Effects of pterostilbene and resveratrol on brain and behavior

Neurochemistry International xxx (2015) 1e7

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Effects of pterostilbene and resveratrol on brain and behavior Shibu M. Poulose, Nopporn Thangthaeng, Marshall G. Miller, Barbara Shukitt-Hale* USDA-Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA

a r t i c l e i n f o

a b s t r a c t

Article history: Received 19 May 2015 Received in revised form 20 July 2015 Accepted 22 July 2015 Available online xxx

Age is the greatest universal risk factor for neurodegenerative diseases. During aging, these conditions progress from minor loss of function to major disruptions in daily life, loss of independence and ultimately death. Because approximately 25% of the world population is expected to be older than age 65 by 2050, and no treatments exist to halt or reverse ongoing neurodegeneration, the need for effective prevention strategies is more pressing that ever before. A growing body of research supports the role of diet in healthy aging, particularly diets rich in bioactive phytochemical compounds. Recently, stilbenes such as resveratrol (3, 5, 40 -trans-trihydroxystilbene) and its analogue, pterostilbene, have gained a significant amount of attention for their potent antioxidant, anti-inflammatory, and anticarcinogenic properties. However, evidence for the beneficial effects of stilbenes on cerebral function is just beginning to emerge. In this review, we summarize the current knowledge on the role of resveratrol and pterostilbene in improving brain health during aging, with specific focus on antioxidant and antiinflammatory signaling and behavioral outcomes. Published by Elsevier Ltd.

Keywords: Pterostilbene Resveratrol Polyphenols Inflammation Aging Brain-signaling

Among many competing theories, aging is the result of chronic, sustained inflammation and oxidative stress, leading to damage to lipids, proteins and nucleic acids, which, in the brain, cause progressive degeneration and death of neurons, leading to behavioral decline (Joseph et al., 2005; Quintanilla et al., 2012). Numerous epidemiological studies have linked diets rich in natural antioxidants and anti-inflammatory compounds from fruits, nuts, vegetables and spices to slower age-related behavioral declines and lower incidence of neurodegenerative diseases (Lau et al., 2007; Miller and Shukitt-Hale, 2012; Poulose et al., 2012). Furthermore, studies performed in our laboratory and others report improvement in cognitive and motor performance when laboratory animals were fed with diets supplemented with fruits, vegetables, or nuts (Shukitt-Hale et al., 2008; Willis et al., 2009). Early experiments revealed the antioxidant and anti-inflammatory properties of the phytochemicals found in these foods (Joseph et al., 2010); however, additional mechanisms of action have since been discovered, including synaptic plasticity, transcriptional regulation, neuronal signaling, autophagy, and receptor function (Miller and ShukittHale, 2012; Poulose et al., 2014a). In the late 1980s, French epidemiologists found that, despite

* Corresponding author. Neuroscience and Aging Lab USDA HNRCA at Tufts University 711 Washington Street, Boston, MA 02111, USA. E-mail address: [email protected] (B. Shukitt-Hale).

high dietary cholesterol and saturated fat intake, France had a low incidence and mortality rate due to coronary heart disease, as well as certain types of cancer. These findings quickly gained popularity and this phenomenon was later coined the ‘French paradox’ (de Lorgeril et al., 2002; Renaud and de Lorgeril, 1992). In 1992, it was hypothesized that a compound found in wine, i.e., resveratrol (trans-3,40 ,5-trihydroxystilbene; RES), may be accountable for the French paradox (Renaud and de Lorgeril, 1992). Resveratrol, a nonflavonoid polyphenol in the stilbene group, was first detected in the roots of white hellebore (Veratrum grandiflorum) (Tome-Carneiro et al., 2013). Today, RES has been detected in various food sources, such as grapes, berries, red wine, chocolate and peanuts (Paul et al., 2010) and remains the most well-known stilbene. Like RES, pterostilbene (trans-3,5-dimethoxy-4hydroxystilbene; PTE) is a stilbenoid, dimethylated analog of resveratrol, allowing it to have a higher bioavailability than resveratrol; it is found in grapes, blueberries and heartwood (Pterocarpus marsupium) (McCormack and McFadden, 2013). Over the last two decades, more than 2500 research articles have reported the health benefits of RES and other stilbenes. These beneficial health effects include life-span extension, weight loss, and protection against cardiovascular disease, neurodegenerative disease, stroke-induce brain damage, cancer, and cancer metastasis (Kasiotis et al., 2013; McCormack and McFadden, 2013). However, only more recently have the beneficial effects of stilbenes on cerebral function started to emerge. This review will summarize the current knowledge of the effects of

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Please cite this article in press as: Poulose, S.M., et al., Effects of pterostilbene and resveratrol on brain and behavior, Neurochemistry International (2015), http://dx.doi.org/10.1016/j.neuint.2015.07.017

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resveratrol and pterostilbene in improving brain health during aging, with a focus on antioxidant and anti-inflammatory signaling and behavioral outcomes. 1. Structure, biosynthesis and bioavailability of resveratrol and pterostilbene Resveratrol and PTE belong to a group of phytochemicals known as stilbenoids, which biosynthesize as part of a plant's defense mechanism in response to biotic and abiotic stress, such as infection, insect infestation, heat and ultraviolet exposure (Langcake and Pryce, 1977). All stilbenoids have two aromatic rings connected by a methylene bridge backbone, where either hydroxyl, methyl, methoxy, prenyl, or geranyl can be substituted, and sugars can be combined to form glycosides, producing a group of compounds with diverse chemical structures and properties. Stilbenes are predominantly found in the trans-isomer in nature due to the increase in stability; however, cis-isomer is sometimes detected (Borriello et al., 2010). In plants, stilbene biosynthesis shares similar substrates and biosynthetic pathways with flavonoids. Even though most plants produce flavonoids, only a few species of plants synthesize stilbenes. The biosynthetic pathway of stilbenes starts with phenylalanine, which undergoes multiple enzymatic reactions to produce p-coumaroyl-CoA. Then, in the presence of malonyl-CoA and stilbene synthase, RES is produced via aldol reaction (Fig. 1). RES is converted to produce PTE through an O-Methyltransferase-facilitated reaction. Despite their structural similarity, PTE is found to be more bioavailable (80%) than RES (20%) (Kapetanovic et al., 2011). This is, in part, due to the presence of two methoxy-groups on PTE, making it more lipophilic (Cichocki et al., 2008) and increasing oral bioavailability (Kapetanovic et al., 2011). A study by Chang and colleagues demonstrated that PTE was found at higher concentrations in the serum and brain than RES when given at the same dose to both male and female mice for 8 weeks (Chang et al., 2012). Oral administration of RES in humans has a high absorption rate but low bioavailability due to its extensive first pass and short halflife (Cottart et al., 2010). Approximately 50e98% of absorbed RES is

non-covalently bound to albumin, low density lipoprotein, and hemoglobin (Jannin et al., 2004; Lu et al., 2007). Pharmacokinetic studies in humans and animal models show that RES is rapidly metabolized by phase II enzymes in the intestine and liver to produce glucuronide and sulfate derivatives, leaving approximately 1% of the parent compound in circulation (Rotches-Ribalta et al., 2012). The major metabolites of RES detected in plasma are resveratrol-3-O-sulfate and resveratrol-3-O-glucuronice, and it has been estimated that approximately half of these metabolites are bound to plasma proteins (Burkon and Somoza, 2008). Intravenous administration of RES to rats showed that plasma RES has a half-life of 0.13 h (Marier et al., 2002) and 70e98% of RES can be recovered from urine and feces within 24 h after ingestion (Boocock et al., 2007a,b). Moreover, colon microbes have been reported to metabolize unabsorbed RES to produce dihydroresveratrol (Juan et al., 2010). The contribution of RES metabolites to resveratrol's overall health benefits has yet to be determined. The bloodebrain barrier prevents 98% of small molecules and 100% of large molecules from reaching the brain (Kanwar et al., 2012). To date, there is limited information on how RES and PTE cross the blood-brain barrier (BBB) or localize within the brain. A recent study by Ouzzine and colleagues (2014) suggests that the RES metabolites, glucuronides and sulfo-conjugates, cross the BBB via UDP-glucuronosyltransferases (UGTs). However, only a small percent of RES crossed BBB and accumulated in the brain. Vitrac and coworkers reported that when a single dose of 14C-RES (50 mg/ kg body weight) was given orally, only 6.1 mg of RES glucoside/g (tissue weight) was detected in the mouse brain (Vitrac et al., 2003). Few studies indicate the beneficial effect of resveratrol when administered to the rats via intraperitoneal injections (Sinha et al., 2002; Wang et al., 2002). In Mongolian gerbils, i.p. injections of 30 mg/kg of RES decreased neuronal death in the CA1 region of the hippocampus 4 days after ischemia, which was mediated via reduced glial cell activation (Wang et al., 2002). Similarly, in male Wistar rats, which were subjected to focal ischemia by middle cerebral artery occlusion, an i.p. injection of 20 mg/kg of trans-RES for 21 days prevented motor impairment (Sinha et al., 2002). It is generally assumed that PTE can also cross the BBB due to its structural similarities to and better intestinal absorption than RES (Temsamani and Merillon, 2015). Few studies offer insights into the neuroavailability and tissue distribution of PTE within the brain. Joseph and coworkers (2008) have shown that dietary supplementation of PTE at 2.5 mg/kg (low dose) or 10 mg/kg (high dose) for 12e13 weeks in 19-month-old Fischer rats had detectable levels of PTE in the serum with around 4 ng/mL at the low dose and about 25e30 ng/ml at the high dose. However, when measured in the hippocampus, only the high dose had detectable levels (1.5 ng/g of hippocampal tissue). These studies independently confirm that RES is neuroavailable and exerts neuroprotective effects. 2. Effects of pterostilbene and resveratrol during cellular stress in brain

Fig. 1. General biosynthesis pathway for resveratrol and stilbenes.

Oxidative damage, alteration in Ca2þ homeostasis, and loss of autophagy function in the brain cause disruption in numerous signaling pathways and alterations in protein homeostasis, which contribute to the loss of cognitive function during aging (Poulose et al., 2014b; Thibault et al., 2007; Yamaguchi, 2012). Both RES and PTE have been shown to protect cells from oxidative stress, excitotoxicity, and dysregulation of autophagy (Jeong et al., 2012; Ko et al., 2015). In vitro studies suggest that both RES and PTE can scavenge and neutralize superoxide, hydroxyl, and metal-induced radicals (Rossi et al., 2013; Saw et al., 2014). Besides acting as a ROS scavenger, RES has been demonstrated to activate intracellular signaling necessary to mount anti-oxidative defenses. A study by

Please cite this article in press as: Poulose, S.M., et al., Effects of pterostilbene and resveratrol on brain and behavior, Neurochemistry International (2015), http://dx.doi.org/10.1016/j.neuint.2015.07.017

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Frombaum and colleagues (Frombaum et al., 2012) demonstrated that RES (50 or 100 mM) protected HT22 cells, a hippocampal neuronal cell-line, against glutamate-induced oxidative stress and neurotoxicity by activating PI3K/Akt and GSK-3b/b-catenin signaling pathways to induce manganese superoxide-dismutase (MnSOD) expression and thereby reduce mitochondrial dysregulation. Moreover, at high doses, RES has been shown to modulate MnSOD expression through the SIRT1/FOXO pathway both in vitro (Danz et al., 2009) and in vivo (Kao et al., 2010; Pfluger et al., 2008). RES can effectively activate the nuclear factor erythroid-related factor 2/antioxidant responsive element (Nrf2/ARE) pathway, a major cellular antioxidant enzyme system (Ungvari et al., 2009, 2007). Studies using an ischemia/reperfusion model (Ren et al., 2011; Sinha et al., 2002) and a neuronal cell-line (PC 12 cells) (Chen et al., 2005) demonstrate that RES treatment attenuates elevation of lipid peroxidation through activation of the Nrf2/ARE pathway, which up-regulates heme-oxygenase 1 (HO1) and superoxide-dismutases (SODs) expression. In an ischemia/reperfusion animal model, the reduction in oxidative stress by RES via Nrf2/ARE activation reduced motor impairment and infarct size (Ren et al., 2011; Sinha et al., 2002). Recently, a study by Li and colleagues provided further evidence supporting the role of RES in Nrf2/ARE activation. In this study, exposure of the dimerized form, but not any other form, of RES (30 mM) directly increased Nrf2 transcriptional activities in vitro (Li et al., 2015a). Taken together, these results suggest that RES activates Nrf/ARE in a structurally specific mechanism, possibly binding directly to Nrf2 or Keap-1; however, the exact mechanism is not yet defined. Besides the aforementioned pathways, there is evidence suggesting that RES is able to up-regulate signaling molecules that are linked to multiple pathways, such as elevating cAMP levels, peroxisome proliferator activated receptor-gamma coactivator 1a (PGC-1a) activity, and SIRT1 (Baur et al., 2006; Park et al., 2012). Like RES, a diet supplemented with PTE was found to increase MnSOD expression in an accelerated aging/Alzheimer's mouse model (SAMP8) when compared to those on control diet (Chang et al., 2012). The up-regulation of MnSOD by PTE was independent of the SIRT1/FOXO pathway (Chang et al., 2012). However, recent evidence suggests that PTE is a potent ARE inducer (Saw et al., 2014), which may explain the increase in MnSOD observed in SAMP8 mice fed a PTE-supplemented diet. Interestingly, activation of the Nrf2/ARE pathway by PTE has only been associated with non-neuronal cells (Chiou et al., 2011; Saw et al., 2014; Sirerol et al., 2015; Zhang et al., 2014). Although RES and PTE are effective at attenuating oxidative stress, high doses of RES and PTE may inhibit normal immune response to pathogens and alter endogenous antioxidant defense systems. A study by Zhang and colleagues (Zhang et al., 2010b) reported that RES pretreatment inhibited lipopolysaccharide (LPS)induced activation of microglial NADPH oxidase (NOX) and consequently decreased superoxide production. In another study, mice pretreated with 20 mg/kg of RES showed a reduction in glutathione levels (Sinha et al., 2002). These findings should be considered when using RES or PTE as therapeutic agents. N-Methyl-D-aspartate (NMDA) and dopamine receptors play an essential role in motor control, cognition and memory formation (VanDongen, 2009). These two receptor systems interact via shared secondary messengers, e.g. calcium ions (Ca2þ). During aging, increases in oxidative and metabolic stress deplete nicotinamide adenine dinucleotide (NADþ) and disrupt adenosine triphosphate (ATP) biosynthesis (Camandola and Mattson, 2011). Decrements in intracellular NADþ and ATP levels hinder the ability of the cell to pump calcium against gradient to restore intracellular calcium concentration (Camandola and Mattson, 2011). Moreover, excess intracellular reactive oxygen species (ROS) have been shown to

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damage the plasma membrane, which can further disturb Ca2þ homeostasis (Blanc et al., 1998). Any deviations away from Ca2þ homeostasis promotes cell death, a process known as excitotoxicity (Rzheshevsky, 2014). Treatment with NMDA elevates intracellular Ca2þ and ROS in primary cortical and hippocampal neurons; however, pretreatment of cells with RES (5e100 mM) has been shown to protect against NMDA-induced cell death (Ban et al., 2008; Zhang et al., 2008). Similarly, treatment with RES (5 mM) was able to protect the neuroblastoma cell line SH-SY5Y against dopamine-induced cytotoxicity by ameliorating intracellular oxidative stress and calcium dysregulation (Chao et al., 2010). RES treatment can restore mitochondrial integrity, increase mitochondrial complex IIV activity and ATP biosynthesis, decrease cytochrome c release and DNA damage, and restore neurovasculature of the brain after cerebral ischemic damage in a rat middle cerebral artery occlusion (MCAO) model (Yousuf et al., 2009). RES pretreatment (10e100 mM) also prevented dopaminergic neurons from 1-methyl-4phenylpyridium-, sodium azide-, thrombin- or N-methyl-N0 nitroguanidine-induced neurotoxicity (Bournival et al., 2009; Okawara et al., 2007). In cortical neurons cultured from neonatal SpragueeDawley rats, RES was found to prevent the overexpression of caspase-3 and caspase-12 mRNA, in a concentrationdependent manner, when cells were subjected to oxygen-glucose deprivation/reperfusion (Gong et al., 2007). Interestingly, there is no study investigating the protective effect of PTE against excitotoxicity. However, there are a limited number of studies conducted in non-neuronal cell-types suggesting that PTE may possess similar effects as RES. One study by Joseph and colleagues showed that PTE pretreatment enhanced restoration of intracellular Ca2þ in COS-7 cells transfected with M1 muscarinic receptors (MAChR) following oxotremorine-induced depolarization (Joseph et al., 2008). 3. Pterostilbene and resveratrol: role in neuroinflammation Microglia, the central nervous system's resident immune cells, are the first line of defense in the event of injury and infection (Ransohoff and Perry, 2009). Once activated, microglia are capable of secreting a wide range of pro-inflammatory factors including cytokines, chemokines, ROS, reactive nitrogen species and prostaglandins. Prolonged secretion of these factors is believed to cause neuronal damage, which can further activate microglia and lead to a condition known as microgliosis (Zhang et al., 2010a). Treatment with RES and PTE has been demonstrated to protect neurons against neuroinflammation via inhibition of ROS production (Shin et al., 2010) and suppress activation of NF-kB signaling pathways through inhibition of MAPK signal transduction pathways (Bi et al., 2005; Lorenz et al., 2003) and activation of SIRT1 pathways (Li et al., 2015b). In addition to the MAPK and SIRT1 pathways, PTE may also suppress NF-kB activation through the transcriptional activation of peroxisome proliferator activated receptor-a (PPAR-a) (Chang et al., 2012; Inoue et al., 2003), a receptor complex that plays an essential role in fatty acid metabolism, inflammation, and oxidative stress regulation. In a study by Candelario-Jalil and colleagues (Candelario-Jalil et al., 2007), RES (up to 50 mM) inhibited the production of prostaglandin E2 (PGE2) and 8-iso-prostaglandin F2a, and suppressed the expression of cyclooxygenase-1 and microsomal prostaglandin E synthase-1 in lipopolysaccharide- (LPS-) activated primary rat microglia. Similarly, RES treatment attenuated LPS-induced phosphorylation of p38 MAPK and promoted degradation of IkB-a in numerous microglia cell-lines, thus reducing the production of nitric oxide (NO), tumor necrosis factor a (TNFa) and interleukin-1b (IL-1b) (Bi et al., 2005; Bureau et al., 2008; Lorenz et al., 2003).

Please cite this article in press as: Poulose, S.M., et al., Effects of pterostilbene and resveratrol on brain and behavior, Neurochemistry International (2015), http://dx.doi.org/10.1016/j.neuint.2015.07.017

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Furthermore, Zykova and colleagues (Zykova et al., 2008) demonstrated that RES binds directly to COX-2. RES and its sulfate metabolites have been reported to marginally activate the SIRT1 pathway when combined with the Fluor de Lys®-SIRT1 peptide substrate. Interestingly, RES itself binds only weakly, or not at all, to SIRT1 without the fluorescently labeled peptide substrates, thus suggesting that the beneficial effects of RES may involve SIRT1 substrate. Short-term treatment of PTE, but not RES, was able to return NF-kB expression in SAMP8 mice to the level of control (SAMR1) mice through up-regulated PPAR-a expression (Chang et al., 2012). Previous studies have shown that PPAR-a directly binds to NF-kB; thus disrupting NF-kB transcriptional activity (Hanyu et al., 2010; Nunn et al., 2007). While both RES and PTE have been found to modulate many signaling molecules related to different diseases in different organs and tissues, Fig. 2 summarizes the most important signaling molecules in brain or brain cells. 4. Pterostilbenes and resveratrol: role in behavioral deficits Prior research has shown that RES treatment effectively improves behavioral deficits seen in neurodegenerative diseases (Kennedy et al., 2010; Singleton et al., 2010; Wang et al., 2002) and it is hypothesized that its antioxidant and anti-inflammatory activities are responsible for the positive outcomes (Kumar et al., 2006; Sharma and Gupta, 2002; Yang and Piao, 2003). Administration of RES to rats was associated with improved histological, motor, and cognitive functions, as measured by postural reflex and forelimb placement, corner test, foot-fault test and water maze performance (Kwon et al., 2011; Singleton et al., 2010). Di Liberto and colleagues (Di Liberto et al., 2012) showed that resveratrol significantly increased the dopamine transporter in the striatum of female mice, but not male mice. The authors suggested that the similarity of the chemical structure between RES and synthetic estrogen diethylstilbestrol may explain the differential effect of RES observed between the sexes. Chronic doses of trans RES at 10 and 20 mg/kg i.p. for 21 days significantly inhibited intracerebroventricular streptozotocin-induced cognitive impairment in adult mice (Sharma and Gupta, 2002). In aged 19-month-old Fischer 344 rats, a high dose of PTE at 10 mg/kg for 12e13 weeks improved working memory (Joseph et al., 2008). Similarly,

Fig. 2. Schematic image showing the various signaling molecules modulated by trans -resveratrol and pterostilbene.

significant spatial memory improvements were observed in mouse lemurs with supplementation of RES at 200 mg/kg per day, relative to placebo (Dal-Pan et al., 2011). Initial interventional studies suggest that the beneficial effects of PTE and RES can translate to humans. A randomized doubleeblind placebo-controlled study involving 80 patients with high cholesterol reported a reduction in blood pressure while increasing LDL, when patients were administered 50e125 mg PTE twice daily for 6e8 weeks (Riche et al., 2014). PTE effectively reduced body weight along with blood pressure; however, the increase in LDL levels warrants further evaluation of high-dose PTE use in humans. Recently a double-blind, placebo-controlled human intervention study (Witte et al., 2014) supplemented 23 healthy overweight older individuals with 200 mg/d RES, in combination with quercetin to increase bioavailability, for 6 months (De Santi et al., 2000). Relative to placebo, subjects who received resveratrol showed significantly improved retention of word lists over a 30-min delay, as well as improved functional connectivity of the hippocampus to frontal, parietal, and occipital areas when measured using 3T MRI neuroimaging techniques (Witte et al., 2014). In another RES intervention study among healthy young adults (Kennedy et al., 2010), a single dose of 250 and 500 mg resveratrol improved cerebral blood flow, which has been previously associated with improvements in cognitive function (Sorond et al., 2008). Further studies are currently underway to assess the cognitive effects of resveratrol in healthy older adults and AD patients.

5. Role in pterostilbene and resveratrol in aging Pterostilbene also had been demonstrated to have beneficial effects on cognition and neuronal function during aging. In a study by Joseph and colleagues (Joseph et al., 2008), aged rats (18months-old) fed with either a 2.5 mg/kg or 10 mg/kg PTEsupplemented diet for 12e13 weeks performed significantly better in the water maze, relative to rats fed a control diet, and performance was correlated with PTE levels in the hippocampus. Moreover, PTE prevented the decrease in oxotremorine enhancement of dopamine release from striatal slices of aged rats exposed to the oxidative stressor H2O2. In another study, PTE and RES were given at the same dose (120 mg/kg body weight) to mice in a model of accelerated aging/Alzheimer's disease (SAMP8) for 8 weeks and PTE, but not RES, preserved cognitive function as measured by the radial-arm water maze (Chang et al., 2012). The beneficial effects of PTE may be due to its ability to cross the blood brain barrier and to increase intracellular calcium buffering capacity, thus reducing recovery time after depolarization (Joseph et al., 2008), attenuating the release of cytotoxic intermediates, e.g. TNF-alpha, interleukins and reactive nitric oxide by microglia (Hou et al., 2014), and normalizing activation of the c-Jun N-terminal protein kinase signaling pathway, leading to a reduction in phosphorylation of tau protein and disruption in neuronal functions (Chang et al., 2012; Porquet et al., 2013; Sun et al., 2010). In some of the life extension studies targeting sirtuins, class III histone deacetylases which are known to extend lifespan in flies, worms, and yeast (Brachmann et al., 1995), RES has been identified as one of the most potent activators of SIRT1-induced deacetylase activity, thereby extending lifespan in yeast (Howitz et al., 2003). RES has also been shown to extend the lifespan of a short-lived fish by 59% while significantly reducing aggregated proteins in elderly fish brains (Valenzano et al., 2006). The study also revealed that when supplemented at a dose of 120 mg/g in aged fish, RES can delay the age-dependent attenuation of locomotor activity and cognitive performance and reduce the expression of neurofibrillary degeneration in the brain.

Please cite this article in press as: Poulose, S.M., et al., Effects of pterostilbene and resveratrol on brain and behavior, Neurochemistry International (2015), http://dx.doi.org/10.1016/j.neuint.2015.07.017

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6. Summary In summary, resveratrol and pterostilbene can directly and indirectly activate major signaling pathways that protect the brain against oxidative stress and inflammation. These signaling molecules allow the brain to maintain homeostasis, preserve neuronal functions and ultimately, minimize age-related behavioral declines (Fig. 3). While RES has a growing list of potential health benefits, low availability and rapid first pass are the major obstacles in translating pre-clinical findings into meaningful clinical trials. The concentration of RES in most red wines varies between 0.1 and 15 mg/l (Fremont, 2000). Similarly, PTE concentration in certain grapes and berries ranges from 99 to 520 ng/g dry sample (Rimando et al., 2004). Therefore, most studies have used RES or PTE at much higher doses than would normally be achievable in the diet through consumption of red wine, fruit, or seeds (Girbovan et al., 2015; Mohammadshahi et al., 2014; Sharma and Gupta, 2002). A pharmacotoxicity study, conducted in mice, reported that dietary intake of PTE (0e3000 mg/kg body weight/day) for 28 days produced no significant change in body weight, food intake, organ weight, or other clinical signs (Ruiz et al., 2009), whereas oral intake of PTE at 250 g/day caused reduction in blood pressure, body weight and an increase in LDL cholesterol among hypertensive patients (Riche et al., 2014). However, recent studies suggest that chronic administration of RES may produce the plasma levels needed for biological activity (Girbovan et al., 2015; Mohammadshahi et al., 2014). Similarly, in a study using male Wistar rats, a chronic i.p. dose of 20 mg/kg/day of RES for 21 days was required to induce neurogenesis, angiogenensis, and neuronal survival in the hippocampus following global cerebral ischemia and thereby improve cognitive function (Girbovan et al., 2015). Therefore, it is imperative to improve the bioavailability of RES and PTE, possibly through structural modification, coadministration or timing, in order to attain pharmacological benefits. Methylation and polymer conjugation (Siddalingappa et al., 2015) may be the keys to extending the half-life of RES. Furthermore, an in vivo study demonstrated that the bioavailability of RES is affected by circadian rhythm; i.e., intake of RES during the morning hours led to higher bioavailability (Almeida et al., 2009). Another study found that RES in combination with the flavonoid quercetin improved the oral bioavailability of RES through the inhibition of hepatic and duodenal sulphation of RES (De Santi et al., 2000). To date, clinical trials have indicated that RES and PTE are relatively well tolerated, with only moderate

Fig. 3. Schematic image for the neuromodulatory effects of resveratrol and pterostilbene.

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diarrhea reported with high doses of RES (Brown et al., 2010; Cottart et al., 2010) and a rise in LDL in a hypertensive population with high doses of PTE (Riche et al., 2014). Based on the evidence presented, PTE is more bioavailable and better at evoking molecular and functional events than RES in vivo. Although clinical trials are underway to assess the effects of RES in diseases such as dementia and AD, pre-clinical and clinical studies on PTE have yet to be conducted. Furthermore, the biological effects of many of the structural analogues of RES and PTE are unknown, and no studies have identified the metabolites of RES or PTE in brain tissues. There is a need for future studies to identify means of enhancing the efficacy and bioavailability of these compounds and to analyze the metabolites of these compounds in the brain. 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Please cite this article in press as: Poulose, S.M., et al., Effects of pterostilbene and resveratrol on brain and behavior, Neurochemistry International (2015), http://dx.doi.org/10.1016/j.neuint.2015.07.017