Keywords

Resveratrol; polyphenols; cognition; memory; dementia; Alzheimer; neuroprotective; hippocampus

Introduction

The polyphenol resveratrol (RSV) is probably best known for its crucial role in the so-called French paradox. This concept aims to explain the paradoxical epidemiological observation that the French, despite a diet rich in saturated fatty acids, have a relatively low incidence of cardiovascular complications (Catalgol et al., 2012; Kulkarni and Canto, 2015). As integral ingredient of red wine, RSV is among the components of the French diet that are suspected to positively affect coronary health (Catalgol et al., 2012; Kulkarni and Canto, 2015). Furthermore, the moderate consumption of red wine has been linked to lower incidence of age-related neurological disorders, strokes, and cognitive deficits (Bastianetto et al., 2015).

This chapter starts with a brief overview of the sources, pharmacokinetics, and metabolism of RSV to provide the reader with a better understanding of the physiological processes in the context of RSV administration. In the following section, we provide a review of available animal and human studies on the effects of RSV on cognitive functions followed by a discussion of possible underlying mechanisms. The chapter closes with a discussion about the translation and interpretation of these findings in order to put the current research into a wider framework and point out implications for future studies.

Background: Sources and Pharmacokinetics of Resveratrol

The dietary sources of RSV include blueberries, red currants, and peanuts, although red grapes and red wine are the most substantial sources in the human diet (Baur and Sinclair, 2006; Ingram et al., 2006; Smoliga et al., 2011). The naturally occurring variance in concentration depends not only on the specific source but also on environmental factors such as weather and exposure to stressors (Gambini et al., 2015). An extensive overview of the specific polyphenol content in foods is provided in the online database Phenol-Explorer: Database on Polyphenol Content in Foods (for details, see Rothwell et al., 2013). Within plants, RSV acts as a phytoalexin, meaning it is characterized by low molecular weight and is involved in counteracting certain stressors (Gambini et al., 2015). Those stressors include parasites, fungi, ultraviolet radiation, excessive sunlight, and chemical substances (Carrizzo et al., 2013; Gambini et al., 2015).

Human intake of RSV occurs via the consumption of RSV-containing foods or via dietary supplements. In the intestine, RSV is absorbed by passive diffusion or after forming complexes with membrane transporters (Gambini et al., 2015). Absorption rate is supposed to be approximately 75%, which is rather high for a dietary polyphenol, but it also varies between different food items and ways of consumption (Gambini et al., 2015; Pangeni et al., 2014; Vitaglione et al., 2005; Walle, 2011). For example, RSV absorption is lower after a high-fat breakfast compared to after overnight fasting (la Porte, 2010; Robinson et al., 2015; Vaz-da-Silva et al., 2008).

Once RSV reaches the bloodstream, it is present either in free form as glucuronide or as sulfate (Gambini et al., 2015). Usually RSV is quickly metabolized in phase II in the liver or duodenal cells and thus has low bioavailability (Davinelli et al., 2012). Emerging products are sulfates, glucuronides, and as many as five different urinary products (Gambini et al., 2015). This high rate of metabolism could be counteracted by the administration of RSV in combination with other chemicals such as quercetin that inhibit its sulfation and glucuronidation in the liver and duodenal tissue (De Santi et al., 2000; Gambini et al., 2015). However, others could not confirm these effects (la Porte, 2010), so the underlying mechanisms of how quercetin enhances the bioavailability of RSV remains somewhat unclear. The free form of RSV is characterized by a low water solubility, and more than 90% of free RSV binds to plasma lipoproteins (Gambini et al., 2015). Glucuronides and sulfates are either excreted or converted again to free RSV in target organs such as the liver (Gambini et al., 2015; Park and Pezzuto, 2015). Notably, RSV crosses the blood–brain barrier (Davinelli et al., 2012; Turner et al., 2015) and is thought to exert neuroprotective effects within the brain. For example, RSV was found to attenuate neuronal damage caused by a high-fat diet in mice and to protect against apoptotic insults (Chang et al., 2014).

In humans, supplementary RSV intake is considered to be safe and well tolerated up to 5 g per day (Almeida et al., 2009; Anton et al., 2014; Boocock et al., 2007; Brown et al., 2010; Cottart et al., 2014; la Porte, 2010; Patel et al., 2011; Turner et al., 2015). Minor adverse effects appeared at doses higher than 0.5 g RSV per day over long periods, starting from several weeks and up to one year (Cottart et al., 2014). These were described as mainly affecting the abdomen (e.g., flatulence, mild diarrhea) and remaining moderate and reversible (Cottart et al., 2014). Note that all of these observations are based on supplementary RSV products with a high level of purification and lack of contamination (Virmani et al., 2013). Furthermore, interactions with therapeutic products should be addressed in future studies, even though these have been considered to be marginal, to rule out negative consequences of RSV on pharmacotherapy (MacDonald et al., 2009). In addition, future studies should address the effects of RSV derivatives and analogs, as well as the development of methods that could slow down the rapid metabolism of RSV to eventually increase RSV bioavailability (Cottart et al., 2014).

Animal Studies

Using various animal models, previous research investigated the use of RSV on a multitude of diseases and their underlying mechanisms. For example, improved outcomes in cardiovascular diseases and diabetes have been highly investigated and linked with positive effects of RSV not only on inflammation and oxidative stress but also on cancer (e.g., for reviews, see Knutson and Leeuwenburgh, 2008; Kundu and Surh, 2008; Das and Das, 2007).

Considering cognitive functions, a treatment with RSV was associated with improved spatial learning and memory as well as mood proxies in aged rodents (Abraham and Johnson, 2009; Casadesus et al., 2004; Kodali et al., 2015). The animals received RSV by either consuming blueberries or dietary supplements for at least four weeks. Moreover, findings were similar concerning pharmacologically induced learning deficits in rats (Gacar et al., 2011; Yazir et al., 2015) and in diabetic rats (Schmatz et al., 2009).

In addition, these and other studies (Galli et al., 2006; Liu et al., 2014) reported neuroprotective effects of RSV on the hippocampus, a key area involved in memory and spatial navigation in association with the preservation of cognitive functions. This was also accompanied with improvements in the brain’s microvasculature in the RSV-treated rats compared to control animals (Oomen et al., 2009).

Getting closer to humans, the French RESTRIKAL study investigated the effects of RSV and caloric restriction (CR) in nonhuman primates. The study assessed the effect of an 18-month RSV-supplementation in 33 lemurs in comparison to control or CR subjects (Dal-Pan et al., 2011a; Dal-Pan et al., 2011b). RSV supplementation as well as CR led to a significant improvement in working memory, while only RSV treatment significantly enhanced spatial memory performance (Dal-Pan et al., 2011a).

Human Studies

RSV in human studies made its first appearance in the 1990s in context of the French paradox. Afterward many studies reported improved health outcomes regarding cardiovascular diseases in association with RSV intake. However, available data on cardiovascular disease is still in conflict and definite recommendations to the public cannot yet be made (Kakoti et al., 2015; Zordoky et al., 2015).

Since the early studies in the framework of the French paradox, more research was conducted to identify potential beneficial effects of RSV on other leading causes of death such as obesity, diabetes, and cancer. For all of those diseases, the observed findings are promising in animal models, but the data in humans are not consistent enough and too conflicting to draw final conclusions (de Ligt et al., 2015; Scapagnini et al., 2014; Singh et al., 2015). For example, Semba et al. (2014) could not find a positive effect of RSV, measured in urinary samples, on a population-based cohort of 783 community-dwelling older adults (>65 years of age) in Chianti (Italy). They argued that a typical Western diet does not contain enough RSV to affect outcomes such as inflammation, several diseases, and mortality. Data are, however, most convincing in type 2 diabetes research. Here RSV is considered a leading candidate to support conventional pharmacological management (Hausenblas et al., 2015; Szkudelski and Szkudelska, 2015). The improvements of glycemic control and insulin sensitivity after RSV seem especially crucial for positive health outcomes in diabetes (Brasnyo et al., 2011; Szkudelski and Szkudelska, 2015).

Considering neurodegenerative processes and related decreases in cognitive functions, RSV is currently under phase III clinical trials to determine the potential therapeutic usage (Davinelli et al., 2012). Recently, RSV was found to be a safe and well-tolerated substance in populations at risk for Alzheimer’s disease (AD) (Turner et al., 2015). Indeed, over the last few years, evidence from high-quality studies concluded that polyphenols, including RSV, might have a protective role against AD and other neurodegenerative diseases (Davinelli et al., 2012; Pasinetti et al., 2015; Rege et al., 2014; Tellone et al., 2015). Especially in combination with other compounds (e.g., clioquinol), RSV seems to be a candidate in the process of developing new drugs for AD (Mao et al., 2014).

Taken together, previous evidence suggested that RSV exerts numerous positive effects on human health outcomes, especially in diabetes, and including cognitive decline. Many findings observed in animal studies, however, still need to be established in humans. Yet the translation of animal findings to clinical outcomes faces a variety of challenges that need to be tackled (Singh et al., 2015).

One crucially important issue is that human studies on RSV suffer from a wide heterogeneity in study design (Crichton et al., 2013). For example, concerning the sources of RSV, different foods such as red wine and blueberry juice have been investigated as has isolated RSV administration in the form of a dietary supplement. Therefore, it is difficult to compare the actual dosage each participant received. But also within supplementation trials, the dosage varied substantially, e.g., participants of Brasnyo et al. (2011) received 10 mg daily, while others were administered 250 or 500 mg per day (Kennedy et al., 2010). Furthermore, the designs ranged from cross-sectional studies over single-dose experiments to longitudinal studies that incorporated a daily supplementation for several months. However, only a few randomized controlled trials with limited sample sizes are available so far. In addition, the studied outcome measures such as behavioral and neuropsychological tests were considerably different, rendering a comparison between studies difficult. In sum, the heterogeneity in study design and lack of large-scale randomized controlled trials prevent any recommendation for RSV as a supplement in prevention or therapy of any disease, even though most studies provided promising results (reviewed, e.g., in Huhn et al., 2015; Novelle et al., 2015).

Mechanisms

Postulated mechanisms of RSV range from antioxidant and antiinflammatory effects to neuroprotection and mimicking of CR. RSV seems to act on so many different molecular pathways and binding partners that it was previously called a “promiscuous molecule” (Britton et al., 2015). However, this variety of pathways might also explain the diverse range of conditions in which RSV appears to be beneficial for health (Britton et al., 2015). The following section contains a summary of the most commonly discussed mechanisms and binding partners of RSV to explain its various actions.

Limitations and Challenges for Future Studies

RSV administration has led to promising results in animal studies, yet more studies are needed to establish these findings in humans. To allow proper translation from animal models to humans, future work especially address the limitations of previous studies such as flaws in study design and limited sample sizes and tackle challenges such as finding the most appropriate dosage. This might help to draw better conclusions about the impact of RSV on human cognitive functions.

Concerning the administration of RSV, it is important to conduct further studies with isolated RSV and investigate interactions and possible synergistic or antagonistic effects with other agents such as quercetin and piperine (Bigford and Del Rossi, 2014; Johnson et al., 2011; Kakoti et al., 2015; Skroza et al., 2015; Vang, 2015). To improve the in vivo bioavailability of RSV, it is important to get as close to the active dosage used in animal studies as possible to improve the translation of findings (Johnson et al., 2011; Smoliga and Blanchard, 2014). Therefore, one major target for future trials should be the design of novel analogs that are not metabolized as fast as RSV or to increase solubility or half-life in plasma (Granzotto and Zatta, 2014; Pangeni et al., 2014; Rege et al., 2014; Vang, 2015). With regard to cognitive functions, it is especially noteworthy that RSV can be formulated into a muco-adhesive nanocarrier and thus be directly delivered into the brain through the nasal route (Pangeni et al., 2014).

Future animal studies should further address the different mechanisms underlying the effects of RSV to elucidate whether one or several points of action lead to the multitude of biological effects (Vang, 2015). Furthermore, it might be questioned if current animal models—those, e.g., regarding AD—are a good representation of disease-related processes in humans and if useful information can be extracted from using these models or if their use should be discontinued (Franco and Cedazo-Minguez, 2014).

To improve human studies and clinical trials, several variables must be targeted. Among them, sample size generally needs to be increased (Novelle et al., 2015). Within the studies, the large range of dosages makes it difficult to compare results. Also, more accurate tracing studies assessing RSV concentrations and associated metabolites within human plasma, tissue, and organs after RSV treatment would add knowledge about relevant in vivo dosages (Vang, 2015). The combination of novel encapsulation techniques might further help resolve the problem of solubility, stability, and bioavailability in humans (Davidov-Pardo and McClements, 2014). Besides that, it is also noteworthy to define the most accurate and meaningful biomarkers of RSV in human blood and tissues (Franco and Cedazo-Minguez, 2014). Moreover, the time of administration appears to significantly influence results because e.g., Almeida et al. (2009) found morning administration of RSV to have a higher bioavailability.

Future clinical trials should also carefully select the study population under investigation, as selection bias minimizes positive outcomes (Franco and Cedazo-Minguez, 2014; Smoliga et al., 2013). In this context, also the genetic background (including single-nucleotide polymorphisms) and gene expression, along with differences in age, sex, diet, and physical activity should be monitored (Smoliga et al., 2013). Eventually, only large-scale randomized controlled trials and long-term epidemiological studies together with meta-analyses will help to provide definitive answers on the effectiveness of RSV in humans (Smoliga et al., 2013).

Conclusion

After resveratrol first attracted research interest in the context of the French paradox, more studies were employed and found the supposed health benefits to be not only restricted to cardiovascular outcomes but also extended to diabetes, obesity, and even cancer. As our population is turning older and older, it is important to prolong life span as well as add healthy years to the life span (Hubbard and Sinclair, 2014). Therefore, RSV containing foods and red wine in moderate amounts should be recommended as part of a fruit- and vegetable-enriched diet (Carrizzo et al., 2013). Recent research also focused on the effects of RSV on neurodegenerative diseases and cognitive functions. Here the few randomized controlled studies in humans indicate that RSV administration is well tolerated and might enhance cognitive performance in older populations, yet definite conclusions cannot be drawn to date. However, despite all the limitations and considerations for improving future trials, RSV remains a powerful drug candidate with multispectrum therapeutic application that might provide beneficial health outcomes in future trials (Novelle et al., 2015; Pangeni et al., 2014).