, 368, 1279–1290. [Google Scholar] [CrossRef] [PubMed]
Hertog, M.G.; Feskens, E.J.; Hollman, P.C.; Katan, M.B.; Kromhout, D. Dietary antioxidant flavonoids and risk of coronary heart disease: The Zutphen Elderly Study. Lancet1993, 342, 1007–1011. [Google Scholar] [CrossRef]
Joshipura, K.J.; Hu, F.B.; Manson, J.E.; Stampfer, M.J.; Rimm, E.B.; Speizer, F.E.; Colditz, G.; Ascherio, A.; Rosner, B.; Spiegelman, D.; et al. The effect of fruit and vegetable intake on risk for coronary heart disease. Ann. Intern. Med.2001, 134, 1106–1114. [Google Scholar] [CrossRef]
Von Ruesten, A.; Feller, S.; Bergmann, M.M.; Boeing, H. Diet and risk of chronic diseases: Results from the first 8 years of follow-up in the EPIC-Potsdam study. Eur. J. Clin. Nutr.2013, 67, 412–419. [Google Scholar] [CrossRef] [PubMed]
Carter, P.; Gray, L.J.; Troughton, J.; Khunti, K.; Davies, M.J. Fruit and vegetable intake and incidence of type 2 diabetes mellitus: Systematic review and meta-analysis. BMJ2010, 341, c4229. [Google Scholar] [CrossRef]
Sargeant, L.A.; Khaw, K.T.; Bingham, S.; Day, N.E.; Luben, R.N.; Oakes, S.; Welch, A.; Wareham, N.J. Fruit and vegetable intake and population glycosylated haemoglobin levels: The EPIC-Norfolk Study. Eur. J. Clin. Nutr.2001, 55, 342–348. [Google Scholar] [CrossRef] [PubMed]
He, F.J.; Nowson, C.A.; MacGregor, G.A. Fruit and vegetable consumption and stroke: Meta-analysis of cohort studies. Lancet2006, 367, 320–326. [Google Scholar] [CrossRef]
Ness, A.R.; Powles, J.W. Fruit and vegetables and cardiovascular disease: A review. Int. J. Epidemiol.1997, 26, 1–13. [Google Scholar] [CrossRef]
Lunet, N.; Lacerda-Vieira, A.; Barros, H. Fruit and vegetables consumption and gastric cancer: A systematic review and meta-analysis of cohort studies. Nutr. Cancer2005, 53, 1–10. [Google Scholar] [CrossRef]
Masala, G.; Assedi, M.; Bendinelli, B.; Ermini, I.; Sieri, S.; Grioni, S.; Sacerdote, C.; Ricceri, F.; Panico, S.; Mattiello, A.; et al. Fruit and vegetables consumption and breast cancer risk: The EPIC Italy study. Breast Cancer Res. Treat.2012, 132, 1127–1136. [Google Scholar] [CrossRef]
Steinmetz, K.A.; Potter, J.D. Vegetables, fruit and cancer prevention: A review. J. Am. Diet. Assoc.1996, 96, 1027–1039. [Google Scholar] [CrossRef]
Feng, L.; Gwee, X.; Kua, E.H.; Ng, T.P. Cognitive function and tea consumption in community dwelling older Chinese in Singapore. J. Nutr. Health Aging2010, 14, 433–438. [Google Scholar] [CrossRef] [PubMed]
Kuriyama, S.; Hozawa, A.; Ohmori, K.; Shimazu, T.; Matsui, T.; Ebihara, S.; Awata, S.; Nagatomi, R.; Arai, H.; Tsuji, I. Green tea consumption and cognitive function: A cross-sectional study from the Tsurugaya Project 1. Am. J. Clin. Nutr.2006, 83, 355–361. [Google Scholar] [CrossRef]
Manach, C.; Scalbert, A.; Morand, C.; Rémésy, C.; Jiménez, L. Polyphenols: Food sources and bioavailability. Am. J. Clin. Nutr.2004, 79, 727–747. [Google Scholar] [CrossRef]
Scalbert, A.; Williamson, G. Dietary intake and bioavailability of polyphenols. J. Nutr.2000, 130, 2073S–2085S. [Google Scholar] [CrossRef] [PubMed]
Parr, A.J.; Bolwell, G.P. Phenols in the Plant and in Man. The Potential for Possible Nutritional Enhancement of the Diet by Modifying the Phenols Content or Profile. J. Sci. Food Agric.2000, 80, 985–1012. [Google Scholar] [CrossRef]
Petry, N.; Egli, I.; Zeder, C.; Walczyk, T.; Hurrel, R. Polyphenols and phytic acid contribute to the low iron bioavailability from common beans in young women. J. Nutr.2010, 140, 1977–1982. [Google Scholar] [CrossRef]
Hider, R.C.; Liu, Z.D.; Khodr, H.H. Metal chelation of polyphenols. Methods Enzymol.2001, 335, 190–203. [Google Scholar] [PubMed]
Purawatt, S.; Siripinyanond, A.; Shiowatana, J. Flow field-flow fractionation-inductively coupled optical emission spectrometric investigation of the size-based distribution of iron complexed to phytic and tannic acids in food suspension: Implications for iron availability. Anal. Bioanal. Chem.2007, 289, 733–742. [Google Scholar] [CrossRef] [PubMed]
Gazit, E. A possible role for π-stacking in self-assembly of amyloid fibrils. FASEB J.2002, 16, 77–83. [Google Scholar] [CrossRef]
Porat, Y.; Abramowitz, A.; Gazit, E. Inhibition of amyloid fibril formation by polyphenols: Structural similarity and aromatic interactions as a common inhibition mechanism. Chem. Biol. Drug Des.2006, 67, 27–37. [Google Scholar] [CrossRef] [PubMed]
Bieschke, J. Natural compounds may open new routes to treatment of amyloid diseases. Neurotherapeutics2013, 10, 429–439. [Google Scholar] [CrossRef]
Ishii, T.; Ichikawa, T.; Minoda, K.; Kusaka, K.; Ito, S.; Suzuki, Y.; Akagawa, M.; Mochizuki, K.; Goda, T.; Nakayama, T. Human serum albumin as an antioxidant in the oxidation of (−)-epigallocatechin gallate: Participation of reversible covalent binding for interaction and stabilization. Biosci. Biotechnol. Biochem.2011, 75, 100–106. [Google Scholar] [CrossRef]
Palhano, F.L.; Lee, J.; Grimster, N.P.; Kelly, J.W. Toward the molecular mechanism(s) by which EGCG treatment remodels mature amyloid fibrils. J. Am. Chem. Soc.2013, 135, 7503–7510. [Google Scholar] [CrossRef]
Maiti, T.K.; Ghosh, K.S.; Dasgupta, S. Interaction of (−)-epigallocatechin-3-gallate with human serum albumin: Fluorescence, fourier transform infrared, circular dichroism and docking studies. Proteins2006, 64, 355–362. [Google Scholar] [CrossRef] [PubMed]
Yildiz, F. Phytoestrogens in Functional Foods; Taylor & Francis Ltd.: Abingdon, UK, 2005; Volume 210–211, pp. 3–5. [Google Scholar]
Turner, J.V.; Agatonovic-Kustrin, S.; Glass, B.D. Molecular aspects of phytoestrogen selective binding at estrogen receptors. J. Pharm. Sci.2007, 96, 1879–1885. [Google Scholar] [CrossRef] [PubMed]
Bowers, J.L.; Tyulmenkov, V.V.; Jernigan, S.C.; Klinge, C.M. Resveratrol acts as a mixed agonist/antagonist for estrogen receptors alpha and beta. Endocrinology2000, 141, 3657–3667. [Google Scholar] [CrossRef]
Cossette, L.J.; Gaumond, I.; Martinoli, M.G. Combined effect of xenoestrogens and growth factors in two estrogen-responsive cell lines. Endocrine2002, 18, 303–308. [Google Scholar] [CrossRef]
Gélinas, S.; Martinoli, M.G. Neuroprotective effect of estradiol and phytoestrogens on MPP+-induced cytotoxicity in neuronal PC12 cells. J. Neurosci. Res.2002, 70, 90–96. [Google Scholar] [CrossRef] [PubMed]
Ferrel, J.E.; Chang Sing PD, G.; Loew, G.; King, R.; Marnsour, J.M.; Mansour, T.E. Structure/activity studies of flavonoids as inhibitors of cyclic AMP phosphodiesterase and relationship to quantum chemical indices. Mol. Pharmacol.1979, 16, 556–568. [Google Scholar]
Cochet, C.; Feige, J.J.; Pirollet, F.; Keramidas, M.; Chambaz, E.M. Selective inhibition of a cyclic nucleotide independent protein kinase (G type casein kinase) by quercetin and related polyphenols. Biochem. Pharmacol.1982, 31, 1357–1361. [Google Scholar] [CrossRef]
Li, B.; Vik, S.B.; Tu, Y. Theaflavins inhibit the ATP synthase and the respiratory chain without increasing superoxide production. J. Nutr. Biochem.2011, 23, 953–960. [Google Scholar] [CrossRef] [PubMed]
Santel, T.; Pflug, G.; Hemdan, N.Y.; Schäfer, A.; Hollenbach, M.; Buchold, M.; Hintersdorf, A.; Lindner, I.; Otto, A.; Bigl, M. Curcumin inhibits glyoxalase 1: A possible link to its anti-inflammatory and anti-tumor activity. PLoS ONE2008, 3, e3508. [Google Scholar] [CrossRef] [PubMed]
Takasawa, R.; Takahashi, S.; Saeki, K.; Sunaga, S.; Yoshimori, A.; Tanuma, S. Structure-activity relationship of human GLO I inhibitory natural flavonoids and their growth inhibitory effects. Bioorg. Med. Chem.2008, 16, 3969–3975. [Google Scholar] [CrossRef]
Foresti, R.; Bains, S.K.; Pitchumony, T.S.; de Castro Brás, L.E.; Drago, F.; Dubois-Randé, J.L.; Bucolo, C.; Motterlini, R. Small molecule activators of the Nrf2-HO-1 antioxidant axis modulate heme metabolism and inflammation in BV2 microglia cells. Pharmacol. Res.2013, 76, 132–148. [Google Scholar] [CrossRef][Green Version]
Ishii, T.; Ishikawa, M.; Miyoshi, N.; Yasunaga, M.; Akagawa, M.; Uchida, K.; Nakamura, Y. Catechol type polyphenol is a potential modifier of protein sulfhydryls: Development and application of a new probe for understanding the dietary polyphenol actions. Chem. Res. Toxicol.2009, 22, 1689–1698. [Google Scholar] [CrossRef] [PubMed]
Chow, H.H.; Cai, Y.; Hakim, I.A.; Crowell, J.A.; Shahi, F.; Brooks, C.A.; Dorr, R.T.; Hara, Y.; Alberts, D.S. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin. Cancer Res.2003, 9, 3312–3319. [Google Scholar] [PubMed]
Graefe, E.U.; Wittig, J.; Mueller, S.; Riethling, A.K.; Uehleke, B.; Drewelow, B.; Pforte, H.; Jacobasch, G.; Derendorf, H.; Veit, M. Pharmacokinetics and bioavailability of quercetin glycosides in humans. J. Clin. Pharmacol.2001, 41, 492–499. [Google Scholar] [CrossRef] [PubMed]
Manach, C.; Williamson, G.; Morand, C.; Scalbert, A.; Rémésy, C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr.2005, 81, 230S–242S. [Google Scholar] [CrossRef] [PubMed][Green Version]
Scholz, S.; Williamson, G. Interactions affecting the bioavailability of dietary polyphenols in vivo. Int. J. Vitam. Nutr. Res.2007, 77, 224–235. [Google Scholar] [CrossRef]
Van het Hof, K.H.; Kivits, G.A.; Weststrate, J.A.; Tijburg, L.B. Bioavailability of catechins from tea: The effect of milk. Eur. J. Clin. Nutr.1998, 52, 356–359. [Google Scholar] [CrossRef]
Hollman, P.C.; van Het Hof, K.H.; Tijburg, L.B.; Katan, M.B. Addition of milk does not affect the absorption of flavonols from tea in man. Free Radic. Res.2001, 34, 297–300. [Google Scholar] [CrossRef][Green Version]
Yamashita, S.; Sakane, T.; Harada, M.; Sugiura, N.; Koda, H.; Kiso, Y.; Sezaki, H. Absorption and metabolism of antioxidative polyphenolic compounds in red wine. Ann. N. Y. Acad. Sci.2002, 957, 325–328. [Google Scholar] [CrossRef]
Hollman, P.C.; van Trijp, J.M.; Buysman, M.N.; van der Gaag, M.S.; Mengelers, M.J.; de Vries, J.H.; Katan, M.B. Relative bioavailability of the antioxidant flavonoid quercetin from various foods in man. FEBS Lett.1997, 418, 152–156. [Google Scholar] [CrossRef][Green Version]
Olthof, M.R.; Hollman PC, H.; Vree, T.B.; Katan, M.B. Bioavailabilities of quercetin-3-glucoside and quercetin-4’-glucoside do not differ in humans. J. Nutr.2000, 130, 1200–1203. [Google Scholar] [CrossRef] [PubMed]
Manach, C.; Morand, C.; Crespy, V.; Demingné, C.; Texier, O.; Régérat, F.; Rémésy, C. Quercetin is recovered in human plasma as conjugated derivatives which retain antioxidant properties. FEBS Lett.1998, 426, 331–336. [Google Scholar] [CrossRef][Green Version]
Corte-real, J.; Richling, E.; Hoffmann, L.; Bohn, T. Selective factors governing in vitro b-carotene bioaccessibility: Negative influence of low filtration cutoffs and alterations by emulsifiers and food matrices. Nutr. Res.2014, 34, 1101–1110. [Google Scholar] [CrossRef] [PubMed]
Mandalari, G.; Vardaku, M.; Faulks, R.; Bisignano, C.; Martorana, M.; Smeriglio, A.; Trombetta, D. Food matrix effects of polyphenols accessibility from almond skin during simulated human digestion. Nutrients2016, 8, 568. [Google Scholar] [CrossRef] [PubMed]
Azuma, K.; Ippoushi, K.; Ito, H.; Higashio, H.; Terao, J. Combination of lipids and emulsifiers enhances the absorption of orally administered quercetin in rats. J. Agric. Food Chem.2002, 50, 1706–1712. [Google Scholar] [CrossRef]
Donovan, J.L.; Kasim-Karakas, S.; German, J.B.; Waterhouse, A.L. Urinary excretion of catechin metabolites by human subjects after red wine consumption. Br. J. Nutr.2002, 87, 31–37. [Google Scholar] [CrossRef] [PubMed][Green Version]
Murota, K.; Nakamura, Y.; Uehara, M. Flavonoid metabolism: The interaction of metabolites and gut microbiota. Biosci. Biotechnol. Biochem.2018, 82, 600–610. [Google Scholar] [CrossRef] [PubMed]
Shortt, C.; Hasselwander, O.; Meynier, A.; Nauta, A.; Fernández, E.N.; Putz, P.; Rowland, I.; Swann, J.; Türk, J.; Vermeiren, J.; et al. Systematic review of the effects of the intestinal microbiota on selected nutrients and non-nutrients. Eur. J. Nutr.2018, 57, 25–49. [Google Scholar] [CrossRef]
Aura, A.M.; O’Leary, K.A.; Williamson, G.; Ojala, M.; Bailey, M.; Puupponen-Pimiä, R.; Nuutila, A.M.; Oksman-Caldentey, K.M.; Poutanen, K. Quercetin derivatives are deconjugated and converted to hydroxyphenylacetic acids but not methylated by human fecal flora in vitro. J. Agric. Food Chem.2002, 50, 1725–1730. [Google Scholar] [CrossRef]
Sawai, Y.; Kohsaka, K.; Nishiyama, Y.; Ando, K. Serum concentrations of rutoside metabolites after oral administration of a rutoside formulation to humans. Arzneimittelforschung1987, 37, 729–732. [Google Scholar]
Abd El-Mohsen, M.; Bayele, H.; Kuhnle, G.; Gibson, G.; Debnam, E.; Kaila Srai, S.; Rice-Evans, C.; Spencer, J.P. Distribution of [3H]trans-resveratrol in rat tissues following oral administration. Br. J. Nutr.2006, 96, 62–70. [Google Scholar] [CrossRef]
Olivares-Vicente, M.; Barrajon-Catalan, E.; Herranz-Lopez, M.; Segura-Carretero, A.; Joven, J.; Encinar, J.A.; Micol, V. Plant derived polyphenols in human health: Biological activity, matabolites and putative molecular targets. Curr. Drug Matab.2018, 19, 351–369. [Google Scholar] [CrossRef]
Maier-Salamon, A.; Böhmdorfer, M.; Riha, J.; Thalhammer, T.; Szekeres, T.; Jaeger, W. Interplay between metabolism and transport of resveratrol. Ann. N. Y. Acad. Sci.2013, 1290, 98–106. [Google Scholar] [CrossRef]
Marier, J.F.; Vachon, P.; Gritsas, A.; Zhang, J.; Moreau, J.P.; Ducharme, M.P. Metabolism and disposition of resveratrol in rats: Extent of absorption, glucuronidation and enterohepatic recirculation evidenced by a linked-rat model. J. Pharmacol. Exp. Ther.2002, 302, 369–373. [Google Scholar] [CrossRef]
Wenzel, E.; Somoza, V. Metabolism and bioavailability of trans-resveratrol. Mol. Nutr. Food Res.2005, 49, 472–481. [Google Scholar] [CrossRef]
Vitrac, X.; Desmoulière, A.; Brouillaud, B.; Krisa, S.; Deffieux, G.; Barthe, N.; Rosenbaum, J.; Mérillon, J.M. Distribution of [14C]-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration. Life Sci.2003, 72, 2219–2233. [Google Scholar] [CrossRef]
Andreadi, C.; Britton, R.G.; Patel, K.R.; Brown, K. Resveratrol sulfates provide an intracellular reservoir for generation of parent resveratrol, which induces autophagy in cancer cells. Autophagy2014, 10, 524–525. [Google Scholar] [CrossRef]
Marchiani, A.; Mammi, S.; Siligardi, G.; Hussain, R.; Tessari, I.; Bubacco, L.; Delogu, G.; Fabbri, D.; Dettori, M.A.; Sanna, D.; et al. Small molecules interacting with α-synuclein: Antiaggregating and cytoprotective properties. Amino Acids2013, 45, 327–338. [Google Scholar] [CrossRef] [PubMed]
Zunino, S.J.; Storms, D.H. Resveratrol-3-O-glucuronide and resveratrol-4’-O-glucuronide reduce DNA strand breakage but not apoptosis in Jurkat T cells treated with camptothecin. Oncol. Lett.2017, 14, 2517–2522. [Google Scholar] [CrossRef] [PubMed]
Henning, S.M.; Niu, Y.; Liu, Y.; Lee, N.H.; Hara, Y.; Thames, G.D.; Minutti, R.R.; Carpenter, C.L.; Wang, H.; Heber, D. Bioavailability and antioxidant effect of epigallocatechin gallate administered in purified form versus as green tea extract in healthy individuals. J. Nutr. Biochem.2005, 16, 610–616. [Google Scholar] [CrossRef] [PubMed]
Delmas, D.; Aires, V.; Limagne, E.; Dutarte, P.; Mazué, F.; Ghiringhelli, F.; Latruffe, N. Transport, stability and biological activity of RESV. Ann. N. Y. Acad. Sci.2011, 1215, 48–59. [Google Scholar] [CrossRef] [PubMed]
Khan, M.A.; Muzammil, S.; Musarrat, J. Differential binding of tetracyclines with serum albumin and induced structural alterations in drug-bound protein. Int. J. Biol. Macromol.2002, 30, 243–249. [Google Scholar] [CrossRef]
Lancon, A.; Delmas, D.; Osman, H.; Thénot, J.P.; Jannin, B.; Latruffe, N. Human hepatic cell uptake of resveratrol: Involvement of both passive diffusion and carrier-mediated process. Biochem. Biophys. Res. Commun.2004, 316, 1132–1137. [Google Scholar] [CrossRef]
Lu, Z.; Zhang, Y.; Liu, H.; Yuan, J.; Zheng, Z.; Zou, G. Transport of a cancer chemopreventive polyphenol, resveratrol: Interaction with serum albumin and hemoglobin. J. Fluoresc.2007, 17, 580–587. [Google Scholar] [CrossRef]
Yang, F.; Bian, C.; Zhu, L.; Zhao, G.; Huang, Z.; Huang, M. Effect of human serum albumin on drug metabolism: Structural evidence of esterase activity of human serum albumin. J. Struct. Biol.2007, 157, 348–355. [Google Scholar] [CrossRef]
Blache, D.; Rustan, I.; Durand, P.; Lesgards, G.; Loreau, N. Gas chromatographic analysis of resveratrol in plasma, lipoproteins and cells after in vitro incubations. J. Chromatogr. B Biomed. Sci. Appl.1997, 702, 103–110. [Google Scholar] [CrossRef]
Belguendouz, L.; Fremont, L.; Gozzelino, M.T. Interaction of transresveratrol with plasma lipoproteins. Biochem. Pharmacol.1998, 55, 811–816. [Google Scholar] [CrossRef]
Burkon, A.; Somoza, V. Quantification of free and protein-bound trans-resveratrol metabolites and identification of trans-resveratrol-C/O-conjugated diglucuronides – two novel resveratrol metabolites in human plasma. Mol. Nutr. Food Res.2008, 52, 549–557. [Google Scholar] [CrossRef] [PubMed]
Urpi-Sarda, M.; Zamora-Ros, R.; Lamuela-Raventos, R.; Cherubini, A.; Jauregui, O.; de la Torre, R.; Covas, M.I.; Estruch, R.; Jaeger, W.; Andres-Lacueva, C. HPLC-tandem mass spectrometric method to characterize resveratrol metabolism in humans. Clin. Chem.2007, 53, 292–299. [Google Scholar] [CrossRef] [PubMed]
Jannin, B.; Menzel, M.; Berlot, J.P.; Delmas, D.; Lançon, A.; Latruffe, N. Transport of resveratrol, a cancer chemopreventive agent, to cellular targets: Plasmatic protein binding and cell uptake. Biochem. Pharmacol.2004, 68, 1113–1118. [Google Scholar] [CrossRef]
Lin, H.Y.; Lansing, L.; Merillon, J.M.; Davis, F.B.; Thang, H.Y.; Shih, A.; Vitrac, X.; Krisa, S.; Keating, T.; Cao, H.J.; et al. Integrin alphaVbeta3 contains a receptor site for resveratrol. FASEB J.2006, 20, 1742–1744. [Google Scholar] [CrossRef] [PubMed]
Lin, H.Y.; Thang, H.Y.; Keating, T.; Wu, Y.H.; Shih, A.; Hammond, D.; Sun, M.; Hercbergs, A.; Davis, F.B.; Davis, P.J. Resveratrol is pro-apoptotic and thyroid hormone is anti-apoptotic in glioma cells: Both actions are integrin and ERK mediated. Carcinogenesis2008, 29, 62–69. [Google Scholar] [CrossRef] [PubMed]
Figueira, I.; Meneses, R.; Macedo, D.; Costa, I.; Dos Santos, C.N. Polyphenols Beyond Barriers: A Glimpse into the Brain. Curr. Neuropharmacol.2017, 15, 562–594. [Google Scholar] [CrossRef] [PubMed]
Liu, Z.; Hu, M. Natural polyphenol disposition via coupled metabolic pathways. Expert Opin. Drug Metab. Toxicol.2007, 3, 389–406. [Google Scholar] [CrossRef]
Youdim, K.A.; Dobbie, M.S.; Kuhnle, G.; Proteggente, A.R.; Abbott, N.J.; Rice-Evans, C. Interaction between flavonoids and the blood-brain barrier: In vitro studies. J. Neurochem.2003, 85, 180–192. [Google Scholar] [CrossRef]
Youdim, K.A.; Qaiser, M.Z.; Begley, D.J.; Rice-Evans, C.A.; Abbott, N.J. Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic. Biol. Med.2004, 36, 592–604. [Google Scholar] [CrossRef] [PubMed]
Faria, A.; Pestana, D.; Teixeira, D.; Couraud, P.O.; Romero, I.; Weksler, B.; de Freitas, V.; Mateus, N.; Calhau, C. Insights into the putative catechin and epicatechin transport across blood-brain barrier. Food Funct.2011, 2, 39–44. [Google Scholar] [CrossRef] [PubMed]
Milbury, P.E.; Kalt, W. Xenobiotic metabolism and berry flavonoid transport across the blood-brain barrier. J. Agric. Food Chem.2010, 58, 3950–3956. [Google Scholar] [CrossRef] [PubMed]
Campos-Bedolla, P.; Walter, F.R.; Veszelka, S.; Deli, M.A. Role of the blood-brain barrier in the nutrition of the central nervous system. Arch. Med. Res.2014, 45, 610–638. [Google Scholar] [CrossRef]
Schaffer, S.; Halliwell, B. Do polyphenols enter the brain and does it matter? Some theoretical and practical considerations. Genes Nutr.2012, 7, 99–109. [Google Scholar] [CrossRef] [PubMed]
Asensi, M.; Medina, I.; Ortega, A.; Carretero, J.; Bano, M.C.; Obrador, E.; Estrela, J.M. Inhibition of cancer growth by resveratrol is related to its low bioavailability. Free Radic. Biol. Med.2002, 33, 387–398. [Google Scholar] [CrossRef]
Juan, M.E.; Maijo, M.; Planas, J.M. Quantification of trans-resveratrol and its metabolites in rat plasma and tissues by HPLC. J. Pharmaceut. Biomed. Anal.2010, 51, 391–398. [Google Scholar] [CrossRef]
Wang, Q.; Xu, J.; Rottinghaus, G.E.; Simonyi, A.; Lubahn, D.; Sun, G.Y.; Sun, A.Y. Resveratrol protects against global cerebral ischemic injury in gerbils. Brain Res.2002, 958, 439–447. [Google Scholar] [CrossRef]
Abd El-Mohsen, M.M.; Kuhnle, G.; Rechner, A.R.; Schroeter, H.; Rose, S.; Jenner, P.; Rice-Evans, C.A. Uptake and metabolism of epicatechin and its access to the brain after oral ingestion. Free Radic. Biol. Med.2002, 33, 1693–1702. [Google Scholar] [CrossRef]
Suganuma, M.; Okabe, S.; Oniyama, M.; Tada, Y.; Ito, H.; Fujiki, H. Wide distribution of [3H](-)-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue. Carcinogenesis1998, 19, 1771–1776. [Google Scholar] [CrossRef][Green Version]
Dajas, F.; Rivera, F.; Blasina, F.; Arredondo, F.; Echeverry, C.; Lafon, L.; Morquio, A.; Heinzen, H. Cell culture protection and in vivo neuroprotective capacity of flavonoids. Neurotox. Res.2003, 5, 425–432. [Google Scholar] [CrossRef] [PubMed]
Mitsunaga, Y.; Takanaga, H.; Matsuo, H.; Naito, M.; Tsuruo, T.; Ohtani, H.; Sawada, Y. Effect of bioflavonoids on vincristine transport across blood-brain barrier. Eur. J. Pharmacol.2000, 395, 193–201. [Google Scholar] [CrossRef]
Watanabe, C.M.; Wolffram, S.; Ader, P.; Rimbach, G.; Packer, L.; Maguire, J.J.; Schultz, P.G.; Gohil, K. The in vivo neuromodulatory effects of the herbal medicine ginkgo biloba. Proc. Natl. Acad. Sci. USA2001, 98, 6577–6580. [Google Scholar] [CrossRef][Green Version]
Karuppagounder, S.S.; Pinto, J.T.; Xu, H.; Chen, H.L.; Beal, M.F.; Gibson, G.E. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer’s disease. Neurochem. Int.2009, 54, 111–118. [Google Scholar] [CrossRef] [PubMed]
Yang, F.; Lim, G.P.; Begum, A.N.; Ubeda, O.J.; Simmons, M.R.; Ambegaokar, S.S.; Chen, P.P.; Kayed, R.; Glabe, C.G.; Frautschy, S.A.; et al. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques and reduces amyloid in vivo. J. Biol. Chem.2005, 280, 5892–5901. [Google Scholar] [CrossRef]
Kelloff, G.J.; Boone, C.W.; Crowell, J.A.; Steele, V.E.; Lubet, R.A.; Doody, L.A.; Malone, W.F.; Hawk, E.T.; Sigman, C.C. New agents for cancer chemoprevention. J. Cell. Biochem.1996, 26, 1–28. [Google Scholar] [CrossRef]
Mandel, S.; Weinreb, O.; Reznichenko, L.; Kalfon, L.; Amit, T. Green tea catechins as brain-permeable, non toxic iron chelators to “iron out iron” from the brain. J. Neural Transm. Suppl.2006, 2006, 249–257. [Google Scholar]
Degenhardt, L.; Mathers, B.; Vickerman, P.; Rhodes, T.; Latkin, C.; Hickman, M. Prevention of HIV infection for people who inject drugs: Why individual, structural and combination approaches are needed. Lancet2010, 376, 285–301. [Google Scholar] [CrossRef]
Kerbel, R.S.; Yu, J.; Tran, J.; Man, S.; Viloria-Petit, A.; Klement, G.; Coomber, B.L.; Rak, J. Possible mechanisms of acquired resistance to anti-angiogenic drugs: Implications for the use of combination therapy approaches. Cancer Metastasis Rev.2001, 20, 79–86. [Google Scholar] [CrossRef]
Rodríguez, A.; Mendia, A.; Sirvent, J.M.; Barcenilla, F.; de la Torre-Prados, M.V.; Solé-Violán, J.; Rello, J.; CAPUCI Study Group. Combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock. Crit. Care Med.2007, 35, 1493–1498. [Google Scholar] [CrossRef]
Yang, Y.; Zhang, Z.; Li, S.; Ye, X.; Li, X.; He, K. Synergy effects of herb extracts: Pharmacokinetics and pharmacodynamic basis. Fitoterapia2014, 92, 133–147. [Google Scholar] [CrossRef]
Wagner, H.; Ulrich-Merzenich, G. Synergy research: Approaching a new generation of phytopharmaceuticals. Phytomedicine2009, 16, 97–110. [Google Scholar] [CrossRef]
Ulrich-Merzenich, G.; Panek, D.; Zeitler, H.; Vetter, H.; Wagner, H. Drug development from natural products: Exploiting synergistic effects. Indian J. Exp. Biol.2010, 48, 208–219. [Google Scholar] [PubMed]
Chen, T.C.; Wang, W.; Golden, E.B.; Thomas, S.; Sivakumar, W.; Hofman, F.M.; Louie, S.G.; Schönthal, A.H. Green tea epigallocatechin gallate enhances therapeutic efficacy of temozolomide in orthotopic mouse glioblastoma models. Cancer Lett.2011, 302, 100–108. [Google Scholar] [CrossRef]
Gazova, Z.; Siposova, K.; Kurin, E.; Mučaji, P.; Nagy, M. Amyloid aggregation of lysozyme: The synergy study of red wine polyphenols. Proteins2013, 81, 994–1004. [Google Scholar] [CrossRef] [PubMed]
Kurin, E.; Mučaji, P.P.; Nagy, M. In vitro antioxidant activities of three red wine polyphenols and their mixtures: An interaction study. Molecules2012, 17, 14336–14348. [Google Scholar] [CrossRef] [PubMed]
Nichols, M.; Zhang, J.; Polster, B.M.; Elustondo, P.A.; Thirumaran, A.; Pavlov, E.V.; Robertson, G.S. Synergistic neuroprotection by epicatechin and quercetin: Activation of convergent mitochondrial signaling pathways. Neuroscience2015, 308, 75–94. [Google Scholar] [CrossRef]
Conte, A.; Pellegrini, S.; Tagliazucchi, D. Synergistic protection of PC12 cells from beta-amyloid toxicity by resveratrol and catechin. Brain Res. Bull.2003, 62, 29–38. [Google Scholar] [CrossRef]
Sanz, M.M.; Johnson, L.E.; Ahuja, S.; Ekström, P.A.; Romero, J.; van Veen, T. Significant photoreceptor rescue by treatment with a combination of antioxidants in an animal model for retinal degeneration. Neuroscience2007, 145, 1120–1129. [Google Scholar] [CrossRef]
Gundimeda, U.; McNeill, T.H.; Barseghian, B.A.; Tzeng, W.S.; Rayudu, D.V.; Cadenas, E.; Gopalakrishna, R. Polyphenols from green tea prevent antineuritogenic action of Nogo-A via 67-kDa laminin receptor and hydrogen peroxide. J. Neurochem.2015, 132, 70–84. [Google Scholar] [CrossRef]
Gundimeda, U.; McNeill, T.H.; Fan, T.K.; Deng, R.; Rayudu, D.; Chen, Z.; Cadenas, E.; Gopalakrishna, R. Green tea catechins potentiate the neuritogenic action of brain-derived neurotrophic factor: Role of 67-kDa laminin receptor and hydrogen peroxide. Biochem. Biophys. Res. Commun.2014, 445, 218–224. [Google Scholar] [CrossRef]
Kwon, K.J.; Kim, J.N.; Kim, M.K.; Lee, J.; Ignarro, L.J.; Kim, H.J.; Shin, C.Y.; Han, S.H. Melatonin synergistically increases resveratrol-induced heme oxygenase-1 expression through the inhibition of ubiquitin-dependent proteasome pathway: A possible role in neuroprotection. J. Pineal. Res.2011, 50, 110–123. [Google Scholar] [CrossRef]
Olanow, C.W.; Rascol, O.; Hauser, R.; Feigin, P.D.; Jankovic, J.; Lang, A.; Langston, W.; Melamed, E.; Poewe, W.; Stocchi, F.; et al. A doubleblind, delayed-start trial of rasagiline in Parkinson’s disease. N. Engl. J. Med.2009, 361, 1268–1278. [Google Scholar] [CrossRef]
Masellis, M.; Collinson, S.; Freeman, N.; Tampakeras, M.; Levy, J.; Tchelet, A.; Eyal, E.; Berkovich, E.; Eliaz, R.E.; Abler, V.; et al. D2 receptor gene variants and response to rasagiline in early Parkinson’s disease: A pharmacogenetic study. Brain2016, 139, 2050–2062. [Google Scholar] [CrossRef]
Reznichenko, L.; Kalfon, L.; Amit, T.; Youdim, M.B.; Mandel, S.A. Low dosage of rasagiline and epigallocatechin gallate synergistically restored the nigrostriatal axis in MPTP-induced parkinsonism. Neurodegener. Dis.2010, 7, 219–231. [Google Scholar] [CrossRef]
Faggi, L.; Pignataro, G.; Parrella, E.; Porrini, V.; Vinciguerra, A.; Cepparulo, P.; Cuomo, O.; Lanzillotta, A.; Mota, M.; Benarese, M.; et al. Association of Valproate and Resveratrol Reduces Brain Injury in Ischemic Stroke. Int. J. Mol. Sci.2018, 19, 172. [Google Scholar] [CrossRef]
Herges, K.; Millward, J.M.; Hentschel, N.; Infante-Duarte, C.; Aktas, O.; Zipp, F. Neuroprotective effect of combination therapy of glatiramer acetate and epigallocatechin-3-gallate in neuroinflammation. PLoS ONE2011, 6, e25456. [Google Scholar] [CrossRef]
Kang, K.S.; Wen, Y.; Yamabe, N.; Fukui, M.; Bishop, S.C.; Zhu, B.T. Dual beneficial effects of (-)-epigallocatechin-3-gallate on levodopa methylation and hippocampal neurodegeneration: In vitro and in vivo studies. PLoS ONE2010, 5, e11951. [Google Scholar] [CrossRef]
Doostdar, H.; Burke, M.D.; Mayer, R.T. Bioflavonoids: Selective substrates and inhibitors for cytochrome P450CYP1A and CYP1B1. Toxicology2000, 144, 31–38. [Google Scholar] [CrossRef]
Chang, T.K.; Chen, J.; Yeung, E.Y. Effect of Ginkgo biloba extract on procarcinogen-bioactivating human CYP1 enzymes: Identification of isorhamnetin, kaempferol and quercetin as potent inhibitors of CYP1B1. Toxicol. Appl. Pharmacol.2006, 213, 18–26. [Google Scholar] [CrossRef]
Czuczwar, P.; Paszkowski, T.; Lisiecki, M.; Woźniak, S.; Stępniak, A. The safety and tolerance of phytotherapies in menopausal medicine—A review of the literature. Prz Menopauzalny2017, 16, 8–11. [Google Scholar] [CrossRef]
Galati, G.; O’Brien, P.J. Potential toxicity of flavonoids and other dietary phenolics: Significance for their chemopreventive and anticancer properties. Free Radic. Biol. Med.2004, 37, 287–303. [Google Scholar] [CrossRef]
Boocock, D.J.; Faust, G.E.; Patel, K.R.; Schinas, A.M.; Brown, V.A.; Ducharme, M.P.; Booth, T.D.; Crowell, J.A.; Perloff, M.; Gescher, A.J.; et al. Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent. Cancer Epidemiol. Biomark. Prev.2007, 16, 1246–1252. [Google Scholar] [CrossRef]
Vaz-da-Silva, M.; Loureiro, A.I.; Falcao, A.; Nunes, T.; Rocha, J.F.; Fernandes-Lopes, C.; Soares, E.; Wright, L.; Almeida, L.; Soares-da-Silva, P. Effect of food on the pharmacokinetic profile of trans-resveratrol. Int. J. Clin. Pharmacol. Ther.2008, 46, 564–570. [Google Scholar] [CrossRef]
Almeida, L.; Vaz-da-Silva, M.; Falcao, A.; Soares, E.; Costa, R.; Loureiro, A.I.; Fernandes-Lopes, C.; Rocha, J.F.; Nunes, T.; Wright, L.; et al. Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers. Mol. Nutr. Food Res.2009, 53, 7–15. [Google Scholar] [CrossRef]
Herrschaft, H.; Nacu, A.; Likhachev, S.; Sholomov, I.; Hoerr, R.; Schlaefke, S. Ginkgo biloba extract EGb 761® in dementia with neuropsychiatric features: A randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg. J. Psychiatr. Res.2012, 46, 716–723. [Google Scholar] [CrossRef]
Ihl, R.; Tribanek, M.; Bachinskaya, N.; GOTADAY Study Group. Efficacy and tolerability of a once daily formulation of Ginkgo biloba extract EGb 761® in Alzheimer’s disease and vascular dementia: Results from a randomised controlled trial. Pharmacopsychiatry2012, 45, 41–46. [Google Scholar] [CrossRef]
Ringman, J.M.; Frautschy, S.A.; Teng, E.; Begum, A.N.; Bardens, J.; Beigi, M.; Gylys, K.H.; Badmaev, V.; Heath, D.D.; Apostolova, L.G.; et al. Oral curcumin for Alzheimer’s disease: Tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. Alzheimers Res. Ther.2012, 4, 43. [Google Scholar] [CrossRef]
Bailey, D.G.; Malcolm, J.; Arnold, O.; Spence, J.D. Grapefruit juice drug interactions. Br. J. Clin. Pharmacol.1998, 46, 101–110. [Google Scholar] [CrossRef]
Hodek, P.; Trefil, P.; Stiborová, M. Flavonoids—Potent and versatile biologically active compounds interacting with cytochromes P450. Chem. Biol. Interact.2002, 139, 1–21. [Google Scholar] [CrossRef]
Uno, T.; Yasui-Furukori, N. Effect of grapefruit in relation to human pharmacokinetic study. Curr. Clin. Pharmacol.2006, 1, 157–161. [Google Scholar]
Koga, N.; Ohta, C.; Kato, Y.; Haragushi, K.; Endo, T.; Ogawa, K.; Ohta, H.; Yano, H. In vitro metabolism of nobiletin, a polymethoxy-flavonoid, by human liver microsomes and cytochrome P450. Xenobiotica2011, 41, 927–933. [Google Scholar] [CrossRef]
Ofer, M.; Wolffram, S.; Koggel, A.; Spahn-Langguth, H.; Langguth, P. Modulation of drug transport by selected flavonoids: Involvement of P-gp and OCT? Eur. J. Pharm. Sci.2005, 25, 263–271. [Google Scholar] [CrossRef]
Bailey, D.G. Fruit juice inhibition of uptake transport: A new type of food–drug interaction. Br. J. Clin. Pharmacol.2010, 70, 645–655. [Google Scholar] [CrossRef]
Owira, P.M.; Ojewole, J.A. The grapefruit: An old wine in a new glass? Metabolic and cardiovascular perspectives Cardiovasc. J. Afr.2010, 21, 280–285. [Google Scholar]
Jáuregui-Garrido, B.; Jáuregui-Lobera, I. Interactions between antihypertensive drugs and food. Nutr. Hosp.2012, 27, 1866–1875. [Google Scholar]
Eaton, E.A.; Walle, U.K.; Lewis, A.J.; Hudson, T.; Wilson, A.A.; Walle, T. Flavonoids, potent inhibitors of the human P-form phenolsulfotransferase: Potential role in drug metabolism and chemoprevention. Drug Metab. Dispos.1996, 24, 232–237. [Google Scholar]
Von Moltke, L.L.; Weemhoff, J.L.; Bedir, E.; Khan, I.A.; Harmatz, J.S.; Goldman, P.; Greenlatt, D.J. Inhibition of human cytochrome P450 by components of Ginkgo biloba. J. Pharm. Pharmacol.2004, 56, 1039–1044. [Google Scholar] [CrossRef]
Martin, P.M.; Horwitz, K.B.; Ryan, D.S.; McGuire, W.L. Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinology1978, 103, 1860–1867. [Google Scholar] [CrossRef]
Nifli, A.P.; Bosson-Kouame, A.; Papadopoulou, N.; Kogia, C.; Kampa, M.; Castagnino, C.; Stournaras, C.; Vercauteren, J.; Castanas, E. Monomeric and oligomeric flavanols are agonists of membrane androgen receptors. Exp. Cell. Res.2005, 309, 329–339. [Google Scholar] [CrossRef]
Stubert, J.; Gerber, B. Isoflavones—Mechanism of Action and Impact on Breast Cancer Risk. Breast Care2009, 4, 22–29. [Google Scholar] [CrossRef]
Zhang, G.Q.; Chen, J.L.; Liu, Q.; Zhang, Y.; Zeng, H.; Zhao, Y. Soy Intake Is Associated with Lower Endometrial Cancer Risk: A Systematic Review and Meta-Analysis of Observational Studies. Medicine (Baltimore)2015, 94, e2281. [Google Scholar] [CrossRef]
Mgbonyebi, O.P.; Russo, J.; Russo, I.H. Antiproliferative effect of synthetic resveratrol on human breast epithelial cells. Int. J. Oncol.1998, 12, 865–869. [Google Scholar] [CrossRef]
Della Ragione, F.; Cucciola, V.; Borriello, A.; Della Pietra, V.; Racioppi, L.; Soldati, G.; Manna, C.; Galletti, P.; Zappia, V. Resveratrol arrests the cell division cycle at S/G2 phase transition. Biochem. Biophys. Res. Commun.1998, 250, 53–58. [Google Scholar] [CrossRef]
Hsieh, T.C.; Burfeind, P.; Laud, K.; Backer, J.M.; Traganos, F.; Darzynkiewicz, Z.; Wu, J.M. Cell cycle effects and control of gene expression by resveratrol in human breast carcinoma cell lines with different metastatic potentials. Int. J. Oncol.1999, 15, 245–252. [Google Scholar] [CrossRef] [PubMed]
Kaushik, S.; Shyam, H.; Sharma, R.; Balapure, A.K. Genistein synergizes centchroman action in human breast cancer cells. Indian J. Pharmacol.2016, 48, 637–642. [Google Scholar]
Choi, E.J.; Jung, J.Y.; Kim, G.H. Genistein inhibits the proliferation and differentiation of MCF-7 and 3T3-L1 cells via the regulation of ERα expression and induction of apoptosis. Exp. Ther. Med.2014, 8, 454–458. [Google Scholar] [CrossRef][Green Version]
Gehm, B.D.; McAndrews, J.M.; Chien, P.Y.; Jameson, J.L. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc. Natl. Acad. Sci. USA1997, 94, 14138–14143. [Google Scholar] [CrossRef] [PubMed][Green Version]
Lu, R.; Serrero, G. Resveratrol, a natural product derived from grape, exhibits antiestrogenic activity and inhibits the growth of human breast cancer cells. J. Cell. Physiol.1999, 179, 297–304. [Google Scholar] [CrossRef]
De Lemos, M.L. Effects of soy phytoestrogens genistein and daidzein on breast cancer growth. Ann. Pharmacother.2001, 35, 1118–1121. [Google Scholar] [CrossRef]
Shike, M.; Doane, A.S.; Russo, L.; Cabal, R.; Reis-Filho, J.S.; Gerald, W.; Cody, H.; Khanin, R.; Bromberg, J.; Norton, L. The effects of soy supplementation on gene expression in breast cancer: A randomized placebo-controlled study. J. Natl. Cancer Inst.2014, 106. [Google Scholar] [CrossRef]
Saleh, M.C.; Connell, B.J.; Saleh, T.M. Resveratrol induced neuroprotection is mediated via both estrogen receptor subtypes, ER(α) and ER(β). Neurosci. Lett.2013, 548, 217–221. [Google Scholar] [CrossRef]
Turner, R.T.; Evans, G.L.; Zhang, M.; Maran, A.; Sibonga, J.D. Is resveratrol an estrogen agonist in growing rats? Endocrinology1999, 140, 50–54. [Google Scholar] [CrossRef] [PubMed]
Lecomte, S.; Lelong, M.; Bourgine, G.; Efstathiou, T.; Saligaut, C.; Pakdel, F. Assessment of the potential activity of major dietary compounds as selective estrogen receptormodulators in two distinct cell models for proliferation and differentiation. Toxicol. Appl. Pharmacol.2017, 325, 61–70. [Google Scholar] [CrossRef] [PubMed]
Bookout, A.L.; Jeong, Y.; Downes, M.; Yu, R.T.; Evans, R.M.; Mangelsdorf, D.J. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell2006, 126, 789–799. [Google Scholar] [CrossRef] [PubMed]
Nwachukwu, J.C.; Srinivasan, S.; Bruno, N.E.; Parent, A.A.; Hughes, T.S.; Pollock, J.A.; Gjyshi, O.; Cavett, V.; Nowak, J.; Garcia-Ordonez, R.D.; et al. Resveratrol modulates the inflammatory response via an estrogen receptor-signal integration network. Elife2014, 3, e02057. [Google Scholar] [CrossRef] [PubMed]
Levin, J.; Maaß, S.; Schuberth, M.; Respondek, G.; Paul, F.; Mansmann, U.; Oertel, W.H.; Lorenzl, S.; Krismer, F.; Seppi, K.; Poewe, W.; et al. The PROMESA-protocol: Progression rate of multiple system atrophy under EGCG supplementation as anti-aggregation-approach. J. Neural Transm. (Vienna)2016, 123, 439–445. [Google Scholar] [CrossRef]
Maurer, K.; Ihl, R.; Dierks, T.; Frölich, L. Clinical efficacy of Ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type. J. Psychiatr. Res.1997, 31, 645–655. [Google Scholar] [CrossRef]
Montes, P.; Ruiz-Sanchez, E.; Rojas, C.; Rojas, P. Ginkgo biloba Extract 761: A Review of Basic Studies and Potential Clinical Use in Psychiatric Disorders. Cns Neurol. Disord. Drug Targets2015, 14, 132–149. [Google Scholar] [CrossRef] [PubMed]
Schulz, V. Ginkgo extract or cholinesterase inhibitors in patients with dementia: What clinical trials and guidelines fail to consider. Phytomedicine2003, 10, 74–79. [Google Scholar] [CrossRef] [PubMed]
Andrieu, S.; Ousset, P.J.; Coley, N.; Ouzid, M.; Mathiex-Fortunet, H.; Vellas, B.; GuidAge study GROUP. GuidAge study: A 5-year double blind, randomised trial of EGb 761 for the prevention of Alzheimer’s disease in elderly subjects with memory complaints. i. rationale, design and baseline data. Curr. Alzheimer Res.2008, 5, 406–415. [Google Scholar] [CrossRef] [PubMed]
Vellas, B.; Coley, N.; Ousset, P.J.; Berrut, G.; Dartigues, J.F.; Dubois, B.; Grandjean, H.; Pasquier, F.; Piette, F.; Robert, P.; et al. Long-term use of standardised Ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): A randomised placebo-controlled trial. Lancet Neurol.2012, 11, 851–859. [Google Scholar] [CrossRef]
DeKosky, S.T.; Williamson, J.D.; Fitzpatrick, A.L.; Kronmal, R.A.; Ives, D.G.; Saxton, J.A.; Lopez, O.L.; Burke, G.; Carlson, M.C.; Fried, L.P.; et al. Ginkgo biloba for prevention of dementia: A randomized controlled trial. JAMA2008, 300, 2253–2262. [Google Scholar] [CrossRef] [PubMed]
Dodge, H.H.; Zitzelberger, T.; Oken, B.S.; Howieson, D.; Kaye, J. A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline. Neurology2008, 70, 1809–1817. [Google Scholar] [CrossRef][Green Version]
Snitz, B.E.; O’Meara, E.S.; Carlson, M.C.; Arnold, A.M.; Ives, D.G.; Rapp, S.R.; Saxton, J.; Lopez, O.L.; Dunn, L.O.; Sink, K.M.; et al. Ginkgo biloba for preventing cognitive decline in older adults: A randomized trial. JAMA2009, 302, 2663–2670. [Google Scholar] [CrossRef]
Scherrer, B.; Andrieu, S.; Ousset, P.J.; Berrut, G.; Dartigues, J.F.; Dubois, B.; Pasquier, F.; Piette, F.; Robert, P.; Touchon, J.; et al. Analysing Time to Event Data in Dementia Prevention Trials: The Example of the GuidAge Study of EGb761. J. Nutr. Health Aging2015, 19, 1009–1011. [Google Scholar] [CrossRef]
Baum, L.; Lam, C.W.; Cheung, S.K. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J. Clin. Psychopharmacol.2008, 28, 110–113. [Google Scholar] [CrossRef]
Beck, S.M.; Ruge, H.; Schindler, C.; Burkart, M.; Miller, R.; Kirschbaum, C.; Goschke, T. Effects of Ginkgo biloba extract EGb 761® on cognitive control functions, mental activity of the prefrontal cortex and stress reactivity in elderly adults with subjective memory impairment—A randomized double-blind placebo-controlled trial. Hum. Psychopharmacol.2016, 31, 227–242. [Google Scholar] [CrossRef]
Nasab, N.M.; Bahrammi, M.A.; Nikpour, M.R.; Rahim, F.; Naghibis, S.N. Efficacy of rivastigmine in comparison to ginkgo for treating Alzheimer’s dementia. J. Pak. Med. Assoc.2012, 62, 677–680. [Google Scholar]
Kennedy, D.O.; Wightman, E.L.; Reay, J.L.; Lietz, G.; Okello, E.J.; Wilde, A.; Haskell, C.F. Am Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: A double-blind, placebo-controlled, crossover investigation. J. Clin. Nutr.2010, 91, 1590–1597. [Google Scholar] [CrossRef]
Wightman, E.L.; Reay, J.L.; Haskell, C.F.; Williamson, G.; Dew, T.P.; Kennedy, D.O. Effects of resveratrol alone or in combination with piperine on cerebral blood flow parameters and cognitive performance in human subjects: A randomised, double-blind, placebo-controlled, cross-over investigation. Br. J. Nutr.2014, 112, 203–213. [Google Scholar] [CrossRef]
Wightman, E.L.; Haskell-Ramsay, C.F.; Reay, J.L.; Williamson, G.; Dew, T.; Zhang, W.; Kennedy, D.O. The effects of chronic trans-resveratrol supplementation on aspects of cognitive function, mood, sleep, health and cerebral blood flow in healthy, young humans. Br. J. Nutr.2015, 114, 1427–1437. [Google Scholar] [CrossRef] [PubMed]
Brickman, A.M.; Khan, U.A.; Provenzano, F.A.; Yeung, L.K.; Suzuki, W.; Schroeter, H.; Wall, M.; Sloan, R.P.; Small, S.A. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat. Neurosci.2014, 17, 1798–1803. [Google Scholar] [CrossRef][Green Version]
Witte, A.V.; Kerti, L.; Margulies, D.S.; Flöel, A. Effects of resveratrol on memory performance, hippocampal functional connectivity and glucose metabolism in healthy older adults. J. Neurosci.2014, 34, 7862–7870. [Google Scholar] [CrossRef]
Moussa, C.; Hebron, M.; Huang, X.; Ahn, J.; Rissman, R.A.; Aisen, P.S.; Turner, R.S. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. J. Neuroinflammation2017, 14, 1. [Google Scholar] [CrossRef] [PubMed][Green Version]
Riva, S.; Monti, D.; Luisetti, M.; Danieli, B. Enzymatic modification of natural compounds with pharmacological properties. Ann. N. Y. Acad. Sci.1998, 864, 70–80. [Google Scholar] [CrossRef]
Colin, D.; Gimazane, A.; Lizard, G.; Izard, J.C.; Solary, E.; Latruffe, N.; Delmas, D. Effects of resveratrol analogs on cell cycle progression, cell cycle associated proteins and 5fluoro-uracil sensitivity in human derived colon cancer cells. Int. J. Cancer2009, 124, 2780–2788. [Google Scholar] [CrossRef][Green Version]
Marel, A.K.; Lizard, G.; Izard, J.C.; Latruffe, N.; Delmas, D. Inhibitory effects of trans-resveratrol analogs molecules on the proliferation and the cell cycle progression of human colon tumoral cells. Mol. Nutr. Food Res.2008, 52, 538–548. [Google Scholar] [CrossRef]
Chao, J.; Li, H.; Cheng, K.W.; Yu, M.S.; Chang, R.C.; Wang, M. Protective effects of pinostilbene, a resveratrol methylated derivative, against 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells. J. Nutr. Biochem.2010, 21, 482–489. [Google Scholar] [CrossRef]
Huo, C.; Wan, S.B.; Lam, W.H.; Li, L.; Wang, Z.; Landis-Piwowar, K.R.; Chen, D.; Dou, Q.P.; Chan, T.H. The challenge of developing green tea polyphenols as therapeutic agents. Inflammopharmacology2008, 16, 248–252. [Google Scholar] [CrossRef][Green Version]
Lambert, M.; Olsen, L.; Jaroszewski, J.W. Stereoelectronic effects on 1H nuclear magnetic resonance chemical shifts in methoxybenzenes. J. Org. Chem.2006, 71, 9449–9457. [Google Scholar] [CrossRef]
Mythri, R.B.; Harish, G.; Dubey, S.K.; Misra, K.; Bharath, M.M. Glutamoyl diester of the dietary polyphenol curcumin offers improved protection against peroxynitrite-mediated nitrosative stress and damage of brain mitochondria in vitro: Implications for Parkinson’s disease. Mol. Cell. Biochem.2011, 347, 135–143. [Google Scholar] [CrossRef]
Solberg, N.O.; Chamberlin, R.; Vigil, J.R.; Deck, L.M.; Heidrich, J.E.; Brown, D.C.; Brady, C.I.; Vander, T.A.; Garwood, M.; Bisoffi, M.; et al. Optical and SPION-Enhanced MR Imaging Shows that trans-Stilbene Inhibitors of NF-κB Concomitantly Lower Alzheimer’s Disease Plaque Formation and Microglial Activation in AβPP/PS-1 Transgenic Mouse Brain. J. Alzheimers Dis.2014, 40, 191–212. [Google Scholar] [CrossRef]
Hauss, F.; Liu, J.; Michelucci, A.; Coowar, D.; Morga, E.; Heuschling, P.; Luu, B. Dual bioactivity of resveratrol fatty alcohols: Differentiation of neural stem cells and modulation of neuroinflammation. Bioorg. Med. Chem. Lett.2007, 17, 4218–4222. [Google Scholar] [CrossRef]
Biasutti, L.; Mattarei, A.; Azzolini, M.; La Spina, M.; Sassi, N.; Romio, M.; Paradisi, C.; Zoratti, M. Resveratol derivatives as pharmacological tools. Ann. N. Y. Acad. Sci.2017, 1403, 27–37. [Google Scholar] [CrossRef]
Frozza, R.L.; Bernardi, A.; Hoppe, J.B.; Meneghetti, A.B.; Battastini, A.M.; Pohlmann, A.R.; Guterres, S.S.; Salbego, C. Lipid-core nanocapsules improve the effects of resveratrol against Abeta-induced neuroinflammation. J. Biomed. Nanotechnol.2013, 9, 2086–2104. [Google Scholar] [CrossRef] [PubMed]
Neves, A.R.; Lúcio, M.; Martins, S.; Lima, J.L.; Reis, S. Novel resveratrol nanodelivery systems based on lipid nanoparticles to enhance its oral bioavailability. Int. J. Nanomed.2013, 8, 177–187. [Google Scholar][Green Version]
Augustin, M.A.; Sanguansri, L.; Lockett, T. Nano- and micro-encapsulated systems for enhancing the delivery of resveratrol. Ann. N. Y. Acad. Sci.2013, 1290, 107–112. [Google Scholar] [CrossRef]
Tsilioni, I.; Panagiotidou, S.; Theoharides, T.C. Exosomes in neurologic and psychiatric disorders. Clin. Ther.2014, 36, 882–888. [Google Scholar] [CrossRef] [PubMed]
Siddique, Y.H.; Khan, W.; Singh, B.R.; Naqvi, A.H. Synthesis of alginate-curcumin nanocomposite and its protective role in transgenic Drosophila model of Parkinson’s disease. ISRN Pharmacol.2013, 2013, 794582. [Google Scholar] [CrossRef]
Amiot, M.J.; Romier, B.; Anh Dao, T.M.; Fanciullino, R.; Ciccolini, J.; Burcelin, R.; Pechere, L.; Emond, C.; Savouret, J.F.; Seree, E. Optimization of trans-resveratrol bioavailability for human therapy. Biochimie2013, 95, 1233–1238. [Google Scholar] [CrossRef]
Xiao, Y.; Chen, X.; Yang, L.; Zhu, X.; Zou, L.; Meng, F.; Ping, Q. Preparation and oral bioavailability study of curcuminoid-loaded microemulsion. J. Agric. Food Chem.2013, 61, 3654–3660. [Google Scholar] [CrossRef]
Ahirrao, M.; Shrotriya, S. In vitro and in vivo evaluation of cubosomal in situ nasal gel containing resveratrol for brain targeting. Drug Dev. Ind. Pharm.2017, 43, 1686–1693. [Google Scholar] [CrossRef]
Fang, Z.; Bhandari, B. Encapsulation of polyphenols—A review. Trends Food Sci. Technol.2010, 21, 510–523. [Google Scholar] [CrossRef]
Yang, Q.Q.; Wei, X.L.; Fang, R.Y.; Wang, M.; Ge, Y.T.; Zhang, D.; Cheng, L.Z.; Corke, H. Nanochemoprevention with therapeutic benefits: An updates review focused on epigallocatechin gallate delivery. Crit. Rev. Food Nutr.2019, 23, 1–22. [Google Scholar] [CrossRef] [PubMed]
Cirillo, G.; Hampel, S.; Spizzirri, U.G.; Parisi, O.I.; Picci, N.; Iemma, F. Carbon nanotubes hybrid hydrogels in drug delivery: A perspective review. BioMed Res. Int.2014, 2014, 825017. [Google Scholar] [CrossRef]
Cirillo, G.; Hampel, S.; Klingeler, R.; Puoci, F.; Iemma, F.; Curcio, M.; Parisi, O.I.; Spizzirri, U.G.; Picci, N.; Leonhardt, A.; et al. Antioxidant multi-walled carbon nanotubes by free radical grafting of gallic acid: New materials for biomedical applications. J. Pharm. Pharmacol.2011, 63, 179–188. [Google Scholar] [CrossRef]
Kostarelos, K.; Lacerda, L.; Pastorin, G.; Wu, W.; Wieckowski, S.; Luandsilivay, J.; Godefroy, S.; Pantarotto, D.; Briand, J.P.; Muller, S.; et al. Cellular uptake of functionalized carbon nanotubes is independent of functional group and cell type. Nat. Nanotechnol.2007, 2, 108–113. [Google Scholar] [CrossRef]
Colvin, V.L. The potential environmental impact of engineered nanomaterials. Nat. Biotechnol.2003, 21, 1166–1170. [Google Scholar] [CrossRef]
Lopez-Nicolas, J.M.; Núñez-Delicado, E.; Pérez-López, A.J.; Barrachina, A.C.; Cuadra-Crespo, P. Determination of stoichiometric coefficients and apparent formation constants for beta-cyclodextrin complexes of trans-resveratrol using reversed-phase liquid chromatography. J. Chromatogr. A2006, 1135, 158–165. [Google Scholar] [CrossRef]
Laza-Knoerr, A.L.; Gref, R.; Couvreur, P. Cyclodextrins for drug delivery. J. Drug Target2010, 18, 645–656. [Google Scholar] [CrossRef]
Tapeinos, C.; Battaglini, M.; Ciofani, G. Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases. J. Control. Release2017, 264, 306–332. [Google Scholar] [CrossRef]
Hanson, L.R.; Frey, W.H., 2nd. Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci.2008, 9, 5. [Google Scholar] [CrossRef] [PubMed]
Chapman, C.D.; Frey, W.H., 2nd; Craft, S.; Danielyan, L.; Hallschmid, M.; Schiöth, H.B.; Benedict, C. Intranasal treatment of central nervous system dysfunction in humans. Pharm. Res.2013, 30, 2475–2484. [Google Scholar] [CrossRef] [PubMed]
Rosenbloom, M.H.; Barclay, T.R.; Pyle, M.; Owens, B.L.; Cagan, A.B.; Anderson, C.P.; Frey, W.H., 2nd; Hanson, L.R. A single-dose pilot trial of intranasal rapid-acting insulin in apolipoprotein E4 carriers with mild-moderate Alzheimer’s disease. CNS Drugs2014, 28, 1185–1189. [Google Scholar] [CrossRef]
Dewey, R.B., Jr.; Maraganore, D.M.; Ahlskog, J.E.; Matsumoto, J.Y. A double-blind, placebo-controlled study of intranasal apomorphine spray as a rescue agent for off-states in Parkinson’s disease. Mov. Disord.1998, 13, 782–787. [Google Scholar] [CrossRef]
Crowe, T.P.; Greenlee, M.H.W.; Kanthasamy, A.G.; Hsu, W.H. Mechanism of intranasal drug delivery directly to the brain. Life Sci.2018, 195, 44–52. [Google Scholar] [CrossRef]
Desai, P.P.; Patravale, V.B. Curcumin Cocrystal Micelles-Multifunctional Nanocomposites for Management of Neurodegenerative Ailments. J. Pharm. Sci.2018, 107, 1143–1156. [Google Scholar] [CrossRef]
Lungare, S.; Hallam, K.; Badhan, R.K. Phytochemical-loaded mesoporous silica nanoparticles for nose-to-brain olfactory drug delivery. Int. J. Pharm.2016, 513, 280–293. [Google Scholar] [CrossRef][Green Version]
Nasr, M. Development of an optimized hyaluronic acid-based lipidic nanoemulsion co-encapsulating two polyphenols for nose to brain delivery. Drug Deliv.2016, 23, 1444–1452. [Google Scholar] [CrossRef]
Helson, L. Curcumin (diferuloylmethane) delivery methods: A review. Biofactors2013, 39, 21–26. [Google Scholar] [CrossRef]
Sharma, R.A.; McLelland, H.R.; Hill, K.A.; Ireson, C.R.; Euden, S.A.; Manson, M.M.; Pirmohamed, M.; Marnett, L.J.; Gescher, A.J.; Steward, W.P. Pharmacodynamic and pharmacokinetic study of oral Curcuma extract in patients with colorectal cancer. Clin. Cancer Res.2001, 7, 1894–1900. [Google Scholar]
DiMauro, T.M. Intranasally Administering Curcumin to the Brain to Treat Alzheimer’s Disease. U.S. Patent US20080075671A1, 22 September 2006. [Google Scholar]
Dhuria, S.V.; Hanson, L.R.; Frey, W.H., 2nd. Intranasal delivery to the central nervous system: Mechanisms and experimental considerations. J. Pharm. Sci.2010, 99, 1654–1673. [Google Scholar] [CrossRef]
Pannala, A.S.; Rice-Evans, C.A.; Halliwell, B.; Singh, S. Inhibition of peroxynitrite-mediated tyrosine nitration by catechin polyphenols. Biochem. Biophys. Res. Commun.1997, 232, 164–168. [Google Scholar] [CrossRef]
Hollman, P.C.; Cassidy, A.; Comte, B.; Heinonen, M.; Richelle, M.; Richling, E.; Serafini, M.; Scalbert, A.; Sies, H.; Vidry, S. The biological relevance of direct antioxidant effects of polyphenols for cardiovascular health in humans is not established. J. Nutr.2011, 141, 989S–1009S. [Google Scholar] [CrossRef]
Di Meo, F.; Lemaur, V.; Cornil, J.; Lazzaroni, R.; Duroux, J.L.; Olivier, Y.; Trouillas, P. Free radical scavenging by natural polyphenols: Atom versus electron transfer. J. Phys. Chem. A2013, 117, 2082–2092. [Google Scholar] [CrossRef]
Del Rio, D.; Rodriguez-Mateos, A.; Spencer, J.P.; Tognolini, M.; Borges, G.; Crozier, A. Dietary (poly)phenolics in human health: Structures, bioavailability and evidence of protective effects against chronic diseases. Antioxid. Redox Signal.2013, 18, 1818–1892. [Google Scholar] [CrossRef]
Hollman, P.C. Unravelling of the health effects of polyphenols is a complex puzzle complicated by metabolism. Arch. Biochem. Biophys.2014, 559, 100–105. [Google Scholar] [CrossRef]
Benzie, I.F.; Szeto, Y.T.; Strain, J.J.; Tomlinson, B. Consumption of green tea causes rapid increase in plasma antioxidant power in humans. Nutr. Cancer.1999, 34, 83–87. [Google Scholar] [CrossRef]
Calabrese, E.J. Neuroscience and hormesis: Overview and general findings. Crit. Rev. Toxicol.2008, 38, 249–252. [Google Scholar] [CrossRef]
Calabrese, E.J.; Baldwin, L.A. The frequency of U-shaped dose responses in the toxicological literature. Toxicol. Sci.2001, 62, 330–338. [Google Scholar] [CrossRef]
Calabrese, E.J.; Baldwin, L.A. The hormetic dose-response model is more common than the threshold model in toxicology. Toxicol. Sci.2003, 71, 246–250. [Google Scholar] [CrossRef]
Calabrese, E.J.; Baldwin, L.A. Toxicology rethinks its central belief. Nature2003, 421, 691–692. [Google Scholar] [CrossRef]
Peper, A. Aspects of the relationship between drug dose and drug effect. Dose Response2009, 7, 172–192. [Google Scholar] [CrossRef] [PubMed]
Szende, B.; Tyihák, E.; Király-Véghely, Z. Dose-dependent effect of resveratrol on proliferation and apoptosis in endothelial and tumor cell cultures. Exp. Mol. Med.2000, 32, 88–92. [Google Scholar] [CrossRef] [PubMed][Green Version]
Dudley, J.; Das, S.; Mukherjee, S.; Das, D.K. Resveratrol, a unique phytoalexin present in red wine, delivers either survival signal or death signal to the ischemic myocardium depending on dose. J. Nutr. Biochem.2009, 20, 443–452. [Google Scholar] [CrossRef] [PubMed]
Conte, A.; Pellegrini, S.; Tagliazucchi, D. Effect of resveratrol and catechin on PC12 tyrosine kinase activities and their synergistic protection from beta-amyloid toxicity. Drugs Exp. Clin. Res.2003, 29, 243–255. [Google Scholar] [PubMed]
Liu, D.; Gharavi, R.; Pitta, M.; Gleichmann, M.; Mattson, M.P. Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons. Neuromol. Med.2009, 11, 28–42. [Google Scholar] [CrossRef]
Brunet, A.; Sweeney, L.B.; Sturgill, J.F.; Chua, K.F.; Greer, P.L.; Lin, Y.; Tran, H.; Ross, S.E.; Mostoslavsky, R.; Cohen, H.Y.; et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science2004, 303, 2011–2015. [Google Scholar] [CrossRef] [PubMed]
Doss, M. Evidence supporting radiation hormesis in atomic bomb survivor cancer mortality data. Dose Response2012, 10, 584–592. [Google Scholar] [CrossRef] [PubMed]
Tang, F.R.; Loke, W.K. Molecular mechanisms of low dose ionizing radiation-induced hormesis, adaptive responses, radioresistance, bystander effects and genomic instability. Int. J. Radiat. Biol.2015, 91, 13–27. [Google Scholar] [CrossRef]
Calabrese, E.J. Biphasic dose responses in biology, toxicology and medicine: Accounting for their generalizability and quantitative features. Environ. Pollut.2013, 182, 452–460. [Google Scholar] [CrossRef]
Martins, I.J. Increased risk for obesity and diabetes with neurodegeneration in developing countries. J. Mol. Genet. Med.2013, S1:001, 1–8. [Google Scholar] [CrossRef]
Faggi, L.; Porrini, V.; Lanzillotta, A.; Benarese, M.; Mota, M.; Tsoukalas, D.; Parrella, E.; Pizzi, M. A polyphenol-enriched supplement exerts potent epigenetic-protective activity in a cell-based model of brain ischemia. Nutrients2019, 11, 345. [Google Scholar] [CrossRef] [PubMed]
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