Promising Neuroprotective Effects of Oligostilbenes
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Nutrition and Aging 3 (2015) 49–54 49 DOI 10.3233/NUA-150050 IOS Press Promising neuroprotective effects of oligostilbenes Hamza Temsamani, Stephanie´ Krisa, Jean-Michel Merillon´ and Tristan Richard∗ Universit´e de Bordeaux, ISVV, EA 3675 GESVAB, 33140 Villenave d’Ornon, France Abstract. Stilbenes (resveratrol derivatives) are a polyphenol class encountered in a large number of specimens in the vegetal realm. They adopt a variety of structures based on their building block: resveratrol. As the most widely studied stilbene to date, resveratrol has shown multiple beneficial effects on multiple diseases and on neurodegenerative diseases. Except for resveratrol, however, the biological activities of stilbenes have received far less attention, even though some of them have shown promising effects on neurodegenerative disease. This review covers the chemistry of stilbenes and offers a wide insight into their neuroprotective effects. Keywords: Resveratrol, stilbene, oligostilbene, neuroprotection 1. Introduction concerning the derivatives of resveratrol and their pro- tective effects on neurodegenerative diseases. Even if “French paradox” [1] is not universally accepted [2], evidences of beneficial effects of wine consumption on health were validated [3–5] and since 2. Polyphenols and stilbenes then has led to a growing interest in polyphenols. Many of these natural secondary metabolites have been Stilbenes constitute a class of phenolic compounds investigated owing to their beneficial effects on human [16, 17]. Polyphenols are mainly synthesized trough health. Indeed, studies have demonstrated a correlation the shikimate pathway and are characterized by at least between moderate wine consumption and a decrease in one hydroxyl group linked to an aromatic cycle. They the risk of cancer, cardiovascular diseases and neurode- can be divided into two groups: flavonoid and non- generative diseases [6]. Polyphenols are thought to be flavonoid compounds. Flavonoids are characterized responsible for this correlation [7]. by a typical structure on C6-C2-C6 and are synthe- Resveratrol is considered to be one of the wine sized through the malonate pathway. They are mainly polyphenols underpinning the “French Paradox” [8]. available in their glycosylated forms in plants and are It is a powerful antioxidant with several beneficial often colored. Many compound families are included impacts on health [9], especially its ability to prevent within the flavonoids: flavonols, flavonols, flavones, neurodegenerative diseases [10, 11]. It is the main isoflavones, flavanones and anthocyanins. building block of wine stilbenes [12]. Studies have The basic skeleton of stilbenes comprises two aro- demonstrated that stilbenes share the ability of resver- matic rings joined by an ethylene bridge (Fig. 1). This atrol in having potentially positive effects on health basic structure gives rise to a wide range of different [13–15]. This manuscript summarizes the main results compounds: monomers differing in the number and position of their hydroxyl groups, substitution with ∗ ´ Corresponding author: T. Richard, Universite de Bordeaux, sugars and other residues and the steric configuration of ISVV, EA 3675 GESVAB, 33140 Villenave d’Ornon, France. Tel: +33 557 122 710; Fax: +33 557 122 717; E-mail: tristan.richard@ the molecules; condensation of the monomers leading u-bordeaux.fr. to the formation of complex oligomers [18]. ISSN 1879-7717/15/$35.00 © IOS Press and the authors. All rights reserved This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License. 50 H. Temsamani et al. / Oligostilbenes and neuroprotection Fig. 1. Main monomeric stilbenes. Vine derivatives such as table grapes, grape juice unrecognized [24]. Recent results indicate that the bio- and wine are the main dietary source of stilbenes in logical activities of other stilbenes are at least equal to the Western diet. Their concentration in wine is about those of resveratrol. Hopeaphenol and vitisin A, two 10 milligrams per liter [19]. They are also found in the oligomers, inhibit propagation of the canine tumor cell- range of a few milligrams to a few hundred milligrams line more efficiently than resveratrol [25]. -viniferin per kilogram of dry matter in various dietary sources glucoside and scirupsin A are two dimers with a bet- such as raisins, red fruits, peanuts and rhubarb [19]. ter inhibition than resveratrol on the aggregation of Resveratrol is the most well-known stilbene. It was -amyloid peptide, a peptide involved in Alzheimer’s first described as a vine phytoalexin [20] but further disease [13]. Thus, some stilbenes could prove to be studies showed it to be a beneficial compound for more promising beneficial compounds than resveratrol health [21]. Resveratrol is nowadays renowned as a against specific diseases. powerful anti-oxidant and anti-inflammatory, and is thus associated with the beneficial impact of moderate wine consumption on health, especially with regard to 3. Resveratrol bioavailability the cardiovascular diseases, cancer, aging and even the neurodegenerative diseases. Studies on the bioavailability of stilbenes have Compared to resveratrol, the other stilbenes have focused mainly on resveratrol at the expense of the received less attention. The presence of stilbene other stilbenes. Resveratrol bioavailability has been oligomers was recently reported in wine [22, 23]. studied in animal models and human [26–29]. Its Nevertheless, the stilbene content in wine remains intestinal absorption in rat is as high as 70 % [27]. H. Temsamani et al. / Oligostilbenes and neuroprotection 51 Table 1 of compounds with the ability to treat and prevent brain Maximum content of piceid (resveratrol glucoside) in organs of mice injuries is one of the most promising avenues of inves- after oral administration of piceid 50 mg/kg body weight [30] tigation. Stilbenes, and particularly resveratrol, have Tissues Concentration (g/g) displayed interesting neuroprotective activities. Heart 5.0 As for bioavailability, most of the studies on the Liver 4.5 neuroprotective effects of stilbenes have focused on Spleen 28.0 resveratrol. Resveratrol is known to act through various Lung 10.4 mechanisms to prevent the two most widespread neu- Kidney 2.6 Stomach 168.8 rodegenerative diseases, Alzheimer’s and Parkinson’s Small intestine 108.7 diseases [10, 31]. Brain 6.1 Alzheimer’s disease is the most widespread neu- Testis 29.1 rodegenerative disease. Two proteins are involved in this disease: τ-protein and amyloid -peptide (A). Once absorbed, it is metabolized into its glucoronides Their excessive accumulation triggers a cellular dys- and sulfoconjugates [27, 28]. In our laboratory, we function [32]. Neuron cytoskeletons are stabilized by τ monitored the distribution of 14C-resveratrol in mouse -protein but abnormal clusters of this phosphorylated tissue 3 hours after oral intake [29]. Radioactivity protein can form into cells and are an initial hallmark of  was recorded in the brain, lungs, heart, liver, kidneys, Alzheimer’s disease. Extracellular aggregation of A  spleen, colon, and testicles. The highest concentra- is the second hallmark. A is the product of the sequen- tions were detected in the duodenum and kidneys and tial proteolytic cleavage of the transmembrane protein the lowest in the heart, testicles and brain. Pharma- APP (Amyloid Protein Precursor) by two enzymes: a  ␥ cokinetics and tissue distribution of piceid (resveratrol -secretase and a -secretase. Aggregation of this toxic glucoside) following a single oral dose of 50 mg/kg and insoluble peptide leads to the onset of amyloid were studied in rat model [30]. The result shows that plaques, also known as senile plaques. Those plaques piceid is quickly absorbed, at 10 min, the concentra- induce oxidative stress and an inflammatory process, tions of piceid in most tissues reached peak level. in addition to the neuronal malfunction. This amyloid The tissue distribution of piceid was presented in cascade triggers several phenomena leading to neu- Table 1. Piceid was absorbed throughout the gastroin- ronal death (Fig. 2). testinal tract with considerable absorption taking place Resveratrol has shown its ability to interfere with in the stomach and small intestine. There was no long- this amyloid cascade (Fig. 2). It decreases the accumu- term accumulation of piceid in rat tissues. Resveratrol lation of reactive oxygen species (ROS) and protects  and its derivatives are thus able to penetrate tissues. the PC12 cell-line against A -induced damage [33]. Nevertheless the bioavailability of stilbene oligomers It inhibits the chemical mediators of inflammation remains unknown. No supposition about bioavailabil- on microglial cells, modulates the lipoxygenase and ity can be made only regarding a stilbene structure. cyclo-oxygenase enzymes and inhibits inductive nitric About the Brain Blood Barrier (BBB), only resvera- oxide synthase (iNOS) and the production of cytokines trol has been studied far enough to show an ability to and transcription factors [34]. It is thought to act  cross the BBB. One can suppose that complex stilbenes on proteasome activation by reducing the A secre- will not be able to cross the BBB. But the dimers could tion on cell lines transfected with the APP 695 gene, cross it. The commercialization of stilbene dimers such without any direct impact on the secretases activated  as -viniferin will allow addressing this problem. during A synthesis [35]. Moreover, resveratrol