Phenolic Compounds Characteristic of the Mediterranean Diet in Mitigating Microglia-Mediated Neuroinflammation

fncel-12-00373 October 20, 2018 Time: 18:46 # 1 REVIEW published: 23 October 2018 doi: 10.3389/fncel.2018.00373 Edited by: Stefania Ceruti, Università degli Studi di Milano, Italy Reviewed by: Rui F. M. Silva, Universidade de Lisboa, Portugal João O. Malva, University of Coimbra, Portugal *Correspondence: Ana M. Troncoso [email protected] Received: 31 May 2018 Accepted: 01 October 2018 Published: 23 October 2018 Citation: Hornedo-Ortega R, Cerezo AB, de Pablos RM, Krisa S, Richard T, García-Parrilla MC and Troncoso AM (2018) Phenolic Compounds Characteristic of the Mediterranean Diet in Mitigating Microglia-Mediated Neuroinflammation. Front. Cell. Neurosci. 12:373. doi: 10.3389/fncel.2018.00373 Phenolic Compounds Characteristic of the Mediterranean Diet in Mitigating Microglia-Mediated Neuroinflammation Ruth Hornedo-Ortega1, Ana B. Cerezo2, Rocío M. de Pablos3, Stéphanie Krisa1, Tristan Richard1, M. Carmen García-Parrilla2and Ana M. Troncoso2* 1MIB, Unité de Recherche Oenologie, EA4577, USC 1366 INRA, ISVV, Unive. de Bordeaux, Bordeaux, France, 2Departamento de Nutrición y Bromatología, Toxicología y Medicina Legal, Área de Nutrición y Bromatología, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain, 3Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain Neuroinflammation is a pathological feature of quite a number of Central Nervous System diseases such as Alzheimer and Parkinson’s disease among others. The hallmark of brain neuroinflammation is the activation of microglia, which are the immune resident cells in the brain and represents the first line of defense when injury or disease occur. Microglial activated cells can adopt different phenotypes to carry out its diverse functions. Thus, the shift into pro-inflammatory/neurotoxic or antiinflammatory/neuroprotective phenotypes, depending of the brain environment, has totally changed the understanding of microglia in neurodegenerative disease. For this reason, novel therapeutic strategies which aim to modify the microglia polarization are being developed. Additionally, the understanding of how nutrition may influence the prevention and/or treatment of neurodegenerative diseases has grown greatly in recent years. The protective role of Mediterranean diet (MD) in preventing neurodegenerative diseases has been reported in a number of studies. The Mediterranean dietary pattern includes as distinctive features the moderate intake of red wine and extra virgin olive oil, both of them rich in polyphenolic compounds, such as resveratrol, oleuropein and hydroxytyrosol and their derivatives, which have demonstrated anti-inflammatory effects on microglia on in vitro studies. This review summarizes our understanding of the role of dietary phenolic compounds characteristic of the MD in mitigating microglia-mediated neuroinflammation, including explanation regarding their bioavailability, metabolism and blood–brain barrier. Keywords: neuroinflammation, microglia, phenolic compounds, wine, olive oil, Mediterranean diet Frontiers in Cellular Neuroscience | www.frontiersin.org 1October 2018 | Volume 12 | Article 373 fncel-12-00373 October 20, 2018 Time: 18:46 # 2 Hornedo-Ortega et al. Phenolic Compounds Mitigate Microglia-Mediated Neuroinflammation INTRODUCTION Among age-related diseases, neurodegenerative disorders are the most prevalent. According to the World Health Organization (WHO), worldwide, around 50 million people have dementia, and every year, there are nearly 10 million new cases. Also the proportion of the general population aged 60 and over with dementia at a given time is between 5 to 8 per 100 people and the total number of people with dementia is expected to increase to 82 million in 2030 and 152 in 2050 (WHO, 2015, 2017). Among them, Alzheimer’s disease (AD) and Parkinson’s disease (PD), are most common and of great concern since they are chronic and progressive and affect a significant portion of the aged population. AD is the most common form of dementia, accounting for around 60–70% of total cases (WHO, 2017). At the same time their poor diagnosis and lack of effective treatment worsens the problem (Figueira et al., 2017;Pennisi et al., 2017). Since their prevalence remains growing, they currently represent a challenge for society and healthcare systems (Deak et al., 2015;Peña-Altamira et al., 2017). Although age is the main risk factor for dementia, there are other recognized risk factors, quite a number of them related with diet such as mid-life hypertension, obesity or unbalanced diets (WHO, 2018). Hence, neurodegenerative disorders are recognized to be complex, progressive and multifactorial. At the same time genetic factors are associated since familial and sporadic forms are described with lifestyle and environmental factors involved (Nicolia et al., 2014;Peña-Altamira et al., 2017). Pharmacological treatments for AD and PD currently available have the potential to delay the progression or even reduce the symptoms at a certain level (Pennisi et al., 2017). At the same time, they have common pathological features such as oxidative stress, abnormal protein aggregation, inflammation and apoptosis of neurons (Angeloni et al., 2017). In this context and due to the limited efficacy of pharmacological treatment and the multifactorial nature of these disorders, a multifaceted approach seems appropriate. Diet interventions are a promising approach to prevent and delay the progression, with so far an important Abbreviations: α-syn, α-synuclein; 6-OHDA, 6-hydroxydopamine; Aβ, amyloidβ; AD, Alzheimer’s disease; ADH, alcohol dehydrogenase; ALR, aldehyde/aldose reductase; AMPK, adenosine monophosphate-activated protein kinase; AP-1, activator protein -1; BBB, blood-brain barrier; CNS, central nervous system; COX-2, cyclooxygenase 2; DG, dentate gyrus; DOPAC, 3,4-dihydroxyphenylacetic acid; DOPAL, 3,4-duhydroxyphenyl aldehyde; Drp1, dynamin-related protein 1; EFSA, European Food Safety Authority; ERK, extracellular signal-regulated kinase; EVVO, extra virgin olive oil; GSK-3, glycogen synthase kinase- 3; HT, hydroxytyrosol; IL, interleukin; INF-γ, interferon-γ; iNOS, inducible nitric oxide synthase; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; MAPKs, mitogen-activated protein kinases; MD, Mediterranean diet; MPO, myeloperoxidase; MPTP, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine; mTOR, mammalian target of rapamycin; NAD, adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; NF-κB, nuclear factor-Kappa B; NO, nitric oxide; Nrf2, nuclear factor–erythroid 2- related factor; oAβ, oligomeric Aβ; OLE, oleuropein; PD, Parkinson’s disease; PGE- 2, prostaglandin E2; PI3K/Akt, phosphatidylinositol-3-kinase and protein kinase B; ROS, reactive oxygen species; RV, resveratrol; SIRT, sirtuin; SN, substantia nigra; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription; STS, stilbene synthase; TGB-β, transforming growth factor beta; TNF-α, tumor necrosis factor; UGTs, uridine 50-diphosphoglucuronosyl transferases; VOO, virgin olive oil; WHO, World Health Organization. body of evidence and experimental support (Almeida et al., 2016; Figueira et al., 2016;Angeloni et al., 2017;Pennisi et al., 2017; Pistollato et al., 2018). Although prevalence data of neurodegenerative diseases within the EU-28 countries do not support lower prevalence figures for Mediterranean countries (Alzheimer Europe, 2013), MD is still widely recognized for its healthy pattern (Castro- Quezada et al., 2014). According to the last data provided by Eurostat (Eurostat, 2016), life expectancy at age 65 in Mediterranean countries is significantly higher than the average for EU-28 countries. Since neurodegenerative diseases are strongly aged-related, it is not surprising that its overall prevalence values in Mediterranean countries remain indistinct than another EU-28 countries. Mediterranean diet has been proposed as a healthy dietary pattern with increasing evidence supporting its beneficial effects toward quite a number of age-related pathologies, among them neurodegenerative disorders and cognitive dysfunctions (Féart et al., 2009, 2010, 2013;Tangney et al., 2011). A number of studies have shown how adherence to the MD pattern is associated with a reduction on cognitive decline and a reduced risk of dementia, AD and PD (Scarmeas et al., 2006, 2009;Di Giovanni, 2009;Alcalay et al., 2012;Gardener et al., 2012;Singh et al., 2014;Casamenti et al., 2015;Safouris et al., 2015;Anastasiou et al., 2017). In addition, MD dietary patterns (a vegetable-based diet and a moderate alcohol intake, especially wine) have been also observed in the so-called “Blue Zones.” These zones are population areas [Sardinia (Italy), Okinawa (Japan), Loma Linda (California), Nicoya Peninsula (Costa Rica) and Icarian (Greece)] which share apart of similar dietary patterns to MD, other special particularities as a stress free and active life-style (regular physical activity) and a familial, social and spirituality life (Buettner and Skemp, 2016). “Blue Zones” have been object of investigation due to the high and exceptional longevity (centenarians/nonagenarians) of their population (Poulain et al., 2013). In fact, it has been observed that older Blue Zone Sardinians present fewer cognitive failures in comparison with the population of other Italian zone (Lombardy). This observation has been related with the presence of a superior working memory performance and lower levels of depressive symptoms associated to the life style pattern including the diet (Fastame et al., 2014a,b, 2015;Fastame and Penna, 2014). This potential of MD in preventing neurodegenerative disorders has been mainly related with its high content in plant foods: fruits and vegetables and olive oil, sources of an array of bioactive compounds (Morris et al., 2006;Scarmeas et al., 2006, 2009;Féart et al., 2010, 2013;Kelsey et al., 2010;Nooyens et al., 2011;Scapagnini et al., 2011;Tangney et al., 2011;Alcalay et al., 2012;Davinelli et al., 2014;Angeloni et al., 2017;Figueira et al., 2017). Bioactive compounds comprise an heterogeneous group of thousands of molecules present mainly in plant foods and also known as phytochemicals. They can be classified into a number of groups, depending on authors, being carotenoids, phytosterols, polyphenolic compounds and sulfur compounds the most abundant. Research on the protective effect of food polyphenols toward the prevention of neurodegenerative disorders has been extensive Frontiers in Cellular Neuroscience | www.frontiersin.org 2October 2018 | Volume 12 | Article 373 fncel-12-00373 October 20, 2018 Time: 18:46 # 3 Hornedo-Ortega et al. Phenolic Compounds Mitigate Microglia-Mediated Neuroinflammation in recent years (Singh et al., 2008;Joseph et al., 2009; Dixon and Pasinetti, 2010;Spencer, 2010;Jones et al., 2012; Vauzour et al., 2018). Virgin olive oil (VOO) and wine are two characteristic polyphenol-rich food items of the MD. Among polyphenols, stilbenes seem to be one of the most promising groups of compounds due to its bioactivity, with red wine being the main source of the most abundant dietary stilben: resveratrol (RV). Most important polyphenols in VOO are tyrosol derivates, showing hydroxytyrosol (HT) and oleuropein (OLE) the most relevant neuroprotective effects (Daccache et al., 2011;Barbaro et al., 2014;Casamenti et al., 2015;Rigacci and Stefani, 2015). Additionally, HT has also been found in both red and white wine in significant amounts (Fernández-Mar et al., 2012). In fact, dietary supplementation with extra virgin olive oil (EVOO) improves behavioral deficits in aging rats (Pitozzi et al., 2010). Moreover the longitudinal “Three city study” found an association between protective effects of the MD and cognition in an elderly population (Berr et al., 2009). Several clinical trials and population studies show olive phenolic compounds as the main responsible for the protective effects against agingassociated cognitive disorders and neurodegenerative diseases such AD, with a simultaneous improvement of cognitive performance (Scarmeas et al., 2006;Valls-Pedret et al., 2012, 2015;Rigacci and Stefani, 2015;Rodríguez-Morató et al., 2015; Casamenti and Stefani, 2017;Loughrey et al., 2017). Despite the evidence supporting the potential benefit of MD, the epidemiological evidences are scarce and need further critical discussion. Polyphenols are an extensive group of molecules, whose number is of several thousands, and encompass very different structures, concentrations in food and beverages and bioactivities. Usually, after ingestion only a minor part is readily absorbed in the upper intestine, most frequently they are hydrolyzed and metabolized prior to their absorption (Bolca et al., 2013;Faria et al., 2014). The non-absorbed portion reaches the colon where it is extensively utilized by gut microbiota yielding low molecular weight compounds, mainly low molecular weight fatty acids (Manach et al., 2004; Crozier et al., 2009;Selma et al., 2009;Laparra and Sanz, 2010; Williamson and Clifford, 2010;Rodriguez-Mateos et al., 2014). One main issue is if these compounds are able to pass the blood brain barrier (BBB), reaching significant concentrations in brain. Different families of dietary polyphenols present neuroprotective properties but they need a good permeability across the BBB to be really effective (Bisht et al., 2010;Figueira et al., 2017). At the same time low absorption rates and rapid metabolism and excretion could limit their efficacy (Almeida et al., 2016). Nevertheless, the question of the actual dose reaching the target tissues remains uncertain (Vauzour, 2012). The mechanisms by which polyphenols are able to prevent and counteract neurodegenerative diseases include interfering with amyloid aggregation, reducing oxidative stress and regulating signaling pathways and cytokines expression, with a marked effect on reducing inflammation (Ramassamy, 2006;Essa et al., 2012;Martínez-Huélamo et al., 2017;Sarubbo et al., 2017). In fact, inflammatory markers, many of them derived from activated microglia, are widely present in neurodegenerative diseases and polyphenols have been proposed as active agents having antiinflammatory effects on microglia (Sundaram and Gowtham, 2012;Peña-Altamira et al., 2017;Cayero-Otero et al., 2018). Despite the broad evidence supported by both in vitro and in vivo studies, it is worth highlighting that we should be cautious when extrapolating the findings based on cell culture or animal research to the human disease. Nevertheless, these approaches are fundamental to underpin the effects observed in human intervention studies. Recently, Weber (2015) has analyzed the inherent benefits and drawbacks of both in vitro and in vivo methodologies used for assessing neuroprotection. In summary, in vitro approaches make possible to conduct a rapid screen (and test different concentrations) to assess the potential effects of bioactives and represent a good model to glimpse the cellular effects and discern the mechanism of action. Moreover, in vitro techniques can be used to study protective activities over the course of a few weeks, compared to in vivo, that may need several months. However, the compounds are sometimes tested at concentrations that are not achieved in nervous system tissue and without taking account the different human physiological processes such digestion, metabolism and the role of gut microbiota. In addition, many cellular lines are genetically modified and consequently it may not represent the real characteristics of cells in the brain. Concerning in vivo methodology, it allows deepening to determine more adequately the protective effects of bioactives or even their metabolites in the different brain areas and enables to determine the extent dietary compounds that can pass to the brain (Weber, 2015). However, one of the most current important challenge for neurodegenerative research is to develop better animals models that properly reflect both disease etiology and progression (Franco and Cedazo-Minguez, 2014), that can replace the based massive overexpression protein animal models that are not fitted for this goal. In despite of all above mentioned, unfortunately, it has been described that only a third of the preclinical animal research are later translated at the level of human randomized trials (Hackam and Redelmeier, 2006). This review summarizes the evidence of the role of certain dietary phenolic compounds characteristic of the MD (stilbenes, HT and OLE) in mitigating microglia-mediated neuroinflammation by inhibiting key signaling pathways. SHIFT IN MICROGLIAL PHENOTYPES AS A TARGET TO COMBAT NEURODEGENERATIVE DISORDERS As stated above, neuroinflammation is a common feature shared by most neurodegenerative disease, such as AD and PD. Alzheimer’s disease, the most common form of dementia in the elderly, is characterized by the accumulation of amyloidβ(Aβ) both in the brain parenchyma (amyloid plaques) and blood vessels (cerebral amyloid angiopathy), and by the presence of neurofibrillary tangles (Wuwongse et al., 2010). AD is characterized by a progressive cognitive decline, memory loss and atrophic changes in some brain areas in response Frontiers in Cellular Neuroscience | www.frontiersin.org 3October 2018 | Volume 12 | Article 373 fncel-12-00373 October 20, 2018 Time: 18:46 # 4 Hornedo-Ortega et al. Phenolic Compounds Mitigate Microglia-Mediated Neuroinflammation to massive neuronal death and synaptic degeneration (Wenk, 2003;Wuwongse et al., 2010). There is strong evidence demonstrating a close correlation between Aβaccumulation and neuroinflammation, and the active role of the immune system in the etiology of AD. Aβis toxic to neurons by itself, which in turn overactivates microglia (Yankner et al., 1990;Heneka et al., 2010) with the subsequent deleterious effect to neurons (Block et al., 2007). PD is the second most prevalent neurodegenerative disease, affecting approximately 1–3% of the population (Obeso et al., 2000). This neurodegenerative disorder is characterized by a slow and progressive degeneration of dopaminergic neurons in the SN (Obeso et al., 2000). This loss of dopamine is responsible for many of the symptoms that accompany the disease, including motor dysfunction, mood alterations and cognitive impairment (Olanow et al., 2003). Evidence of neuroinflammation as an underlying process in PD has been accumulating since the presence of activated microglia in the substantia nigra (SN) of PD patients was first reported by McGeer et al. (1988). This increase of activated microglia is accompanied by an increase in the expression of pro-inflammatory cytokines (Tansey et al., 2007; Hirsch and Hunot, 2009). Neuroinflammation is mainly carried out by microglia cells, the macrophages of the central nervous system (CNS). Although very similar in terms of morphology and functions, peripheral macrophages and microglia have distinctive characteristics among which are their origin, functions and markers. Besides, macrophages/microglia have diverse functions that range from fighting bacterial infection to tissue regeneration and wound healing. The diverse functions of microglial cells in the CNS are mirrored by equally diverse phenotypes. A classical model of pro-inflammatory/M1 versus an antiinflammatory/M2 microglia has been extensively used. However, the complex and different functions of microglial cells can only be explained by the existence of varied and plastic microglial phenotypes mediated by distinct gene expression programs and a network of molecular pathways that relay environmental signals via signaling cascades (Amici et al., 2017). Therefore, M1 and M2 are just the extremes of a broad spectrum of phenotypes that cover the different functions of microglia. These different phenotypes can be achieved by stimulating microglial cells with different compounds. Hence, when stimulated with lipopolysaccharide (LPS) (a bacterial cell wall product of Gram-negative bacteria) and interferon gamma (IFN-γ), macrophages/microglia has long been known as classically activated or M1 (Martinez and Gordon, 2014), while when activated with IL-4 macrophages/microglia show an alternative activated phenotype or M2. In order to standardize the nomenclature and facilitate the communication of macrophage/microglia data, a novel nomenclature has been proposed in which the letter M is followed by a parenthesis that includes the stimuli used for activation (Murray et al., 2014). The knowledge of the molecular programs that control the inflammatory phenotypes versus resolution provides a unique opportunity to find new targets that allow modulating these phenotypes and, therefore, controlling the excessively inflammatory responses that accompany neurodegenerative diseases. The knowledge of these molecular mechanisms is greatly advancing in recent years. Functionally, M1 microglia is responsible for fighting infections, for which it adopts a clear pro-inflammatory phenotype with microbicidal, antigen-presenting and immuneenhancing functions. This type of microglia is characterized by the production of NO by the iNOS, encoded by the Nos2 gene; (MacMicking et al., 1997;Arnold et al., 2014) and by the expression of inflammatory chemokines and cytokines, such as interleukin IL-6, IL-12, IL-1β, IL-23, and TNF-αthat attract new cells of the immune system to the site of infection (Mosser and Edwards, 2008;Murray et al., 2014). In the context of neurodegenerative disease this phenotype produces harmful effects in the neuronal population. When neutrophils undergo apoptosis and microglia switch to a resolution/M2 phenotype, the initial acute inflammation evolves to a resolution phase (Serhan et al., 2014). This resolution/wound healing phase is mediated by lipid mediators, such as classical eicosanoids, phospholipids and sphingolipids, endocannabinoids and specialized proresolving mediators (Chiurchiù and Maccarrone, 2016), that promote the switch of microglia to the M2 phenotype (Bosurgi et al., 2017). Resolution/M2 microglia suppresses IL-12 secretion and induces the release of IL-10, TGB-β, IL-1R antagonist and decoy IL-R II (Brancato and Albina, 2011). Besides, these microglial cells induce the expression of arginase-1 instead of iNOS, switching arginine metabolism from production of NO to ornithine, and also increase polyamines production for extracellular matrix and collagen synthesis (Gordon and Martinez, 2010). This phenotype promotes the neuroregeneration and tissue repair. Taking into account the importance of inflammation in neurodegenerative diseases, the scientific community is searching for new strategies that may induce a shift in microglial cells from inflammatory and neurotoxic phenotype to an anti-inflammatory and neuroprotective one. In this sense, several compounds have shown immunomodulatory properties, making them possible candidates for co-adjuvant therapies to treat neurodegenerative diseases. RV AND OTHER STILBENES: BIOAVAILABILITY, PHARMACOKINETICS AND BLOOD–BRAIN BARRIER PERMEABILITY Stilbenes such as RV (Figure 1) are found in many plant species including Arachis hypogaea (peanut), Vitis vinifera (grape wine) and many tree species such as Picea,Pinus, and Eucalyptus (REF BD stilbenes). Stilbenes are synthetized in plants by the condensation reaction of 4-coumaroyl CoA and 3 molecules of malonyl CoA under the action of stilbene synthase (STS). STS is the key specific enzyme of stilbene-producing plants (Soleas et al., 1997). The distribution of STS and stilbenes is organ-specific and tissue-specific (Wang et al., 2010). Stilbene production is increased in response to abiotic and biotic stresses such as UV-radiations, hydric stress or infectious diseases. Concerning Frontiers in Cellular Neuroscience | www.frontiersin.org 4October 2018 | Volume 12 | Article 373 fncel-12-00373 October 20, 2018 Time: 18:46 # 5 Hornedo-Ortega et al. Phenolic Compounds Mitigate Microglia-Mediated Neuroinflammation FIGURE 1 | Chemical structure of RV and derivatives and OLE. dietary sources, stilbenes have been identified in peanuts, blueberries, and cranberries (Neveu et al., 2010). Nevertheless grape skins and red wine constitute the main primary dietary sources in the human diet (Weiskirchen and Weiskirchen, 2016). The levels of RV, the most studied stilbene, range from nondetectable levels to 29.2 mg/L in red wines (Stervbo et al., 2007). In addition to RV, red wine contains several other stilbenes such piceid (its glucoside), piceatannol and its glucoside astringin, pterostilbene, or viniferins (Pezet et al., 1994;Vitrac et al., 2005;Guebailia et al., 2006). These compounds are present as constitutive compounds of the woody organs and as induced substances in leaves and grape berries acting as phytoalexins (Vrhovsek et al., 2012;Gabaston et al., 2017). The possible beneficial effect on human health of stilbenes depends heavily on their absorption, bioavailability, and metabolism. First at all, due to its structure, RV is poorly soluble in water (<0.05 mg/mL) which could affect its bioavailability. Organic solvents such as alcohol increase its solubility. At least 70% of resveratrol ingested is absorbed, and readily metabolized to form mainly glucuronide and sulfate derivatives (Fernández- Mar et al., 2012). A rapid passive diffusion of RV and the formation of complexes with membrane transporters have been reported at the intestinal level (Delmas et al., 2011). Phase II metabolism of both resveratrol and its metabolites takes place at hepatic level (Kaldas et al., 2003;Li et al., 2003). Furthermore, it is known that RV can induce its own metabolism by increasing the activity of phase II detoxifying enzymes (Lançon et al., 2004). In addition, it has been described that RV can undergoes some returning cycles to the small intestine due to the enterohepatic transport (Crozier et al., 2009). Therefore, three different forms: glucuronide, sulfate or free RV are the main forms found in the bloodstream. At the same time, only trace amounts of unchanged RV have been detected in plasma (Walle et al., 2004). The main metabolites excreted in urine and feces (probably by enterohepatic cycle) have been RV sulfate and RV glucuronide derivatives (Marier et al., 2002). Besides, RV and its metabolites have been found distributed among various organs, such as liver, kidney, lung, brain, small intestinal mucosa, and colonic mucosa (Vitrac et al., 2003; Wenzel and Somoza, 2005). Additionally, mention should also be made of the significance of formation of RV metabolites by gut microbiota. Dihydroresveratrol (Walle et al., 2004), 3,40- dihydroxy-trans-stilbene and 3,4-dihydroxybibenzyl (lunularin) (apart from glucuronides and sulfates) have been identified as RV metabolites after microbiota biotransformation with human fecal material (Bode et al., 2013). Bioavailability of unchanged RV is very low (almost zero) due to the rapid and extensive biotransformation, despite that it shows several in vivo activities (mouse and humans) (Walle et al., 2004;Gambini et al., 2015;de Vries et al., 2018). Concerning other stilbenes, piceatannol (Figure 1) has been identified in wine and tea (Neveu et al., 2010). Its absorption, bioavailability and metabolism seem to be similar to that of RV (Piotrowska et al., 2012). In vivo experiments indicated that piceatannol is a metabolite of RV (Niles et al., 2006) an that it seems to be absorbed from the intestine after oral ingestion and rapidly metabolized to both glucuronidation and sulfation. Recent studies have identified also piceatannol metabolites such as O-methyl conjugates and isorhapontigenin (methylated derivative of piceatannol) and its conjugates demonstrating that piceatannol is not only a RV metabolite (Setoguchi et al., 2014). In addition the same authors found that piceatannol was absorbed twofold greater in the intact form than RV. All these data suggests that piceatannol has a more complicated metabolic pathway due in part to the presence of a catechol ring, which enables methylation and increases the number of pathways available Frontiers in Cellular Neuroscience | www.frontiersin.org 5October 2018 | Volume 12 | Article 373 fncel-12-00373 October 20, 2018 Time: 18:46 # 6 Hornedo-Ortega et al. Phenolic Compounds Mitigate Microglia-Mediated Neuroinflammation during its metabolism (Setoguchi et al., 2014). Nevertheless, more studies are necessary to gain more knowledge on piceatannol metabolism and to investigate its biological properties. Pterostilbene (Figure 1) is a dimethyl ether analog of RV (Wang and Sang, 2018). It has been observed in different berries (Rimando et al., 2004) and red wine (Pezet et al., 1994). It was reported that, due to its lipophilic structural characteristic, pterostilbene exhibits better bioavailability than RV (Kapetanovic et al., 2011). Pterostilbene metabolism encompasses glucuronidation and sulfatation, being this last predominant (Kapetanovic et al., 2011). Shao et al. (2010) also identified other metabolites in mice urine such as monohydroxylated and demethylated pterostilbene derivatives (Shao et al., 2010). In addition, pinostilbene (a demethylated pterostilbene) was recently identified as a mayor pterostilbene colonic metabolite in mice (Sun et al., 2016). However, no pharmacokinetic investigations of pterostilbene have been performed in humans yet. Therefore, complementary studies are also necessary for a better understanding of its metabolism and properties. Resveratrol has been the most widely stilbene studied and a great number of activities have been endorsed, including neuroprotective capacity (Fernández-Mar et al., 2012). Recently, it has been proved that RV and its major metabolites crossed the human BBB, showing CNS effects, with their measurable amounts detected in plasma and cerebrospinal fluid (CSF) (Turner et al., 2015). This fact highlights that this compound could be taken in consideration as a neuroprotective molecule. Nowadays, the study of the health effects of other stilbenes is gaining importance due to the existing evidence proving more potent activity for RV derivatives or related compounds than RV (Zghonda et al., 2011, 2012). RV AND OTHER STILBENES AND THE MOLECULAR MECHANISMS IMPLICATED IN THEIR ANTI-INFLAMMATORY ACTIVITIES Regarding the anti-inflammatory effects of stilbenes (RV and derivatives), an interesting number of works have been published being the in vitro studies more extensive than in vivo ones. In this review, a total of 23 in vitro and 6 in vivo works have been selected (Table 1). Regardless of the different clinical and pathological features between AD and PD, ultimately leading to neuronal cell death, they share common molecular mechanisms such as protein aggregation, oxidative stress, mitochondrial dysfunction and neuroinflammation (Irvine et al., 2008;Yan et al., 2013). With regard to stilbenes, it may be interesting to underline that several properties have been described including neuroprotective activities at different levels such as anti-amyloidogenic efficacy, neuroprotection via modulation of neural mediators and enzymes and interaction/modulation with different signaling pathways (Basli et al., 2012). For example, it has been demonstrated that they can act by reducing the intracellular Aβlevels and by inhibiting Aβfibril formation and toxicity in vitro (Rivière et al., 2007, 2010;Temsamani et al., 2016). Moreover, stilbenes have demonstrated to be effective freeradical scavengers protecting against oxidative stress through the activation of nuclear factor-erythroid-2-related factor-2 (Nrf2) and sirtuin 1 (SIRT1) pathways (Pallàs et al., 2009;Reinisalo et al., 2015). Additionally, oxyresveratrol (the hydroxylated derivative of RV) has shown neuroprotective effects against 6-OHDA, a catecholaminergic neurotoxin formed in PD patients, acting via the reduction of intracellular reactive oxygen species (ROS), attenuation of phospho-c-Jun N-terminal kinase (JNK)-1 and phospho-JNK-2 and increase in cytosolic SIRT1 levels (Chao et al., 2008). Furthermore, Amurensin G (a RV dimer) enhances cell viability in SH-SY5Y cells and inhibits rotenone-induced cell cycle arrest by decreasing G2/M involving an autophagic activity (Ryu et al., 2013). Similarly, amurensin G is reported to protect against Aβ(25−35)-mediated neurotoxicity in rat cerebral cortical neurons and in mice (Jeong et al., 2010). In general, several mechanisms of RV and its derivatives have been proposed on microglia-mediated neuroinflammation including: Nuclear Factor-Kappa B (NF-κB), MAPKs, Janus Kinase/Signal Transducer and Activator of Transcription (JAT/STAT) and SIRT1 pathways. NF-κB Pathway NF-κB is an important transcription factor responsible of the regulation and production of pro-inflammatory factors, including NO, TNF-α, and IL1-β(Lawrence, 2009). NF-κB is normally located in the cytoplasm by binding of its inhibitors IκBs. IκBs are rapidly phosphorylated and degraded via IKK complex when an inflammatory insult occurs, leading to the liberation of NF-κB dimers (p50 and p65). Then, these dimers are translocated to the nucleus regulating the expression of numerous target genes (TNF-α, iNOS, IL-1β, and IL-6 among others) (Tak and Firestein, 2001;Rahman and Fazal, 2011). The effect of stilbenes to prevent the nuclear translocation of NF-κB and the consequent liberation of pro-inflammatory cytokines is one of the well-known and most studied pathways. Multiple works have revealed that RV and it analogs and other stilbenes such as piceatannol are able to prevent the liberation of pro-inflammatory cytokines acting by inhibiting the NF-κB transcription and expression. Therefore, RV (0.04–43.8 µM) suppresses the degradation of IκBαin LPS-stimulated N9 microglial cells and as result of this, inhibits the iNOS expression (Bi et al., 2005). In accordance with this paper, other authors showed that RV at low concentrations (0.5–20 µM) markedly inhibited LPS-mediated nuclear translocation of NF-κB protein and transcriptional activation of NF-κB promoter in C6- microglial cells (Young et al., 2007). Moreover, using microglial and astrocytes cell lines it has been described that RV (5, 25, and 50 µM) can suppress the NFκB activation in both types of cells and also inhibits the AP- 1 in microglia (Lu et al., 2010). AP-1 also acts by activating the extracellular signal-regulated kinase (ERK) subgroup of MAPKs (Fujioka et al., 2004) being this another interesting pathway to combat neuroinflammation. Frontiers in Cellular Neuroscience | www.frontiersin.org 6October 2018 | Volume 12 | Article 373 fncel-12-00373 October 20, 2018 Time: 18:46 # 7 Hornedo-Ortega et al. Phenolic Compounds Mitigate Microglia-Mediated Neuroinflammation TABLE 1 | Summary of RV and derivatives activities (in vivo and in vitro) in counteracting neuroinflammation. Model Compounds Dose Microglia activated by Effect Reference In vivo Adult male C57/BL6 mice RV 20 mg/kg (14 consecutive days) LPS Reduction of microglia activation (Iba-1 +cells) Inhibition of the NF-κB in the hippocampus Induction of activation of SIRT1 Liu et al., 2016 Male Sprague–Dawley rats Pterostilbene 20 mg/kg (3 days) LPS Mitigation of microglial activation in rat hippocampal CA1 and dentate gyrus (DG) Inhibition of IL-6 and TNF-α mRNA expression in rat hippocampus and rat serum Hou et al., 2015 APP/PS1 transgenic mice RV ALD55: (E)-2-fluoro-4 -methoxystilbene) 100 ppm (0.01% weight) (1 year) AβReduction of microglia activation (Iba-1 +cells) Reduction of Aβplaque density Solberg et al., 2014 Male adult Wistar rats RV (Free and in lipid core nanocapsule) 10 mg/kg/day (14 consecutive days) Aβ1−42 Reduction of astrocyte and microglial activation and block JNK activation (RV in lipid core nanocapsule) Increase in phosphorylation/inactivation of GSK-3β(RV and RV in lipid core nanocapsule) Frozza et al., 2013 APP/PS1 transgenic mice RV Diet supplementation (0.35% of RV) (15 weeks) AβReduction of microglial activation (Iba-1 +cells) Capiralla et al., 2012 BALB/c aged mice RV Diet supplementation (0.4% of RV) (4 weeks) LPS Reduction of IL-1βin plasma and in hippocampus Improvement the impaired spatial working memory Abraham and Johnson, 2009 In vitro C8-B4 microglial cells RV 100 µM LPS and IFN-γReduction of NO, IL-1α, IL-1β,IL-6, and TNF-α Steiner et al., 2016 BV-2 microglial cells RV 0–30 µM Oligomeric Aβ(oAβ) Inhibition of ROS, NO, TNF-α, and IL-1β Inhibition of protein expression levels of p47phox and gp91phox (NADPH oxidase) Yao et al., 2015 N13 microglial cells RV 1–20 µM LPS Reduction of IL-1β, TNF-αand IL-6 mRNA expression Increment of IL-10 Increase of JAK1phox and STAT3phox and suppression of SOCS3 (JAK–STAT signaling pathway) Cianciulli et al., 2015 Primary microglia RV 1 µM LPS Inhibition of microglial activation Reduction of IL-1β, iNOS, COX-2 and TNF-α Blockage NF-κB stimulation Wang et al., 2015 BV-2 microglial cells Pterostilbene 1–30 µM LPS Suppression of NO, iNOS, IL-6, and TNF-αmRNA expression Inhibition of the phosphorylation of MAPKs Hou et al., 2015 N13 microglial cells RV 10 µM LPS Modulation of SOCS-1 dependent PI3K/Akt signaling cascade Reduction of ROS, SOD, p38, PI3K/Akt, NF-κB activation, NO, and iNOS Dragone et al., 2014 (Continued) Frontiers in Cellular Neuroscience | www.frontiersin.org 7October 2018 | Volume 12 | Article 373 fncel-12-00373 October 20, 2018 Time: 18:46 # 8 Hornedo-Ortega et al. Phenolic Compounds Mitigate Microglia-Mediated Neuroinflammation TABLE 1 | Continued Model Compounds Dose Microglia activated by Effect Reference Primary microglia, astrocytes, and mixed glial cell cultures BV-2 microglial cells RV 5, 10, and 20 µM Rotenone Reduction of MPO, NO, IL-1β, COX-2, TNF-α, and iNOS Reduction of gp91phox (NADPH oxidase) Attenuation of cell death in co-culture Chang et al., 2013 Rat primary cortical neuron-glia cultures RV 15–60 µM LPS Inhibition of microglial activation (decrease of Iba-1 +cells) Inhibition of TNF-α, iNOS, IL-1β, and NO Zhang et al., 2013 BV-2 microglial cells RV 50 µM LPS Aβ Inhibition of NF-κB activation (interfering with IKK and IκB phosphorylation) Reduction of IL-6, TNF-α, M-CSF, MCP-1, MCP-5, CD54, IL-1ra, IL-27, iNOS, and COX-2 Diminution of STAT1 and STAT3 Reduction of FLAG-tagged TLR4 Capiralla et al., 2012 BV-2 microglial cells RV 25–100 µM LPS Attenuation of NO, PGE2, iNOS, COX-2,TNF-α, IL-1β, and NF-κB Zhong et al., 2012 N9 microglial cells Primary microglia Primary astrocytes RV 0–50 µM LPS Inhibition of TNF-α, IL-6, MCP-1, IL-1β, and iNOS/NO Inhibition on LPS-stimulated phosphorylation of JNK in (astrocytes) Inhibition of NF-κB activation (inhibition of AP-1 activation only in microglia) Lu et al., 2010 Primary rat midbrain neuron-glia and neuron-astroglia cultures RV 60 µM LPS Reduction of NADPH oxidase-mediated generation of ROS Attenuation of translocation of NADPH p47 Implication of MAPK and NFκB signaling pathways Zhang et al., 2010 Microglial BV-2 cells RV 0–50 µM LPS Inhibition of IL-1βproduction Abraham and Johnson, 2009 N9 microglial cell line Cultured rat cortical microglia RV 0.3–30 µM LPS Suppression NO and ROS production Inhibition of iNOS Attenuation of TNF-α Blockage of IκBα phosphorylation and degradation Meng et al., 2008c Primary rat microglia 21 RV derivatives 0–30 µM LPS Reduction of iNOS Inhibition of TNF-αby blocking IκBαphosphorylation and degradation Meng et al., 2008b N9 microglial cells RV 0.1 µM LPS Reduction IL-1αand TNF-α Bureau et al., 2008 N9 microglial cells Primary rat microglial cells RV 0–30 µM LPS Inhibition of NO production and iNOS expression Meng et al., 2008a Primary microglial cell cultures RV 1–50 µM LPS Reduction of PGE2 synthesis and formation of 8-iso-PGF2α and mPGES-1 Inhibition of COX-1 Candelario-Jalil et al., 2007 (Continued) Frontiers in Cellular Neuroscience | www.frontiersin.org 8October 2018 | Volume 12 | Article 373 fncel-12-00373 October 20, 2018 Time: 18:46 # 9 Hornedo-Ortega et al. Phenolic Compounds Mitigate Microglia-Mediated Neuroinflammation TABLE 1 | Continued Model Compounds Dose Microglia activated by Effect Reference C6-microglial cells RV 0.5–20 µM LPS Inhibition of NO, PGE2, iNOS, and COX-2 Suppression of translocation and activation of NF-κB Kim et al., 2007 BV-2 microglial cells 75 trans-stilbenes LPS Inhibition the TNFα-induced activation of NFκB Diminution of COX-2 mRNA expression Heynekamp et al., 2006 BV-2 microglial cells Piceatannol 0–40 µM LPS Inhibition of the release of NO, PGE2, IL-1β, IL-6, TNF-α, iNOS and COX-2 Prevention of NF-κB p65 nuclear translocation Jin et al., 2006 Cultured rat cortical microglia and N9 microglial cells RV 0.01, 0.1, 1, and 10 µg/mL LPS Inhibition on the production of TNF-α, NO, iNOS Suppression of degradation of IκBα Reduction of phosphorylation of p38 (MAPKs signaling pathway) Bi et al., 2005 Additionally, it has been demonstrated that after stimulation of microglia either using LPS or fibrillary Aβ, RV (50 µM) inhibits the NF-κB activation upon LPS stimulation by interfering with IKK and IκB phosphorylation. As a consequence of this inhibition, they (Capiralla et al., 2012) also observed a reduction of the gene expression of IL-6, M-CSF, MCP-1, MCP-5, CD54, IL-1ra, IL-27. Furthermore, RV was able to inhibit the fibrillar Aβ-triggered increase of STAT1, STAT3, and IκBαphosphorylation and also the TNF-αand IL-6 secretion. Moreover, they also demonstrated using a transgenic mice model of AD (APP/PS1), that the supplementation of the diet with 0.35% of RV resulted in a reduction of microglial activation, observing a decrease on the number of Iba-1 cells (Capiralla et al., 2012). The blocking of NF-κB activation by RV (1 µM) has been also recently observed with primary microglia cultures after LPS-stimulation with the confirmation of the reduction of IL-1β, iNOS, COX-2, and TNF-αlevels and in consequence, the protection of primary hippocampal neurons (Wang et al., 2015). Piceatannol (20 and 40 µM) another widely known stilbene compound present in wine, has demonstrated its capacity to prevent the NF-κB p65 nuclear translocation as well as the inhibition of the release of NO, PGE-2, the inhibition of the transcription of IL-1β, IL-6 and TNF-αand the attenuation of the expression of iNOS and COX-2 mRNA and protein levels in LPS treated BV2 microglial cells (Jin et al., 2006). Furthermore, MAPKs are a highly conserved family of serine/threonine protein kinases involved in a great variety of cellular processes such as proliferation, differentiation, motility, stress response, apoptosis and survival (Mordret, 1993; L’Allemain, 1994). Extracellular ERK1/2, JNK, and p38 are the three principal components of MAPK (Cargnello and Roux, 2011;Arthur and Ley, 2013). When extracellular pathogenic and noxious stimuli induce inflammation, MAPKs are activated and translocate to the nucleus where the activation of the transcription machinery of pro-inflammatory genes giving rise to the increase of TNF-αand iNOS takes place. In addition, MAPK participates in the regulation of NF-κB transcriptional activity, thus JNK and p38 are implicated on the cytoplasmatic and nuclear NF-κB activation (Schulze-Osthoff et al., 1997). Some in vitro studies have proved that RV is a potent inhibitor of the phosphorylation of p38, ERK1/2 and JNK induced by LPS in microglial cells (Bi et al., 2005;Zhang et al., 2010;Dragone et al., 2014) and in astrocytes (Lu et al., 2010). Additionally, using lipid-core nanocapsules as a RV carrier, they observed that higher intracerebral concentrations of RV were achieved in those rats injected with Aβ1−42, this fact related with the neuroprotective effect observed. This work also reported the blockage of JNK as a mechanism associated with the protection of astrocyte and microglial activation and Aβtriggering cell disruptions (Frozza et al., 2013). Furthermore, pterostilbene (1–30 µM) significantly suppresses LPS-induced NO production and iNOS mRNA expression, IL-6 and TNF-αproduction and mRNA expression and phosphorylation of MAPKs (p38, JNK, and ERK) in BV-2 microglial cells, which also demonstrates that this pathway is involved in the observed effect. In addition, in vivo data also showed a significantly inhibition of LPS-induced IL-6 and TNF-α mRNA expression in rat hippocampus and a reduction of their amount in rat serum (Hou et al., 2015). NADPH Oxidase Pathway NADPH oxidase is recognized as the key ROS-producing enzyme during inflammation together with iNOS, and is widely expressed in various immune cells including macrophages and microglia (Hernandes and Britto, 2012). This enzyme is required for the production of ROS in activated microglia. Once NADPH oxidase is activated, the cytosolic subunits (p40phox, p47phox, p67phox, and Rac1) are translocated to the membrane-binding cytochrome b558 which consists on the union of p22phox and gp91phox forming the functional oxidase that catalyzes the reduction of oxygen to superoxide free radical (Infanger et al., 2006). Several studies have indicated that both pharmacological inhibition Frontiers in Cellular Neuroscience | www.frontiersin.org 9October 2018 | Volume 12 | Article 373 fncel-12-00373 October 20, 2018 Time: 18:46 # 16 Hornedo-Ortega et al. Phenolic Compounds Mitigate Microglia-Mediated Neuroinflammation alcohol), compared with its derivative nitrohydroxytyrosol. Neurosci Lett. 579, 173–176. doi: 10.1016/j.neulet.2014.07.037 Gambini, J., Inglés, M., Olaso, G., Lopez-Grueso, R., Bonet-Costa, V., Gimeno- Mallench, L., et al. (2015). Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans. Oxid. Med. Cell. Longev. 2015, 837042. doi: 10.1155/2015/83 7042 Gao, H. M., Zhang, F., Zhou, H., Kam, W., Wilson, B., and Hong, J. S. (2011). Neuroinflammation and α-synuclein dysfunction potentiate each other, driving chronic progression of neurodegeneration in a mouse model of Parkinson’s disease. Environ. Health Perspect. 119, 807–814. doi: 10.1289/ehp.1003013 Gardener, S., Gu, Y., Rainey-Smith, S. R., Keogh, J. B., Clifton, P. M., Mathieson, S. L., et al. (2012). Adherence to a Mediterranean diet and Alzheimer’s disease risk in an Austra lian population. Transl. Psychiatry 2:e164. doi: 10.1038/tp. 2012.91 Goldstein, D. S., Jinsmaa, Y., Sullivan, P., Holmes, C., Kopin, I. J., and Sharabi, Y. (2016). 3,4-Dihydroxyphenylethanol (Hydroxytyrosol) Mitigates the Increase in Spontaneous Oxidation of Dopamine during Monoamine Oxidase Inhibition in PC12 Cells. Neurochem. Res. 41, 2173–2178. doi: 10.1007/s11064-016-1959-0 Gordon, S., and Martinez, F. O. (2010). Alternative activation of macrophages: mechanism and functions. Immunity 32, 593–604. doi: 10.1016/j.immuni.2010. 05.007 Granados-Principal, S., El-Azem, N., Pamplona, R., Ramirez-Tortosa, C., Pulido- Moran, M., Vera-Ramirez, L., et al. (2014). Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer. Biochem. Pharmacol. 90, 25–33. doi: 10.1016/j.bcp.2014.04.001 Grossi, C., Rigacci, S., Ambrosini, S., Dami, T., Luccarini, I., Traini, C., et al. (eds) (2013). The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology. PLoS ONE 8:e71702. doi: 10.1371/journal.pone.0071702 Guebailia, H. A., Chira, K., Richard, T., Mabrouk, T., Furiga, A., Vitrac, X., et al. (2006). Hopeaphenol: The first resveratrol tetramer in wines from North Africa. J. Agric. Food Chem. 54, 9559–9564. doi: 10.1021/jf062024g Hackam, D. G., and Redelmeier, D. A. (2006). Translation of research evidence from animals to humans. JAMA 296, 1731–1732. doi: 10.1001/jama.296.14.1731 Heneka, M. T., O’Banion, M. K., Terwel, D., and Kummer, M. P. (2010). Neuroinflammatory processes in Alzheimer’s disease. J. Neural Transm. 117, 919–947. doi: 10.1007/s00702-010-0438-z Hernandes, M. S., and Britto, L. R. (2012). NADPH oxidase and neurodegeneration. Curr. Neuropharmacol. 10, 321–327. doi: 10.2174/ 157015912804143540 Hirsch, E. C., and Hunot, S. (2009). Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 8, 382–397. doi: 10.1016/S1474- 4422(09)70062-6 Heynekamp, J. J., Weber, W. M., Hunsaker, L. A., Gonzales, A. M., Orlando, R. A., Deck, L. M., et al. (2006). Substituted trans-stilbenes, including analogues of the natural product resveratrol, inhibit the human tumor necrosis factor alphainduced activation of transcription factor nuclear factor kappaB. J. Med. Chem. 49, 7182–7189. doi: 10.1021/jm060630x Hou, Y., Li, N., Xie, G., Wang, J., Yuan, Q., Jia, C., et al. (2015). Pterostilbene exerts anti-neuroinflammatory effect on lipopolysaccharide-activated microglia via inhibition of MAPK signalling pathways. J. Funct. Foods. 19, 676–687. doi: 10.1016/j.jff.2015.10.002 Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., et al. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196. doi: 10.1038/nature01960 Infanger, D. W., Sharma, R. V., and Davisson, R. L. (2006). NADPH oxidases of the brain: distribution, regulation, and function. Antioxid. Redox Signal. 8, 1583–1596. doi: 10.1089/ars.2006.8.1583 Irvine, G. B., El-Agnaf, O. M., Shankar, G. M., and Walsh, D. M. (2008). Protein aggregation in the brain: the molecular basis for Alzheimer’s and Parkinson’s diseases. Mol. Med. 14, 451–464. doi: 10.2119/2007-00100.Irvine Jeong, H. Y., Kim, J. Y., Lee, H. K., Ha do, T., Song, K. S., Bae, K., et al. (2010). Leaf andstem of Vitis amurensis and its active components protect against amyloid beta protein (25–35)-induced neurotoxicity. Arch. Pharm. Res. 33, 1655–1664. doi: 10.1007/s12272-010-1015-6 Jin, C. Y., Moon, D. O., Lee, K. J., Kim, M. O., Lee, J. D., Choi, Y. H., et al. (2006). Piceatannol attenuates lipopolysaccharide-induced NF-kappaB activation and NF-kappaB-related proinflammatory mediators in BV2 microglia. Pharmacol. Res. 54, 461–467. doi: 10.1016/j.phrs.2006.09.005 Jones, Q. R., Warford, J., Rupasinghe, H. P., and Robertson, G. S. (2012). Target-based selection of flavonoids for neurodegenerative disorders. Trends Pharmacol. Sci. 33, 602–610. doi: 10.1016/j.tips.2012.08.002 Joseph, J., Cole, G., Head, E., and Ingram, D. (2009). Nutrition, brain aging, and neurodegeneration. J. Neurosci. 29, 12795–12801. doi: 10.1523/JNEUROSCI. 3520-09.2009 Kaldas, M. I., Walle, U. K., and Walle, T. (2003). Resveratrol transport and metabolism by human intestinal caco-2 cells. J. Pharm. Pharmacol. 55, 307–312. doi: 10.1211/002235702612 Kapetanovic, I. M., Muzzio, M., Huang, Z., Thompson, T. N., and McCormick, D. L. (2011). Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemother. Pharmacol. 68, 593–601. doi: 10.1007/s00280-010-1 525-4 Kelsey, N. A., Wilkins, H. M., and Linseman, D. A. (2010). Nutraceutical antioxidants as novel neuroprotective agents. Molecules 15, 7792–7814. doi: 10.3390/molecules15117792 Kim, Y. A., Kim, G. Y., Park, K. Y., and Choi, Y. H. (2007). Resveratrol inhibits nitric oxide and prostaglandin E2 production by lipopolysaccharide-activated C6 microglia. J. Med. Food 10, 218–224. doi: 10.1089/jmf.2006.143 L’Allemain, G. (1994). Deciphering the MAP kinase pathway. Prog. Growth Factor Res. 5, 291–334. doi: 10.1016/0955-2235(94)90011-6 Lançon, A., Delmas, D., Osman, H., Thénot, J. P., Jannin, B., and Latruffe, N. (2004). Human hepatic cell uptake of resveratrol: involvement of both passive diffusion and carrier-mediated process. Biochem. Biophys. Res. Commun. 316, 1132–1137. doi: 10.1016/j.bbrc.2004.02.164 Laparra, J. M., and Sanz, Y. (2010). Interactions of gut microbiota with functional food components and nutraceuticals. Pharmacol. Res. 61, 219–225. doi: 10. 1016/j.phrs.2009.11.001 Lawrence, T. (2009). The Nuclear Factor NF-κB Pathway in Inflammation. Cold Spring Harb. Perspect. Biol. 1:a001651. doi: 10.1101/cshperspect.a00 1651 Ledeboer, A., Breve’, J. J. P., Poole, S., Tilders, F. J. H., and Van Dam, A. M. (2000). Interleukin-10, interleukin-4, and transforming growth factor-b differentially regulate lipopolysaccharide induced production of pro-inflammatory cytokines and nitric oxide in co-cultures of rat astroglial and microglial cells. Glia 30, 134–142. doi: 10.1002/(SICI)1098-1136(200004)30:2<134::AID-GLIA3>3. 0.CO;2-3 Li, Y., Shin, Y. G., Yu, C., Kosmeder, J. W., Hirschelman, W. H., Pezzuto, J. M., et al. (2003). Increasing the throughput and productivity of Caco- 2 cell permeability assays using liquid chromatography-mass spectrometry: application to resveratrol absorption and metabolism. Comb. Chem. High Throughput Screen. 6, 757–767. doi: 10.2174/138620703771826865 Licht-Murava, A., Paz, R., Vaks, L., Avrahami, L., Plotkin, B., Eisenstein, M., et al. (2016). A unique type of GSK-3 inhibitor brings new opportunities to the clinic. Sci. Signal. 9:ra110. doi: 10.1126/scisignal.aah7102 Link, C. D. (2005). Invertebrate models of Alzheimer’s disease. Genes Brain Behav. 4, 147–156. doi: 10.1111/j.1601-183X.2004.00105.x Liu, L., Zhang, Q., Cai, Y., Sun, D., He, X., Wang, L., et al. (2016). Resveratrol counteracts lipopolysaccharide-induced depressive-like behaviors via enhanced hippocampal neurogenesis. Oncotarget 7, 56045–56059. doi: 10.18632/oncotarget.11178 López de las Hazas, M. C., Piñol, C., Macià, A., Romero, M. P., Pedret, A., Solà, R., et al. (2016). Differential absorption and metabolism of hydroxytyrosol and its precursors oleuropein and secoiridoids. J. Funct. Foods 22, 52–63. doi: 10.1016/j.jff.2016.01.030 Loughrey, D. G., Lavecchia, S., Brennan, S., Lawlor, B. A., and Kelly, M. E. (2017). The impact of the mediterranean diet on the cognitive functioning of healthy older adults: a systematic review and meta-analysis. Adv. Nutr. 8, 571–586. doi: 10.3945/an.117.015495 Lu, X., Ma, L., Ruan, L., Kong, Y., Mou, H., Zhang, Z., et al. (2010). Resveratrol differentially modulates inflammatory responses of microglia and astrocytes. J. Neuroinflammation. 7:46. doi: 10.1186/1742-2094-7-46 Luccarini, I., Dami, T., Grossi, C., Rigacci, S., Stefani, M., and Casamenti, F. (eds) (2014). Oleuropein aglycone counteracts Aβ42 toxicity in the rat brain. Neurosci. Lett. 558, 67–72. doi: 10.1016/j.neulet.2013.10.062 Frontiers in Cellular Neuroscience | www.frontiersin.org 16 October 2018 | Volume 12 | Article 373 fncel-12-00373 October 20, 2018 Time: 18:46 # 17 Hornedo-Ortega et al. Phenolic Compounds Mitigate Microglia-Mediated Neuroinflammation MacMicking, J., Xie, Q. W., and Nathan, C. (1997). Nitric oxide and macrophage function. Annu. Rev. Immunol. 15, 323–350. doi: 10.1146/annurev.immunol.15. 1.323 Maiuri, M. C., De Stefano, D., Di Meglio, P., Irace, C., Savarese, M., Sacchi, R., et al. (2005). Hydroxytyrosol, a phenolic compound from virgin olive oil, prevents macrophage activation. Naunyn Schmiedebergs Arch. Pharmacol. 371, 457–465. doi: 10.1007/s00210-005-1078-y Manach, C., Scalbert, A., Morand, C., Rémés, C., and Jiménez, L. (2004). Polyphenols: food sources and bioavailability. Am. J. Clin. Nutr. 79, 727–747. doi: 10.1093/ajcn/79.5.727 Manna, C., Galletti, P., Maisto, G., Cucciolla, V., D’Angelo, S., and Zappia, V. (2000). Transport mechanism and metabolsi of olive oil hydroxytyrosol in Caco-2 cells. FEBS Lett. 470, 341–344. doi: 10.1016/S0014-5793(00)01350-8 Marier, J. F., Vachon, P., Gritsas, A., Zhang, J., Moreau, J. P., and Ducharme, M. P. (2002). Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model. J. Pharmacol. Exp. Ther. 302, 369–373. doi: 10.1124/jpet.102.033340 Martínez-Huélamo, M., Rodríguez-Morató, J., Boronat, A., and de la Torre, R. (2017). Modulation of Nrf2 by Olive Oil and Wine Polyphenols and Neuroprotection. Antioxidants 6, 73. doi: 10.3390/antiox6040073 Martinez, F. O., and Gordon, S. (2014). The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6:13. doi: 10.12703/P6-13 Martín-Peláez, S., Covas, M. I., Fitó, M., Kušar, A., and Pravst, I. (2013). Health effects of olive oil polyphenols: Recent advances and possibilities for the use of health claims. Mol. Nutr. Food Res. 57, 760–771. doi: 10.1002/mnfr.201200421 Mateos, R., Pereira-Caro, G., Saha, S., Cert, R., Redondo-Horcajo, M., Bravo, L., et al. (2011). Acetylation of hydroxytyrosol enhances its transport across differentiated Caco-2 cell monolayers. Food Chem. 125, 865–872. doi: 10.1016/ j.foodchem.2010.09.054 McGeer, P. L., Itagaki, S., and McGeer, E. G. (1988). Expression of the histocompatibility glycoprotein HLA-DR in neurological disease. Acta Neuropathol. 76, 550–557. doi: 10.1007/BF00689592 Meng, X. L., Chen, G. L., Yang, J. Y., Wang, S., Wu, C. F., and Wang, J. M. (2008a). Inhibitory effect of a novel resveratrol derivative on nitric oxide production in lipopolysaccharide-activated microglia. Pharmazie 63, 671–675. Meng, X. L., Yang, J. Y., Chen, G. L., Wang, L. H., Zhang, L. J., Wang, S., et al. (2008b). Effects of resveratrol and its derivatives on lipopolysaccharideinduced microglial activation and their structure-activity relationships. Chem. Biol. Interact. 174, 51–59. doi: 10.1016/j.cbi.2008.04.015 Meng, X. L., Yang, J. Y., Chen, G. L., Zhang, L. J., Wang, L. H., Li, J., et al. (2008c). RV09, a novel resveratrol analogue, inhibits NO and TNF-alpha production by LPS-activated microglia. Int. Immunopharmacol. 8, 1074–1082. doi: 10.1016/j. intimp.2008.03.011 Molina-Holgado, F., Grencis, R., and Rothwell, N. J. (2001). Actions of exogenous and endogenous IL-10 on glial responses to bacterial LPS/cytokines. Glia 33, 97–106. doi: 10.1002/1098-1136(200102)33:2<97::AID-GLIA1009>3.0.CO;2- N Moore, K. W., de Waal, M. R., Coffman, R. L., and O’Garra, A. (2001). Interleukin- 10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765. doi: 10.1146/annurev.immunol.19.1.683 Mordret, G. (1993). MAP kinase kinase: a node connecting multiple pathways. Biol. Cell 79, 193–207. doi: 10.1016/0248-4900(93)90138-5 Morris, M. C., Evans, D. A., Tangney, C. C., Bienias, J. L., and Wilson, R. S. (2006). Associations of vegetable and fruit consumption with age-related cognitive change. Neurology 67, 1370–1376. doi: 10.1146/annurev.immunol.19.1.683 Mosele, J. I., Martín-Peláez, S., Macià, A., Farràs, M., Valls, R. M., Catalán, Ú, et al. (2014). Faecal microbial metabolism of olive oil phenolic compounds: in vitro and in vivo approaches. Mol. Nutr. Food Res. 58, 1809–1819. doi: 10.1002/mnfr.201400124 Mosser, D. M., and Edwards, J. P. (2008). Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969. doi: 10.1038/nri2448 Murray, P. J. (2007). The JAK–STAT signaling pathway: input and output integration. J. Immunol. 178, 2623–2629. doi: 10.4049/jimmunol.178.5. 2623 Murray, P. J., Allen, J. E., Biswas, S. K., Fisher, E. A., Gilroy, D. W., Goerdt, S., et al. (2014). Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20. doi: 10.1016/j.immuni.2014.06. 008 Neveu, V., Perez-Jiménez, J., Vos, F., Crespy, V., du Chaffaut, L., Mennen, L., et al. (2010). Phenol-Explorer: an online comprehensive database on polyphenol contents in foods. Database 2010:ba024. doi: 10.1093/database/bap024 Nicolia, V., Lucarelli, M., and Fuso, A. (2014). Environment, epigenetics and neurodegeneration: Focus on nutrition in Alzheimer’s disease. Exp. Gerontol. 68, 8–12. doi: 10.1016/j.exger.2014.10.006 Niles, R. M., Cook, C. P., Meadows, G. G., Fu, Y.-M., McLaughlin, J. L., and Rankin, G. O. (2006). Resveratrol Is Rapidly Metabolized in Athymic (Nu/Nu) Mice and Does Not Inhibit Human Melanoma Xenograft Tumor Growth. J. Nutr. 136, 2542–2546. doi: 10.1093/jn/136.10.2542 Nooyens, A. C., Bueno-de-Mesquita, H. B., van Boxtel, M. P., van Gelder, B. M., Verhagen, H., and Verschuren, W. M. (2011). Fruit and vegetable intake and cognitive decline in middle-aged men and women: the Doetinchem Cohort Study. Br. J. Nutr. 106, 752–761. doi: 10.1017/S0007114511001024 North, B. J., and Verdin, E. (2004). Sirtuins: Sir2-related NAD-dependent protein deacetylases. Genome Biol. 5:224. doi: 10.1186/gb-2004-5-5-224 Obeso, J. A., Rodriguez-Oroz, M. C., Rodriguez, M., Lanciego, J. L., Artieda, J., Gonzalo, N., et al. (2000). Pathophysiology of the basal ganglia in Parkinson’s disease. Trends Neurosci. 23, S8–S19. doi: 10.1016/S1471-1931(00)00028-8 Obied, H. K., Prenzler, P. D., Omar, S. H., Ismael, R., Servili, M., Esposto, S., et al. (2012). “Chapter Six - Pharmacology of olive biophenols,” in Advances in molecular toxicology, Vol. 6, ed. J. C. Fishbein (Amsterdam: Elsevier), 195–242. Olanow, C. W., Schapira, A. H. V., and Agid, Y. (2003). Neuroprotection for Parkinson’s disease: Prospects and promises. Ann. Neurol. 53, S1–S2. doi: 10. 1002/ana.10566 Pallàs, M., Casadesús, G., Smith, M. A., Coto-Montes, A., Pelegri, C., Vilaplana, J., et al. (2009). Resveratrol and neurodegenerative diseases: activation of SIRT1 as the potential pathway towards neuroprotection. Curr. Neurovasc Res. 6, 70–81. doi: 10.2174/156720209787466019 Pantano, D., Luccarini, I., Nardiello, P., Servili, M., Stefani, M., and Casamenti, F. (2017). Oleuropein aglycone and polyphenols from olive mill waste water ameliorate cognitive deficits and neuropathology. Br. J. Clin. Pharmacol. 83, 54–62. doi: 10.1111/bcp.12993 Park, J., Min, J. S., Chae, U., Lee, J. Y., Song, K. S., Lee, H. S., et al. (2017). Anti-inflammatory effect of oleuropein on microglia through regulation of Drp1-dependent mitochondrial fission. J. Neuroimmunol. 306, 46–52. doi: 10. 1016/j.jneuroim.2017.02.019 Peña-Altamira, E., Petralla, S., Massenzio, F., Virgili, M., Bolognesi, M. L., and Monti, B. (2017). Nutritional and pharmacological strategies to regulate microglial polarization in cognitive aging and Alzheimer’s disease. Front. Aging Neurosci. 9:175. doi: 10.3389/fnagi.2017.00175 Peng, Y., Hou, C., Yang, Z., Li, C., Jia, L., Liu, J., et al. (2016). Hydroxytyrosol Mildly Improve Cognitive Function Independent of APP Processing in APP/PS1 Mice. Mol. Nutr. Food Res. 60, 2331–2342. doi: 10.1002/mnfr.201600332 Pennisi, M., Crupi, R., Di Paola, R., Ontario, M. L., Bella, R., Calabrese, E. J., et al. (2017). Inflammasomes, hormesis, and antioxidants in neuroinflammation: Role of NRLP3 in Alzheimer disease. J. Neurosci. Res. 95, 1360–1372. doi: 10.1002/jnr.23986 Perez-Mana, C., Farre, M., Rodriguez-Morato, J., Papaseit, E., Pujadas, M., Fito, M., et al. (2015). Moderate consumption of wine, through both its phenolic compounds and alcohol content, promotes hydroxytyrosol endogenous generation in humans. A randomized controlled trial. Mol. Nutr. Food Res. 59, 1213–1216. doi: 10.1002/mnfr.201400842 Peyrol, J., Riva, C., and Amiot, M. J. (2017). Hydroxytyrosol in the Prevention of the Metabolic Syndrome and Related Disorders. Nutrients 9:E306. doi: 10.3390/nu9030306 Pezet, R., Pont, V., and Cuenat, P. (1994). Method to determine resveratrol and pterostilbene in grape berries and wines using high-performance liquid chromatography and highly sensitive fluorimetric detection. J. Chromatogr. A 663, 191–197. doi: 10.1016/0021-9673(94)85245-6 Piotrowska, H., Kucinska, M., and Murias, M. (2012). Biological activity of piceatannol: Leaving the shadow of resveratrol. Mutat Res. 750, 60–82. doi: 10.1016/j.mrrev.2011.11.001 Pistollato, F., Iglesias, R. C., Ruiz, R., Aparicio, S., Crespo, J., Lopez, L. D., et al. (2018). Nutritional patterns associated with the maintenance of neurocognitive functions and the risk of dementia and Alzheimer’s disease: A focus on human studies. Pharmacol. Res. 131, 32–43. doi: 10.1016/j.phrs.2018. 03.012 Frontiers in Cellular Neuroscience | www.frontiersin.org 17 October 2018 | Volume 12 | Article 373 fncel-12-00373 October 20, 2018 Time: 18:46 # 18 Hornedo-Ortega et al. Phenolic Compounds Mitigate Microglia-Mediated Neuroinflammation Pitozzi, V., Jacomelli, M., Zaid, M., Luceri, C., Bigagli, E., Lodovici, M., et al. (2010). Effects of dietary extra-virgin olive oil on behaviour and brain biochemical parameters in ageing rats. Br. J. Nutr. 11, 1674–1683. doi: 10.1017/ S0007114509993655 Pitt, J., Roth, W., Lacor, P., Smith, A. B. III, Blankenship, M., Velasco, P., et al. (2009). Alzheimer’s-associated Abeta oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal. Toxicol. Appl. Pharmacol. 2, 189–197. doi: 10.1016/j.taap.2009.07.018 Poulain, M., Herm, A., and Pes, G. (2013). The blue zones: Areas of exceptional longevity around the world. Vienna Yearb. Popul. Res. 11, 87–108. doi: 10.1553/ populationyearbook2013s87 Price, N. L., Gomes, A. P., Ling, A. J. Y., Duarte, F. V., Martin-Montalvo, A., North, B. J., et al. (2012). SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 15, 675–690. doi: 10.1016/j.cmet.2012.04.003 Rahman, A., and Fazal, F. (2011). Blocking NF-κB: an inflammatory issue. Proc. Am. Thorac. Soc. 8, 497–503. doi: 10.1513/pats.201101-009MW Ramassamy, C. (2006). Emerging role of polyphenolic compounds in the treatment of neurodegenerative diseases: A review of their intracellular targets. Eur. J. Pharmacol. 545, 51–64. doi: 10.1016/j.ejphar.2006.06.025 Reinisalo, M., Kårlund, A., Koskela, A., Kaarniranta, K., and Karjalainen, R. O. (2015). Polyphenol Stilbenes: Molecular Mechanisms of Defence against Oxidative Stress and Aging-Related Diseases. Oxid. Med. Cell. Longev. 2015:340520. doi: 10.1155/2015/340520 Richard, N., Arnold, S., Hoeller, U., Kilpert, C., Wertz, K., and Schwager, J. (2011). Hydroxytyrosol is the major anti-inflammatory compound in aqueous olive extracts and impairs cytokine and chemokine production in macrophages. Planta Med. 77, 1890–1897. doi: 10.1055/s-0031-1280022 Rigacci, S., Guidotti, V., Bucciantini, M., Nichino, D., Relini, A., Berti, A., et al. (2011). Aβ(1–42) aggregates into non-toxic amyloid assemblies in the presence of the natural polyphenol oleuropein aglycon. Curr. Alzheimer Res. 8, 841–852. doi: 10.2174/156720511798192682 Rigacci, S., and Stefani, M. (2015). Nutraceuticals and amyloid neurodegenerative diseases: a focus on natural phenols. Expert Rev. Neurother. 15, 41–52. doi: 10.1586/14737175.2015.986101 Rimando, A. M., Kalt, W., Magee, J. B., Dewey, J., and Ballington, J. R. (2004). Resveratrol, pterostilbene, and piceatannol in Vaccinium berries. J. Agric. Food Chem. 52, 4713–4719. doi: 10.1021/jf040095e Rivière, C., Papastamoulis, Y., Fortin, P. Y., Delchier, N., Andriamanarivo, S., Waffo-Téguo, P., et al. (2010). New stilbene dimers against amyloid fibril formation. Bioorg. Med. Chem. Lett. 20, 3441–3443. doi: 10.1016/j.bmcl.2009. 09.074 Rivière, C., Richard, T., Quentin, L., Krisa, S., Mérillon, J. M., and Monti, J. P. (2007). Inhibitory activity of stilbenes on Alzheimer’s beta-amyloid fibrils in vitro. Bioorg. Med. Chem. 15, 1160–1167. doi: 10.1016/j.bmc.2006. 09.069 Robles-Almazán, M., Pulido-Moran, M., Moreno-Fernandez, J., Ramirez- Tortosa, C., Rodriguez-Garcia, C., Quiles, J. L., et al. (2018). Hydroxytyrosol: Bioavailability, toxicity, and clinical applications. Food Res. Int. 105, 654–667. doi: 10.1016/j.foodres.2017.11.053 Rodriguez-Mateos, A., Vauzour, D., Krueger, C. G., Shanmuganayagam, D., Reed, J., Calani, L., et al. (2014). Bioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: an update. Arch. Toxicol. 88, 1803–1853. doi: 10.1007/s00204-014-1330-7 Rodríguez-Morató, J., Boronat, A., Kotronoulas, A., Pujadas, M., Pastor, A., Olesti, E., et al. (2016). Metabolic disposition and biological significance of simple phenols of dietary origin: Hydroxytyrosol and tyrosol. Drug Metab. Rev. 48, 218–236. doi: 10.1080/03602532.2016.1179754 Rodríguez-Morató, J., Xicota, L., Fitó, M., Farré, M., Dierssen, M., and de la Torre, R. (2015). Potential role of olive oil phenolic compounds in the prevention of neurodegenerative diseases. Molecules 20, 4655–4680. doi: 10. 3390/molecules20034655 Romero, C., and Brenes, M. (2012). Analysis of Total Contents of Hydroxytyrosol and Tyrosol in Olive Oils. J. Agric. Food Chem. 60, 9017–9022. doi: 10.1021/ jf3026666 Roy, A., Fung, Y. K., Liu, X., and Pahan, K. (2006). Up-regulation of microglial CD11b expression by nitric oxide. J. Biol. Chem. 281, 14971–14980. doi: 10. 1074/jbc.M600236200 Rubió, L., Macià, A., Valls, R. M., Pedret, A., Romero, M. P., Solà, R., et al. (2012). A new hydroxytyrosol metabolite identified in human plasma: hydroxytyrosol acetate sulphate. Food Chem. 134, 1132–1136. doi: 10.1016/j.foodchem.2012. 02.192 Ryu, H. W., Oh, W. K., Jang, I. S., and Park, J. (2013). Amurensin G induces autophagy and attenuates cellular toxicities in a rotenone model of Parkinson’s disease. Biochem. Biophys. Res. Commun. 433, 121–126. doi: 10.1016/j.bbrc. 2013.02.053 Safouris, A., Tsivgoulis, G., Sergentanis, T. N., and Psaltopoulou, T. (2015). Mediterranean diet and risk of dementia. Curr. Alzheimer Res. 12, 736–744. doi: 10.2174/1567205012666150710114430 Salminen, A., Kaarniranta, K., and Kauppinen, A. (2013). Crosstalk between Oxidative Stress and SIRT1: Impact on the Aging Process. Int. J. Mol. Sci. 14, 3834–3859. doi: 10.3390/ijms14023834 Sarubbo, F., Moranta, D., Asensio, V. J., Miralles, A., and Esteban, S. (2017). Effects of Resveratrol and Other Polyphenols on the Most Common Brain Age-Related Diseases. Curr. Med. Chem 24, 4245–4266. doi: 10.2174/ 0929867324666170724102743 Scarmeas, N., Stern, Y., Mayeux, R., Manly, J. J., Schupf, N., and Luchsinger, J. A. (2009). Mediterranean diet and mild cognitive impairment. Arch. Neurol. 66, 216–225. doi: 10.1001/archneurol.2008.536 Scapagnini, G., Vasto, S., Abraham, N. G., Caruso, C., Zella, D., and Fabio, G. (2011). Modulation of Nrf2/ARE pathway by food polyphenols: a nutritional neuroprotective strategy for cognitive and neurodegenerative disorders. Mol. Neurobiol. 44, 192–201. doi: 10.1007/s12035-011-8181-5 Scarmeas, N., Stern, Y., Tang, M. X., Mayeux, R., and Luchsinger, J. A. (2006). Mediterranean diet and risk for Alzheimer’s disease. Ann. Neurol. 6, 912–921. doi: 10.1002/ana.20854 Schulze-Osthoff, K., Ferrari, D., Riehemann, K., and Wesselborg, S. (1997). Regulation of NF-κB Activation by MAP Kinase Cascades. Immunobiology 198, 35–49. doi: 10.1016/S0171-2985(97)80025-3 Selma, M. V., Espín, J. C., and Tomás-Barberán, F. A. (2009). Interaction between phenolics and gut microbiota: Role in human health. J. Agric. Food Chem. 57, 6485–6501. doi: 10.1021/jf902107d Serhan, C. N., Chiang, N., Dalli, J., and Levy, B. D. (2014). Lipid mediators in the resolution of inflammation. Cold Spring Harb. Perspect. Biol. 7:a016311. doi: 10.1101/cshperspect.a016311 Serra, A., Rubio, L., Borras, X., Macia, A., Romero, M. P., and Motilva, M. J. (2012). Distribution of olive oil phenolic compounds in rat tissues after administration of a phenolic extract from olive cake. Mol. Nutr. Food Res. 56, 486–496. doi: 10.1002/mnfr.201100436 Servili, M., Selvaggini, R., Esposto, S., Taticchi, A., Montedoro, G., and Morozzi, G. (2004). Health and sensory properties of virgin olive oil hydrophilic phenols: Agronomic and technological aspects of production that affect their occurrence in the oil. J. Chromatogr. A 1054, 113–127. doi: 10.1016/j.chroma.2004. 08.070 Setoguchi, Y., Oritani, Y., Ito, R., Inagaki, H., Maruki-Uchida, H., Ichiyanagi, T., et al. (2014). Absorption and Metabolism of Piceatannol in Rats. J. Agric. Food Chem. 62, 2541–2548. doi: 10.1021/jf404694y Shao, X., Chen, X., Badmaev, V., Ho, C. T., and Sang, S. (2010). Structural identification of mouse urinary metabolites of pterostilbene using liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 24, 1770–1778. doi: 10.1002/rcm.4579 Shuai, K., and Liu, B. (2003). Regulation of JAK-STAT signalling in the immune system. Nat. Rev. Immunol. 3, 900–911. doi: 10.1038/nri1226 Singh, M., Arseneault, M., Sanderson, T., Murthy, V., and Ramassamy, C. (2008). Challenges for research on polyphenols from foods in Alzheimer’s disease: bioavailability, metabolism, and cellular and molecular mechanisms. J. Agric. Food Chem. 56, 4855–4873. doi: 10.1021/jf0735073 Singh, B., Parsaik, A. K., Mielke, M. M., Erwin, P. J., Knopman, D. S., Petersen, R. C., et al. (2014). Association of Mediterranean diet with mild cognitive impairment and Alzheimers disease: A systematic review and meta-analysis. J. Alzheimer’s Dis. 39, 271–282. doi: 10.3233/JAD-130830 Soleas, G. J., Diamandis, E. P., and Goldberg, D. M. (1997). Resveratrol: A molecule whose time has come? And gone? Clin. Biochem. 30, 91–113. doi: 10.1016/ S0009-9120(96)00155-5 Spencer, J. P. (2010). The impact of fruit flavonoids on memory and cognition. Br. J. Nutr. 104, S40–S47. doi: 10.1017/S0007114510003934 Frontiers in Cellular Neuroscience | www.frontiersin.org 18 October 2018 | Volume 12 | Article 373 fncel-12-00373 October 20, 2018 Time: 18:46 # 19 Hornedo-Ortega et al. Phenolic Compounds Mitigate Microglia-Mediated Neuroinflammation Solberg, N. O., Chamberlin, R., Vigil, J. R., Deck, L. M., Heidrich, J. E., Brown, D. C., et al. (2014). Optical and SPION-enhanced MR imaging shows that transstilbene inhibitors of NF-κB concomitantly lower Alzheimer’s disease plaque formation and microglial activation in AβPP/PS-1 transgenic mouse brain. J. Alzheimers Dis. 40, 191–212. doi: 10.3233/JAD-131031 Starr, R., Willson, T. A., Viney, E. M., Murray, L. J. L., Rayner, J. R., Jenkins, B. J., et al. (1997). A family of cytokine-inducible inhibitors of signalling. Nature 387, 917–921. doi: 10.1038/43206 Stervbo, U., Vang, O., and Bonnesen, C. (2007). A review of the content of the putative chemopreventive phytoalexin resveratrol in red wine. Food Chem. 101, 449–457. doi: 10.1016/j.foodchem.2006.01.047 Steiner, N., Balez, R., Karunaweera, N., Lind, J. M., Münch, G., and Ooi, L. (2016). Neuroprotection of Neuro2a cells and the cytokine suppressive and anti-inflammatory mode of action of resveratrol in activated RAW264.7 macrophages and C8-B4 microglia. Neurochem. Int. 95, 46–54. doi: 10.1016/j. neuint.2015.10.013 Sun, Y., Wu, X., Cai, X., Song, M., Zheng, J., Pan, C., et al. (2016). Identification of pinostilbene as a major colonic metabolite of pterostilbene and its inhibitory effects on colon cancer cells. Mol. Nutr. Food Res. 60, 1924–1932. doi: 10.1002/ mnfr.201500989 Sundaram, R. S., and Gowtham, L. (2012). Microglia and regulation of inflammation-mediated neurodegeneration: Prevention and treatment by phytochemicals and metabolic nutrients. Int. J. Green Pharm. 6, 81–92. doi: 10.4103/0973-8258.102807 Tak, P. P., and Firestein, G. S. (2001). NF-kappaB: a key role in inflammatory diseases. J. Clin. Invest. 107, 7–11. doi: 10.1172/JCI11830 Takeda, Y., Bui, V. N., Iwasaki, K., Kobayashi, T., Ogawa, H., and Imai, K. (2014). Influence of olive-derived hydroxytyrosol on the toll-like receptor 4-dependent inflammatory response of mouse peritoneal macrophages. Biochem. Biophys. Res. Commun. 446, 1225–1230. doi: 10.1016/j.bbrc.2014.03.094 Tangney, C. C., Kwasny, M. J., Li, H., Wilson, R. S., Evans, D. A., and Morris, M. C. (2011). Adherence to a Mediterranean-type dietary pattern and cognitive decline in a community population. Am. J. Clin. Nutr. 3, 601–607. doi: 10.3945/ ajcn.110.007369 Tansey, M. G., McCoy, M. K., and Frank-Cannon, T. C. (2007). Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp. Neurol. 208, 1–25. doi: 10.1016/j.expneurol.2007.07.004 Temsamani, H., Krisa, S., Decossas-Mendoza, M., Lambert, O., Mérillon, J. M., and Richard, T. (2016). Piceatannol and Other Wine Stilbenes: A Pool of Inhibitors against α-Synuclein Aggregation and Cytotoxicity. Nutrients 8:367. doi: 10.3390/nu8060367 Tuck, K. L., Freeman, M. P., Hayball, P. J., Stretch, G. L., and Stupans, I. (2001). The in vivo fate of hydroxytyrosol and tyrosol, antioxidant phenolic constituents of olive oil, after intravenous and oral dosing of labeled compounds to rats. J. Nutr. 131, 1993–1996. doi: 10.1093/jn/131.7.1993 Tuck, K. L., and Hayball, P. J. (2002). Major phenolic compounds in olive oil: Metabolism and health effects. J. Nutr. Biochem. 13, 636–644. doi: 10.1016/ S0955-2863(02)00229-2 Turner, R. S., Thomas, R. G., Craft, S., van Dyck, C. H., Mintzer, J., Reynolds, B. A., et al. (2015). A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease. Neurology 85, 1383–1391. doi: 10.1212/WNL. 0000000000002035 Valls-Pedret, C., Lamuela-Raventos, R. M., Medina-Remon, A., Quintana, M., Corella, D., Pintó, X., et al. (2012). Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk. J. Alzheimers Dis. 4, 773–782. doi: 10.3233/JAD-2012- 111799 Valls-Pedret, C., Sala-Vila, A., Serra-Mir, M., Corella, D., de la Torre, R., Martinez- Gonzalez, M. A., et al. (2015). Mediterranean diet and age-related cognitive decline: A randomized clinical trial. JAMA Intern. Med. 175, 1094–1103. doi: 10.1001/jamainternmed.2015.1668 Vauzour, D. (2012). Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. Oxid Med Cell Longev. 2012:914273. doi: 10.1155/2012/914273 Vauzour, D., Corsini, S., Müller, M., and Spencer, J. P. E. (2018). Inhibition of PP2A by hesperetin may contribute to Akt and ERK1/2 activation status in cortical neurons. Arch. Biochem. Biophys. 650, 14–21. doi: 10.1016/j.abb.2018.04.020 Visioli, F., and Bernardini, E. (2011). Extra virgin olive oil’s polyphenols: Biological activities. Curr. Pharm. Des. 17, 786–804. doi: 10.2174/138161211795428885 Visioli, F., Caruso, D., Plasmati, E., Patelli, R., Mulinacci, N., Romani, A., et al. (2001). Hydroxytyrosol, as a component of olive mill waste water, is dose dependently absorbed and increases the antioxidant capacity of rat plasma. Free Radic. Res. 34, 301–305. doi: 10.1080/10715760100300271 Visioli, F., Galli, C., Bornet, F., Mattei, A., Patelli, R., Galli, G., et al. (2000). Olive oil phenolics are dose-dependently absorbed in humans. FEBS Lett. 468, 159–160. doi: 10.1016/S0014-5793(00)01216-3 Visioli, F., Galli, C., Grande, S., Colonnelli, K., Patelli, C., Galli, G., et al. (2003). Hydroxytyrosol excretion differs between rats and humans and depends on the vehicle of administration. J. Nutr. 133, 2612–2615. doi: 10.1093/jn/133.8. 2612 Vissers, M. N., Zock, P. L., and Katan, M. B. (2004). Bioavailability and antioxidant effects of olive oil phenols in humans: a review. Eur. J. Clin. Nutr. 58, 955–965. doi: 10.1038/sj.ejcn.1601917 Vissers, M. N., Zock, P. L., Roodenburg, A. J., Leenen, R., and Katan, M. B. (2002). Olive oil phenols are absorbed in humans. J. Nutr. 132, 409–417. doi: 10.1093/jn/132.3.409 Vitrac, X., Bornet, A., Vanderlinde, R., Valls, J., Richard, T., Delaunay, J. C., et al. (2005). Determination of stilbenes (delta-viniferin, trans-astringin, transpiceid, cis- and trans-resveratrol, epsilon-viniferin) in Brazilian wines. J. Agric. Food Chem. 53, 5664–5669. doi: 10.1021/jf050122g Vitrac, X., Desmoulière, A., Brouillaud, B., Krisa, S., Deffieux, G., Barthe, N., et al. (2003). Distribution of [14C]-trans-resveratrol, a cancer chemopreventive polyphenol, in mouse tissues after oral administration. Life Sci. 72, 2219–2233. doi: 10.1016/S0024-3205(03)00096-1 Vrhovsek, U., Malacarne, G., Masuero, D., Zulini, L., Guella, G., Stefanini, M., et al. (2012). Profiling and accurate quantification of trans-resveratrol, transpiceid, trans-pterostilbene and 11 viniferins induced by Plasmopara viticola in partially resistant grapevine leaves. Aust. J. Grape Wine Res. 18, 11–19. doi: 10.1111/j.1755-0238.2011.00163.x Walle, T., Hsieh, F., DeLegge, M. H., Oatis, J. E., and Walle, U. K. (2004). High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab. Dispos. 32, 1377–1382. doi: 10.1124/dmd.104.000885 Wang, F., Cui, N., Yang, L., Shi, L., Li, Q., Zhang, G., et al. (2015). Resveratrol Rescues the Impairments of Hippocampal Neurons Stimulated by Microglial Over-Activation In Vitro. Cell. Mol. Neurobiol. 35, 1003–1015. doi: 10.1007/ s10571-015-0195-5 Wang, W., Tang, K., Yang, H. R., Wen, P. F., Zhang, P., Wang, H. L., et al. (2010). Distribution of resveratrol and stilbene synthase in young grape plants (Vitis vinifera L. cv. Cabernet Sauvignon) and the effect of UV-C on its accumulation. Plant Physiol. Biochem. 48, 142–152. doi: 10.1016/j.plaphy.2009.12.002 Wang, P., and Sang, S. (2018). Metabolism and pharmacokinetics of resveratrol and pterostilbene. Biofactors 44, 16–25. doi: 10.1002/biof.1410 Weber, J. T. (2015). Methodologies and limitations in the analysis of potential neuroprotective compounds derived from natural products. New Horiz. Transl. Med. 2, 81–85. Weiskirchen, S., and Weiskirchen, R. (2016). Resveratrol: How Much Wine Do You Have to Drink to Stay Healthy? Adv. Nutr. 7, 706–718. doi: 10.3945/an. 115.011627 Wenk, G. L. (2003). Neuropathologic changes in Alzheimer’s disease. J. Clin. Psychiatry 64, 7–10. Wenzel, E., and Somoza, V. (2005). Metabolism and bioavailability of transresveratrol. Mol. Nutr. Food Res. 49, 472–481. doi: 10.1002/mnfr.200500010 WHO (2015). World Report on Ageing and Health 2015. Geneva: World Health Organization. WHO (2017). Global Action Plan on the Public Health Response to Dementia 2017-2025. Geneva: World Health Organization. WHO (2018). Towards a dementia plan: a WHO guide. Geneva: World Health Organization. Williamson, G., and Clifford, M. N. (2010). Colonic metabolites of berry polyphenols: the missing link to biological activity? Br J Nutr. 104, S48–S66. doi: 10.1017/S0007114510003946 Wu, Y. T., Lin, L. C., and Tsai, T. H. (2009). Measurement of free hydroxytyrosol in microdialysates from blood and brain of anesthetized rats by liquid chromatography with fluorescence detection. J. Chromatogr. A 1216, 3501– 3507. doi: 10.1016/j.chroma.2008.10.116 Frontiers in Cellular Neuroscience | www.frontiersin.org 19 October 2018 | Volume 12 | Article 373 fncel-12-00373 October 20, 2018 Time: 18:46 # 20 Hornedo-Ortega et al. Phenolic Compounds Mitigate Microglia-Mediated Neuroinflammation Wuwongse, S., Chang, R. C., and Law, A. C. (2010). The putative neurodegenerative links between depression and Alzheimer’s disease. Prog. Neurobiol. 91, 362–375. doi: 10.1016/j.pneurobio.2010.04.005 Xu, L. C., and Sim, M. K. (1995). Reduction of dihydroxyphenylacetic acid by a novel enzyme in rat brain. Biochem. Pharmacol. 50, 1333–1337. Yan, M. H., Wang, X., and Zhu, X. (2013). Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic. Biol. Med. 62, 90–101. doi: 10.1016/j.freeradbiomed.2012.11.014 Yankner, B. A., Duffy, L. K., and Kirschner, D. A. (1990). Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides. Science 250, 279–282. Yao, Y., Li, J., Niu, Y., Yu, J. Q., Yan, L., Miao, Z. H., et al. (2015). Resveratrol inhibits oligomeric Aβ-induced microglial activation via NADPH oxidase. Mol. Med. Rep. 12, 6133–6139. doi: 10.3892/mmr.2015.4199 Yeung, F., Hoberg, J. E., Ramsey, C. S., Keller, M. D., Jones, D. R., Frye, R. A., et al. (2004). Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369–2380. doi: 10.1038/sj.emboj.7600244 Young, A. K., Gi-Young, K., Kun-Young, P., and Yung Hyun, C. (2007). Resveratrol Inhibits Nitric Oxide and Prostaglandin E2 Production by Lipopolysaccharide-Activated C6 Microglia. J. Med. Food 10, 218–224. doi: 10.1089/jmf.2006.143 Yuskaitis, C. J., and Jope, R. S. (2009). Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity. Cell. Signal. 21, 264–273. doi: 10.1016/j.cellsig.2008.10.014 Zghonda, N., Yoshida, S., Araki, M., Kusunoki, M., Mliki, A., Ghorbel, A., et al. (2011). Greater effectiveness of ε-viniferin in red wine than its monomer resveratrol for inhibiting vascular smooth muscle cell proliferation and migration. Biosci. Biotechnol. Biochem. 75, 1259–1267. doi: 10.1271/bbb.110022 Zghonda, N., Yoshida, S., Ezaki, S., Otake, Y., Murakami, C., Mliki, A., et al. (2012). ε-Viniferin is more effective than its monomer resveratrol in improving the functions of vascular endothelial cells and the heart. Biosci. Biotechnol. Biochem. 76, 954–960. doi: 10.1271/bbb.110975 Zhang, F., Shi, J. S., Zhou, H., Wilson, B., Hong, J. S., and Gao, H. M. (2010). Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity through its anti-inflammatory actions. Mol. Pharmacol. 78, 466–477. doi: 10.1124/mol.110.064535 Zhang, F., Wang, H., Wu, Q., Lu, Y., Nie, J., Xie, X., et al. (2013). Resveratrol protects cortical neurons against microglia-mediated neuroinflammation. Phytother. Res. 27, 344–349. doi: 10.1002/ptr.4734 Zhong, L., Zong, Y., Sun, L., Guo, J., Zhang, W., He, Y., et al. (2012). Resveratrol Inhibits Inflammatory Responses via the Mammalian Target of Rapamycin Signaling Pathway in Cultured LPS-Stimulated Microglial Cells. PLoS ONE 7:e32195. doi: 10.1371/journal.pone.003 2195 Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Copyright © 2018 Hornedo-Ortega, Cerezo, de Pablos, Krisa, Richard, García- Parrilla and Troncoso. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Cellular Neuroscience | www.frontiersin.org 20 October 2018 | Volume 12 | Article 373