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NEUROPHARMACOLOGY
Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Montréal, Québec, Canada
Received February 2, 2006; accepted March 28, 2006.
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Abstract |
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-amyloid-induced toxicity correlated well (r = 0.74) with their apparent affinity in the [3H]resveratrol binding assay. Taken together, these results suggest that the neuroprotective action of various polyphenols and resveratrol analogs could be mediated by the activation of common "receptor" binding sites particularly enriched at the level of the cellular plasma membrane in the rat brain.
; Gescher, 2004). Moreover, there is a growing number of studies indicating that natural polyphenol extracts may reduce the incidence of age-related neurological disorders including macular degeneration, stroke, and dementia (Orgogozo et al., 1997; Commenges et al., 2000; Bastianetto and Quirion, 2002). Thus, it has been postulated that regular consumption of various beverages (e.g., tea and red wine), vegetables, and fruits that contains high amounts of polyphenolic compounds are likely to contribute to health (for review, see Arts and Hollman, 2005).
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), heme oxygenase-1 (Dore, 2005), sirtuins (Kaeberlein et al., 2005), androgen and/or estrogen receptors (Bowers et al., 2000; Gao et al., 2004), insulin-like growth factor-1 (IGF-1) or epidermal growth factor (EGF) receptors (Hou et al., 2005; Shimizu et al., 2005), aryl hydrocarbon receptors (AhR) (Casper et al., 1999; Palermo et al., 2003), and the 67-kDa laminin receptors (LR) (Tachibana et al., 2004). Accordingly, these polyphenols are able to target a variety of cellular sites to induce their effects.
More recently, in vitro and a limited number of in vivo studies have demonstrated that resveratrol and flavonoids (e.g., tea catechins) exert neuroprotective effects in various models of toxicity (Bastianetto and Quirion, 2002; Esposito et al., 2002; Dore, 2005; Simonyi et al., 2005; Bastianetto et al., 2006), suggesting that they could contribute to the beneficial effects of food and beverages in reducing the risk of developing neurological disorders (Arts and Hollman, 2005). It has been postulated that the neuroprotective effects of polyphenols are not solely due to their antioxidant activities but probably involve modulatory effects on signal transduction pathways (Esposito et al., 2002; Han et al., 2004). For example, resveratrol was shown to be able to protect hippocampal cells against -amyloid (A)-induced toxicity through its ability to rapidly activate protein kinase C (Han et al., 2004), whereas another study reported that resveratrol markedly reduced nuclear factor-
B signaling stimulated by A1-42 (Chen et al., 2005). Some of the modulatory effects of resveratrol on intracellular effectors are shared by green tea-derived constituents, such as epigallocatechin gallate (EGCG), with a role for the protein kinase C pathway (Levites et al., 2003).
Based on these observations, we postulated that resveratrol and related polyphenols could regulate, at least partly, neuronal cell functions through specific plasma membrane "receptor"-like mechanism. Accordingly, the main objective of the present study was to identify and characterize the presence of specific binding sites for [3H]resveratrol in the rat brain. Our results reveal the presence of specific [3H]resveratrol binding sites enriched in the plasma membrane fraction of the rat brain. These binding sites are discretely distributed and competed by various polyphenols and catechin gallate esters with affinities relevant to their neuroprotective abilities against A-induced neurotoxicity.
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Materials and Methods |
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was kindly provided by P. Gaudreau (Centre Hospitalier de l'Universite de Montréal, University of Montreal, Montreal, QC, Canada). [3H]Resveratrol was purchased from Moravek Biochemicals Inc. (Brea, CA). Materials used for cell cultures were obtained from Invitrogen (Burlington, ON, Canada), whereas other products were from Sigma-Aldrich or Fisher Scientific (Montreal, QC, Canada). Animal care was according to protocols and guidelines of the McGill University Animal Care Committee in accordance with regulations of the Canadian Council for Animal Care.
Membrane Preparations. Membranes were prepared from rat brains as described previously (Dumont et al., 1998), with minor modifications. In brief, rats were decapitated, and their brains were rapidly removed and homogenized in a Krebs-Ringer phosphate buffer, pH 7.4, containing NaCl (135 mM), KCl (3.6 mM), NaH2PO4 (5 mM), MgCl2 (0.5 mM), CaCl2 (1.5 mM), and HEPES (10 mM), using a Brinkman Polytron (at setting 6 for 15-20 s). Homogenates were centrifuged at 2000g for 15 min, the pellets were rehomogenized in the above buffer, and centrifuged again at 2000g. The resulting pellets were used as PI, primarily containing nucleus and cell debris; the supernatants were pooled and centrifuged at 49,000g for 20 min. These pellets were used as PII as partially purified plasma membrane preparations. The supernatants were used as SII, primarily containing soluble proteins.
[3H]Resveratrol Binding Assay. All binding assays were initiated by adding 100 µl of membrane preparations in a final volume of 500 µl of Krebs buffer containing 0.1% (w/v) bovine serum albumin, 0.05% (w/v) bacitracin, [3H]resveratrol, and competitor as indicated. Isotherm saturations and competition binding assays were performed at room temperature. Saturation experiments were performed in the presence of increasing concentrations of [3H]resveratrol, whereas competition binding experiments were performed in the presence of 20 nM [3H]resveratrol and various competitors at concentrations ranging from 10-10 to 10-4 M. Nonspecific binding was determined in the presence of 100 µM resveratrol. After a 1-h incubation, the binding reaction was terminated by rapid filtration through Schleicher and Schuell number 32 glass filters (previously soaked in 1.0% polyethyleneimine) using a cell harvester filtering apparatus (Brandel Instruments, Gaithersburg, MD). Filters were rinsed three times with 3 ml of ice-cold KRB, and radioactivity remaining on filters was quantified using a beta counter with 45% efficiency (Beckman Instruments, Meriden, CT).
Quantitative Receptor Autoradiography. Receptor autoradiography was performed as described in details elsewhere (Dumont et al., 1998). In brief, rats were sacrificed by decapitation, and their brains were rapidly removed from the skull, frozen in 2-methylbutane at -40°C for 15 s, and then kept at -80°C until needed. Sections (20 µm) were obtained using a cryomicrotome at -17°C, mounted on gelatin-chrome-alum-coated slides, dried overnight in a desiccator at 4°C, and then kept at -80°C until use.
Adjacent coronal sections were preincubated for 60 min at room temperature in KRB at pH 7.4 and then incubated for 60 min in a fresh preparation of KRB containing 20 nM [3H]resveratrol in the presence or absence of 100 µM resveratrol. After a 60-min incubation, sections were washed four times, 1 min each in ice-cold KRB, and then dipped in deionized water to remove salts and rapidly dried. Incubated sections were apposed against Kodak Biomax MR films (PerkinElmer, Woodbridge, ON, Canada) for three months alongside with 3H-radioactive standards (GE Healthcare Canada, Baie d'Urfe, QC, Canada).
Primary Hippocampal Cell Cultures. Hippocampal cell cultures were prepared from embryonic day 19 to 20 fetuses obtained from Sprague-Dawley rats as described previously with minor modifications (Bastianetto et al., 2000a). Cells were grown at day 0 (density of approximately 4 x 104 viable cells per well in 96-well plates) in HEPES-buffered Dulbecco's modified Eagle's medium high-glucose medium supplemented with KCl (20 mM) and fetal bovine serum [10% (v/v)]. The initial medium was removed at days 1 and 5 and replaced with the same medium containing N2 supplement [1% (v/v)]. The experiments were performed using 6-day-old cultures, at which time the hippocampal neurons are fully differentiated (Mattson et al., 1991).
A-Induced Toxicity and Assessment of Cell Viability. On the day of experiment, the medium was removed, and cells were incubated at 37°C in the same medium without N2 supplement and exposed for 24 h to fresh A25-35 (25 µM) in the presence or absence of different compounds. Cell viability was evaluated 24 h later using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium colorimetric assay, as described previously (Bastianetto et al., 2000a). Optical density was determined at 570 nm using a microplate reader (BioTek Instruments Inc., Montreal, QC, Canada).
Statistical Analysis. All binding experiments were repeated at least three times (each in triplicate), and results (mean ± S.E.M.) were expressed as percentage of specific binding or in femtomole/milligram of protein. Binding parameters were determined using Prism, version 3.03 (GraphPad Software Inc. San Diego, CA). The affinity (KD) and maximal binding capacity (Bmax) of the saturation isotherms were estimated by a nonlinear regression curves and were fitted to a one-site and two-site model using hyperbola equations with p < 0.05 considered significant using the Fisher test. Saturation isotherm curves were best-fitted to a one-site model (p > 0.05). The concentration of competitor required to compete for 50% of specific [3H]resveratrol binding was calculated from competition binding curves, and results were expressed as percentage of specific binding representing the mean ± S.E.M. of three to four individual determinations, each in triplicate. Competition curves were fitted to a one-site and a two-site model using Prism, version 3.03 with p < 0.05 considered significant using the Fisher test. Competition binding curves were best-fitted to a one-site model (p > 0.05). Ki values were determined according to the equation of Cheng and Prusoff [Ki = IC50/(1 + C/KD)] (Cheng and Prusoff, 1973). The optical density of the autoradiographic images was measured from Kodak MR films using a microcomputer-assisted video-imaging densitometer (MCID system; Imaging Research, Ste-Catharines, ON, Canada). Survival of vehicle-treated control groups not exposed to A25-35 or drugs was defined as 100%, and the number of surviving cells in the treated groups was expressed as percentage of controls. One-way ANOVA followed by Newman-Keuls multiple comparison test was used to compare control and treated groups with p < 0.05 being considered significant. Cell cultures experiments were repeated four times (each in sextuplicates). EC50 values (concentration of compounds required to block 50% of cell death induced by A25-35 alone) were calculated using Prism.
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Results |
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A series of compounds with structural similarities to resveratrol and tea catechins (Fig. 1) were evaluated next for their ability to compete for specific [3H]resveratrol binding in rat brain membrane homogenates (PII fraction). As shown in Fig. 3, EGCG and (-)-epicatechin gallate (ECG) are most potent to compete for specific [3H]resveratrol binding with Ki value of 25 and 45 nM, respectively, whereas resveratrol was found to be two to four times less potent (Ki = 102 nM) (Table 2). Among the structurally related analogs of resveratrol tested here, 3,5-dihydroxy-trans-stilbene, piceatannol, 3,4,4'-trihydroxy-trans-stilbene, and 3,5-dimethoxy-4'-hydroxy-trans-stilbene were the only compounds that were able to significantly compete against specific [3H]resveratrol binding (Fig. 3 and Table 2). Inactive molecules (up to 10 µM) include estradiol, benzo[a]pyrene, (-)-epicatechin, (-)-epigallocatechin, trans-stilbene, trans-4'-stilbenemethanol, diethylstilbestrol, 3,4-dihydroxystilbene, 3,4,5-trihydroxystilbene, 4,4'-dihydroxy-trans-stilbene, 4-hydroxy-4'-methoxy-trans-stilbene, 3,5-dihydroxy-4'-methoxy-trans-stilbene, 3,4'-dihydroxy-4-methoxy-trans-stilbene, and 4,4'-dihydroxy-3-methoxy-trans-stilbene (Table 2).
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We evaluated next the discrete distribution of specific [3H]resveratrol binding sites in rat brain using quantitative autoradiography. As shown in Fig. 4A, [3H]resveratrol binding is widely distributed in the rat brain, with highest levels seen in the choroid plexus and subfornical organ and lower but significant amounts found in other regions such as the hippocampal formation and the cortex (Fig. 4A). A quantitative analysis confirmed the broad distribution of specific [3H]resveratrol binding in the rat brain (Fig. 4B).
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A functional assay was then used to test the capacity of resveratrol, homologs, and catechins to protect hippocampal cells against A25-35-induced toxicity. This assay was chosen because of the purported protective effects of resveratrol and tea-derived catechins in these cell types that were exposed to A25-35, A1-40, or A1-42 (Han et al., 2004; Bastianetto et al., 2006). The catechin gallates EGCG (EC50 = 5 µM) and ECG (EC50 = 7 µM) and the resveratrol analog 3,4,4'-trihydroxy-trans-stilbene (EC50 = 6 µM) were the most potent neuroprotective agents (Table 2). Additionally, piceatannol (EC50 = 11 µM), resveratrol (EC50 = 13 µM), 3,5-dihydroxy-trans-stilbene (EC50 = 17 µM), and 3,5-dimethoxy-4'-hydroxy-trans-stilbene (EC50 = 26 µM) also exerted neuroprotective effects, albeit with lower potencies (Table 2). In contrast, estradiol, benzo[a]pyrene, trans-stilbene, trans-4'-stilbenemethanol, diethylstilbestrol, 3,4-dihydroxystilbene, 3,4,5-trihydroxystilbene, epicatechin, epigallocatechin, 4,4'-dihydroxy-trans-stilbene, 4-hydroxy-4'-methoxy-trans-stilbene, 3,5-dihydroxy-4'-methoxy-trans-stilbene, 3,4'-dihydroxy-4'-methoxy-trans-stilbene, and 4,4'-dihydroxy-3-methoxy-trans-stilbene were ineffective at up to 50 µM (Table 2) or even neurotoxic by themselves (data not shown). Interestingly, the affinity of polyphenols and various resveratrol analogs to compete for specific [3H]resveratrol binding correlated very well (r = 0.74), with their neuroprotective activity against A25-35-induced toxicity in primary hippocampal cell culture (Fig. 5), suggesting that the neuroprotective effect exerted by these phenolic compounds could be mediated by a common mechanism involving a specific plasma membrane protein.
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Discussion |
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25-35. In contrast, estradiol, trans-stilbene, diethylstilbestrol, benzo-[a]pyrene, and the catechin nongallate esters (i.e., epicatechin and epigallocatechin), which failed to compete for specific [3H]resveratrol binding at concentrations up to 10 µM, failed to protect cells against A25-35-induced toxicity. Taken together, these results suggest the existence, at the level of the cell plasma membrane, of specific resveratrol receptor binding sites that have functional relevance for the neuroprotective effects of these molecules.
Resveratrol and tea catechins possess a wide range of biological and pharmacological properties (see Introduction). For example, it has been shown that polyphenolic compounds contained in grapes and teas have potent protective effects in various models of neurotoxicity (Bastianetto et al., 2000a,b; Levites et al., 2003; Han et al., 2004; Lee et al., 2004). These results are in agreement with the neuroprotective effects of the tea catechin gallates, EGCG and ECG, and resveratrol reported in the present study. However, limited information is currently available on the first biochemical or molecular step leading to these events. The recent series of findings demonstrating that polyphenols and tea catechins can regulate various intracellular pathways, such as mitogen-activated protein kinases (Schroeter et al., 2002), protein kinase C (Levites et al., 2003; Han et al., 2004), proapoptotic proteins (e.g., bax and Bcl-XL) (Choi et al., 2001), caspases (Katunuma et al., 2004), sirtuins (Kaeberlein et al., 2005), and heme oxygenase-1 (Dore, 2005), may be taken as an indication for the existence of an upstream site of action at the level of the plasma membrane. This hypothesis is indeed supported by our findings that the highest level of specific [3H]resveratrol binding was detected in the plasma membrane-enriched fractions (PII). Moreover, plasma membrane specific [3H]resveratrol binding was markedly reduced by treatments with trypsin and protein denaturation (boiling) but not by benzonase treatment, suggesting its proteinaceous nature. Saturation binding experiments revealed that [3H]resveratrol bound to saturable amounts of specific sites with an apparent affinity of 220 nM in the rat brain. Additionally, competition binding experiments demonstrated that specific [3H]resveratrol binding was competed by various natural and synthetic polyphenolic compounds with EGCG, ECG, and resveratrol being most potent. Interestingly, the apparent affinity of these molecules to compete for specific [3H]resveratrol binding correlated well (r = 0.74) with their abilities to protect hippocampal neurons against A-induced neurotoxicity. These structure-activity data strongly suggest that specific [3H]resveratrol binding sites present at the level of the plasma membrane are functionally relevant and may serve as polyphenol "receptors" initiating a cascade of events leading to their various biological effects.
Earlier studies have shown that resveratrol act as a mixed agonist/antagonist on 
and isoforms of estrogen receptors (Bowers et al., 2000). Thus, it has been suggested that some of the effects of resveratrol could be mediated by the activation of estrogen receptors. However, specific [3H]resveratrol binding sites characterized in the present study are most unlikely to represent estrogen receptors. In fact, estradiol was unable to compete against specific [3H]resveratrol binding in rat brain membrane homogenates and was unable to protect primary hippocampal cells against A25-35-induced toxicity. Resveratrol was also shown to compete for the AhR with an apparent affinity of 200 to 1000 nM (Casper et al., 1999), EGCG behaving as an antagonist on this receptor (Palermo et al., 2003). However, it was recently shown that EGCG does not bind directly to AhR but rather to the chaperone protein heat shock protein 90 (Palermo et al., 2005). Moreover, AhR are cytosolic receptors, whereas specific [3H]resveratrol binding sites are particularly enriched in plasma membrane PII preparations. Finally, benzo[a]pyrene, a polycyclic aromatic hydrocarbon with high affinity for AhR, was unable to compete for specific [3H]resveratrol binding and had no neuroprotective effect. Taken together, these data demonstrate that specific [3H]resveratrol binding sites characterized in our study are distinct from the AhR receptors.
It has recently been shown that catechin and epicatechin can compete with high affinity (20 nM) for [3H]testosterone/androgen receptors (Gao et al., 2004). However, epicatechin was rather weak to protect hippocampal cell against A-induced toxicity and almost inactive against specific [3H]resveratrol binding, excluding the androgen receptor as the putative [3H]resveratrol binding sites characterized in our study. It has also been proposed that EGCG may directly interact with EGF (Liang et al., 1997) and IGF-1 (Shimizu et al., 2005) receptors to regulate receptor tyrosine kinase pathways and the phosphorylation of downstream targets involved in the proliferation of tumoral cells (Shimizu and Weinstein, 2005). In these studies, EGCG and resveratrol at high concentrations (50 µM) induced cell death, whereas they were both neuroprotective in our model. Thus, it seems that specific [3H]resveratrol binding sites identified here represent distinct molecular entities compared with those involved in the facilitation of apoptotic processes associated with EGF and IGF-1 receptors.
Interestingly, EGCG was recently shown to bind with nanomolar affinity to the 67-kDa LR (Tachibana et al., 2004). The 67-kDa LR is the mature form of a gene coding for a 37-kDa LR polypeptide, which can exist as a homodimer or heterodimer (Landowski et al., 1995). The apparent affinity (40 nM) of EGCG for the 67-kDa LR (Tachibana et al., 2004) is similar to that obtained in the present study against specific [3H]resveratrol binding. Further studies are now in progress to determine whether specific [3H]resveratrol binding characterized here represents the 67-kDa LR. However, the neuroanatomical distribution of specific [3H]resveratrol binding sites and their enrichment in the choroid plexus argue against the 67-kDa LR being the site recognized by [3H]resveratrol in our study.
Only few resveratrol analogs, such as piceatannol, 3,4,4'-trihydroxy-trans-stilbene, 3,5-dihydroxy-trans-stilbene, and 3,5-dimethoxy-4'-hydroxy-trans-stilbene, shared with catechin gallate esters (ECGC and ECG) the ability to protect hippocampal neuronal cells against A25-35-induced toxicity and to compete for specific [3H]resveratrol binding, demonstrating the existence of clear structure-activity relationships. Indeed, these data suggest that hydroxyl group and gallic acid are required for the neuroprotective activities of resveratrol analogs and catechin gallate esters, respectively. Removing the hydroxyl group in position 4' of resveratrol resulted in an inactive analog against specific [3H]resveratrol binding and A25-35-induced toxicity. Additionally, the presence of at least one methoxyl group (O-CH3) in one of the pyran rings of the polyphenols tested here (4-hydroxy-4'-methoxy-trans-stilbene, 4,4'-dihydroxy-3-methoxy-trans-stilbene, 3,5-dihydroxy-4'-methoxy-trans-stilbene, 3,5-dimethoxy-4'-hydroxy-trans-stilbene, and 3,4'-dihydroxy-4-methoxy-trans-stilbene) resulted in markedly reduced affinities for specific [3H]resveratrol binding and lower potencies to protect against A25-35-induced toxicity. We recently reported that gallic acid shared with catechin gallate esters the ability to block cell death induced by various A peptides (Bastianetto et al., 2006), whereas gallic acid methyl ester was ineffective (data not shown). The structure-activity relationships reported here should be useful toward the development of more potent and selective neuroprotective polyphenols and catechins.
Ligand receptor autoradiography revealed that specific [3H]resveratrol binding sites are widely distributed in the rat brain with highest levels of labeling seen in the choroid plexus and subfornical organ followed by the hippocampus and other areas, suggesting that endothelial cells could be involved in the neuroprotective effects of polyphenols. Interestingly, choroid plexus endothelial cells (as transplanted or added in culture medium) have been shown to be neuroprotective in cultured rat hippocampal neurons and rodent models of neurotoxicity, possibly because of their ability to secrete neurotrophic factors (Watanabe et al., 2005). Additionally, dietary supplementation with the Ginkgo biloba extract EGb 761, a complex extract that contains high amounts of polyphenols and was prescribed in Europe for the treatment of Alzheimer's disease (Le Bars et al., 2000), enhanced transthyretin mRNA levels in the rat hippocampus (Watanabe et al., 2001). Transthyretin is a thyroid and retinoic acid-transporting protein synthesized by the choroid plexus that has been shown to sequester A protein, hence preventing its aggregation and toxicity (Tsuzuki et al., 2000). Thus, polyphenols by acting on specific plasma membrane binding sites could increase the expression of transthyretin, this effect possibly also leading to reduced A toxicity.
In summary, we have shown the presence of specific [3H]resveratrol plasma membrane binding sites in the rat brain. These specific binding sites are of proteinaceous nature, saturable and of rather high affinity. Most importantly, the apparent affinities of a series of analogs of resveratrol and tea catechins for [3H]resveratrol binding correlated well with their neuroprotective abilities, suggesting their functional relevance. Experiments are now in progress to identify more precisely the molecular nature of these specific [3H]resveratrol plasma membrane binding sites in the rat brain.
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Acknowledgements |
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Footnotes |
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Y.-S.H., S.B., and Y.D. have contributed equally to this work.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: resveratrol, 3,5,4'-trihydroxy-trans-stilbene; AhR, aryl hydrocarbon receptor; A, -amyloid; KRB, Krebs-Ringer buffer; EGF, epidermal growth factor; EC, (-)-epicatechin; ECG, (-)-epicatechin gallate; EGCG, (-)-epigallocatechin gallate; IGF, insulin-like growth factor.
Address correspondence to: Dr. Rémi Quirion, Douglas Hospital Research Center, 6875 Blvd. LaSalle, Montréal (Verdun), QC H4H 1R3, Canada. E-mail: remi.quirion{at}douglas.mcgill.ca
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