People have been consuming red wine for thousands of years. Although most people drink wine because of its pleasurable sensory effects, recent studies suggest that drinking red wine may confer several health benefits. Many researchers believe that these health benefits come from a compound in red wine called resveratrol, which has been shown to exhibit neuroprotective effects in several experimental studies in test tubes as well as in various organisms including yeast, worms, and mice. A few studies also provide insight into how resveratrol may affect mice with neurodegenerative disorders and more specifically mice with the mutant huntingtin protein.
Preliminary research has suggested that resveratrol may help protect against common HD complications such as inflammation, oxidative stress, and possibly huntingtin protein aggregation. (For more information on inflammation, click here.) Further studies of resveratrol in the context of neurodegeneration and Huntington’s disease (HD) are required to understand the role of resveratrol and to assess its efficacy as a therapeutic agent. This chapter gives an overview of our current understanding of how resveratrol may combat disease, as well as how these mechanisms may have potential for HD treatment.
Resveratrol in Red Wine^
Scientists became interested in exploring the health benefits of resveratrol when its presence was first reported in red wine, leading to the possibility that it could explain a health phenomenon known as the “French Paradox.” Despite the fact that the French diet is high in saturated fats, the rate of heart disease is lower than that observed in other industrialized countries. This paradox led to the idea that regular consumption of red wine (and thus a higher consumption of resveratrol) may provide additional protection from cardiovascular disease. Recent studies have indicated that resveratrol is not the sole agent responsible for the cardioprotective effects associated with red wine consumption, and that other highly potent red wine constituents may have even greater effects.
Why not white wine or wine in general? The skins and seeds of grapes are used in the production of red wine, but not in the production of white wine. Because resveratrol is most highly concentrated in grape skins, the concentration of resveratrol is significantly higher in red wine than in white wine.
Resveratrol is one member of a class of compounds known as phytoalexins; “phyto” meaning “plant” and “alexin” meaning “to ward off or protect.” Phytoalexins are produced by some plants to respond to stressors such as injury, fungal infection, or ultraviolet radiation. Remarkably, resveratrol may be able to protect humans as well as plants. Studies suggest that a high resveratrol intake is associated with reduced incidence of heart disease, cancer, and age-related diseases such as Alzheimer’s disease. HD may also be a part of this list, but additional research is needed to test this notion.
Alcohol: The Fine Line Between Moderation and Excess^
Alcohol itself (better known in chemistry as ethanol) is toxic to the human body and has no redeeming qualities from a health perspective. After alcohol is consumed, a person’s blood alcohol level rises and the body begins to “detoxify” the alcohol. The first step in this process is the conversion of alcohol to another compound called acetaldehyde. Acetaldehyde stays in the body for several hours, producing a variety of undesirable toxic effects. Acetaldehyde binds readily to the walls of red blood cells. By attaching itself to the red blood cells, acetaldehyde reduces the oxygen supply to most of the cells of the body, including the brain. Acetaldehyde also combines with hemoglobin in the red blood cells and further reduces its ability to carry oxygen, which eventually leads to hypoxia (oxygen starvation at the cellular level).
Additionally, acetaldehyde interferes with the process of microtubule formation. Microtubules are essential to the brain because they provide structural support for nerve cells and their dendrites and they also transport chemicals manufactured in the nerve cells to the dendrites. Without microtubules, dendrites weaken and die. Deficiencies in various vitamins are also induced by acetaldehyde. Although individuals vary in vulnerability to acetaldehyde, it is clear that acetaldehyde is a dangerous and toxic chemical. In addition to the complications already mentioned, alcohol can also do significant damage to the liver and central nervous system. Thus, one must exercise caution when dealing with a powerful substance like alcohol and weighing its potential benefits and costs.
Roles of Resveratrol^
Oxidative stress (also known as oxidative damage) is believed to play a major role in the damage of nerve cells in HD. (For more information on oxidative stress, click here.) Studies indicate that resveratrol is an excellent antioxidant, which means that it is very good at combating oxidative stress. What makes resveratrol such a good antioxidant? Researchers believe that it works by inhibiting monoamine oxidase (MAO), an enzyme primarily found in the liver and nervous system that generates free radicals. Free radicals are dangerous because they are highly reactive. They tend to react with important structures in cells and accelerate cell injury. By reducing levels of MAO, resveratrol decreases the number of free radicals that degrade nerve cells. Decreasing the level of free radicals may slow the progression of neurodegenerative diseases such as HD.
In scientific studies, injecting resveratrol into rats led to decreased levels of certain free radicals in the brain. Additionally, the activities of several antioxidant enzymes increased. Not only can resveratrol help to prevent free radicals from forming, but it can also decrease the toxicity of free radicals by inhibiting a process called lipid peroxidation. Lipid peroxidation is the process whereby free radicals take away electrons from the lipids that make up our cell membranes and thereby cause damage to the cell. (For more information on lipid peroxidation, click here.) Rat studies indicate that resveratrol significantly inhibits lipid peroxidation in cells.
While resveratrol has been shown to be a powerful antioxidant in vitro and in rats, its role as an antioxidant has yet to be tested and confirmed in humans. Because circulating and intracellular levels of resveratrol in humans may be much lower than in vitro models, its true effects on the human body are controversial.
Long-term, or chronic inflammation in the brain is believed to play a significant role in neurodegeneration in HD. Studies indicate that resveratrol acts as an anti-inflammatory agent mainly by inhibiting the action of two key enzymes: cyclooxygenase and lipoxygenase. These enzymes lead to the production of leukotrienes and prostanoids, which are chemicals that significantly contribute to the inflammatory process. Resveratrol inhibits cyclooxygenase and lipoxygenase and their production of inflammatory substances, causing inflammation to decrease.
Resveratrol may also inhibit pro-inflammatory transcription factors, which increase inflammation. Transcription factors are proteins that bind to DNA and regulate gene expression by promoting transcription. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and activator protein-1 (AP-1) are examples of pro-inflammatory transcription factors. NF-kB is a transcription factor for genes that helps cells to survive, bind to a surface, specialize and grow. It is also involved in cell inflammation. AP-1, or activator protein-1, is also a transcription factor involved in cell proliferation and survival. Research has shown that most anti-inflammatory agents suppress NF-kB activation. Studies have indicated that resveratrol may inhibit NF-kB and AP-1 pathways, thus preventing inflammation. Resveratrol has been shown to decrease levels NF-kB directly and indirectly via inhibition of associated MAP kinases, which is discussed in the “MAP kinase” section of this article.
It is still unclear how resveratrol decreases inflammation. Some studies have shown that these anti-inflammatory effects may be partially due to resveratrol’s antioxidant capabilities, while others have shown that resveratrol’s anti-oxidant and anti-inflammatory capabilities are independent of one another. Further research is necessary to arrive at a scientific consensus.
Resveratrol has been shown to have neuroprotective effects in neurons, in rat brains and in cell culture. This suggests that the anti-inflammatory capabilities of resveratrol could potentially be beneficial in HD treatment. However, this hypothesis remains to be tested.
How Resveratrol Works^
Resveratrol has a very simple chemical structure, which enables it to play a role in a wide range of biological processes. As a result, resveratrol is able to act upon many different systems within the body. The following sections discuss some potential mechanisms through which resveratrol may exert its effects. Please note that the mechanisms outlined in the sections “Heme oxygenase,” “MAP Kinase,” “Sirtuins,” and “Prevention of Neurodegeneration,” are interdependent and influence one another in ways that are not yet understood by the scientific community.
Similar to resveratrol, an enzyme called heme oxygenase (HO) also decreases oxidative stress and inflammation. Because of this similarity, researchers hypothesized that resveratrol might exert its function via a mechanism involving HO. This hypothesis was supported by a study that found that when resveratrol was administered to rats, the amount of HO in the rats’ neurons increased. The effect was dose-dependent, meaning that levels of HO increased as more resveratrol was administered. The connection between resveratrol and HO is important because HO is thought to have neuroprotective effects. In addition to being a powerful antioxidant, HO also produces several byproducts that may assist in cell survival.
HO is involved in regulating cellular uptake and storage of iron. Iron levels must be tightly regulated because adequate amounts of iron are essential for many cellular functions, but excessive amounts of iron can lead to the formation of reactive oxygen species (ROS). A ROS is a highly volatile compound, which is likely to damage cells. When resveratrol increases the amount of HO, higher levels of HO may in turn affect the level of iron in the cells. Thus, one way resveratrol may exert its neuroprotective effects is by stimulating HO to balance out iron levels and protect from iron-mediated toxicity.
Although the connection between resveratrol and HO is quite intriguing, further research is needed to determine the exact details of how they work together to protect nerve cells.
Numerous studies have demonstrated that resveratrol interacts with certain mitogen-activated protein (MAP) kinase family members. MAP kinases are proteins that respond to stimuli and regulate important cellular functions including gene expression cell survival and differentiation.
Earlier studies of MAP kinases indicated that resveratrol activated all three subfamilies of the enzymes, some of which have been linked to changes in brain cells changes that form the basis of memory and learning processes. However, the relationship between resveratrol and memory and learning processes has not been tested since the preliminary studies were published.
More recent studies have investigated how the effects of resveratrol on MAP kinases influence the expression of inflammatory mediators NF-kB and AP-1. See the “Anti-inflammatory Capabilities” section in the article to learn more about NF-kB and AP-1. In short, resveratrol inhibits NF-kB and AP-1 by acting on MAP kinases. MAP kinases reduce inflammation in part by encouraging cell death. Studies have also suggested that the inhibition of NF-kB combats beta-amyloid plaques in neurons, helping neurons survive. See the section on “Resveratrol and the Prevention of Neurodegeneration.”
The MAP kinase subfamilies are most likely related to a wide range of other processes, some of which are related HD. It is possible that some MAP kinases regulate heme oxidase, helping to combat oxidative stress and reduce chronic oxidative damage. (See “Heme Oxidase”)
Modulation of MAP kinases by resveratrol may inhibit or activate various pathways which in turn could reduce inflammation, promote cell death when need be, and protect against buildup of toxic protein fragments. However, such potential effects of resveratrol on MAP kinase related pathways and the potential relevance to HD still must be investigated.
Studies in yeast and fruit flies have demonstrated that resveratrol activates a group of enzymes called sirtuins, which promote longevity in a variety of organisms. Sirtuins are important for many cellular processes including gene silencing, regulation of the cell cycle, fatty acid metabolism, apoptosis and longevity. Research has also shown that resveratrol activates an enzyme called SIRT1, the human analog of the Sir2 protein, which is found in yeast. The function of SIRT1 in humans is similar to that of Sir2 in yeast; it mediates the cell cycle, protects the cell during stress, regulates transcription, prevents the destruction of axons, and is involved in extending the life span of cells. In mice, increased production of the SIRT1 gene shows both a protective and pro-aging role in neurons. Furthermore, researchers have demonstrated that both resveratrol and direct expression of the SIRT1 gene slow neurodegeneration and cognitive decline in mouse models of Alzheimer’s disease (AD).
The majority of research supports the hypothesis that resveratrol, by stimulating the activity of sirtuins, mimics the effects of calorie restriction. (For more information on dietary restriction, click here.) Calorie restriction has extended the life span in rodents and primates through a variety of mechanisms, one of which includes increasing levels of SIRT1. It has even been shown to slow disease progression and increase survival in huntingtin mutant mice. Both calorie restriction and resveratrol can decrease chronic oxidative damage, inhibit inflammatory pathways, and increase energy production in the cell. While a few studies suggest that sirtuins act independently of pathways mediated by calorie restriction, these studies do not propose an alternative mechanism for sirtuin action. Regardless of the relationship between resveratrol and calorie restriction, activation of SIRT1 proteins has had positive effects on a variety of organisms including mouse models for HD and AD. This suggests that resveratrol itself may have the potential to delay the onset and progression of HD symptoms.
Resveratrol and the Prevention of Neurodegeneration^
Resveratrol has demonstrated neuroprotective effects through its anti-oxidant and anti-inflammatory capabilities, as well as its influence on sirtuins. Expanding upon these claims, numerous epidemiological studies (studies related to epidemiology) have determined that moderate red wine consumption is correlated with a lower incidence of dementia and a reduction in Alzheimer’s disease. (For a comparison of Alzheimer’s and HD, click here.) Nevertheless, it should be noted that the notion that red wine intake lowers AD risk is controversial. Based upon controlled studies, a dose of resveratrol much higher than the amount in red wine is needed for any positive effects. The correlation between reduced risk of dementia and moderate red wine consumption does not mean that red wine consumption or resveratrol are responsible for the reduced risk. Studies are ongoing to prove if correlation will translate to causation in this case.
Evidence suggests the possibility that resveratrol can prevent neurodegeneration in AD via protection against beta-amyloid plaques. Beta-amyloid (Aβ) plaques are an accumulation of small fibers called beta-amyloid fibrils and are present in the brains of people suffering from Alzheimer’s disease (AD). (For more on beta-amyloid plaques, click here.) These plaques are thought to greatly contribute to the neurodegenerative process of AD. Over the past decade, there has been compelling evidence that resveratrol has the ability to protect against the neurotoxic effects of amyloid-related proteins.
In one study, researchers treated mice injected with the AD gene with resveratrol, which reduced the number of Aβ plaques. Another study found that moderate consumption of red wine lowered Aβ levels and reduced its neurotoxic effect, implying that red wine intake may have a beneficial effect against AD pathology by promoting mechanisms that work against the accumulation of beta-amyloid plaques. Additional studies in mice and in cell cultures have supported these findings.
Because of the parallels between huntingtin protein aggregates and beta-amyloid fibrils, these results are promising developments in the search for treatments for neurodegenerative disorders like HD. It is possible that resveratrol may also have the ability to decrease huntingtin protein aggregates. However, this hypothesis remains to be tested and other substances that have decreased beta-amyloid fibrils have had no effect on huntingtin protein aggregates.
Future studies aimed at elucidating a more detailed understanding of the various cellular mechanisms involved in the neuroprotective effects of resveratrol have the potential to open new avenues for the treatment of neurodegenerative diseases such as HD. It is necessary to further study resveratrol in animals and most importantly, humans, before it can be proven as a safe, effective treatment for HD.
Therapeutic Potential of Resveratrol^
There are two measures that are used to determine the effectiveness of a drug: pharmacokinetics, how the body processes a drug, and bioavailability, the degree to which a drug or other substance becomes available to the target tissue after administration. Both the pharmacokinetics and bioavailability of resveratrol are still inconclusive. Studies in mice, rats and dogs have consistently shown that resveratrol can be absorbed and distributed in the blood stream at relatively high concentrations. However, due to its rapid metabolism and elimination from the human body, the potential impact of resveratrol on humans is debatable. There are a few major problems with resveratrol:
First, humans who receive an oral dose have plasma concentrations of resveratrol that peak after only 30 or 60 minutes. This shows that resveratrol is indeed metabolized quickly and may not be able to exert its positive effects before being metabolized.
Second, the dose of resveratrol needed to experience positive health effects remains unclear. Sirtris Pharmaceuticals Inc. is using very high doses in phase II clinical trials (2500 mg and 5000 mg per day) of this drug for diabetes. However, other scientists believe resveratrol supplements should be taken in lower doses. No other human clinical trials or studies have been conducted in order to determine the amount of resveratrol needed to exert its positive effects. The amount of resveratrol in a bottle of red wine can vary between types of grapes and growing seasons, and can vary between 0.2 and 5.8 milligrams per liter. While some research suggests that drinking a moderate amount of red wine (1 to 3 glasses a day) may provide enough of the active compound to exert protective effects, controlled scientific studies have not been undertaken to verify this hypothesis. Although resveratrol can be concentrated and obtained in capsule form, taking these supplements may not have the same effect as drinking red wine, primarily due to the reason explained below.
Third, resveratrol degrades quickly when it is exposed to oxygen. For example, resveratrol is no longer active in wine if the bottle has been opened for 24 hours. This directly applies to the manufacturing of resveratrol supplements, which are most likely exposed to air during the manufacturing process or storage. This presents an obstacle to supplement preparation and necessitates careful handling of the substance. It is very likely that the majority of marketed preparations of resveratrol do not contain the active form that is found in red wine.
While a few phase I clinical trials have shown that resveratrol is safe in certain doses for healthy participants and people with type II diabetes, many more clinical trials on humans are necessary before conclusions can be made regarding the effects of resveratrol in the context of neurodegenerative diseases such as Huntington’s disease.
Resveratrol has been shown to have wide-ranging positive effects on many diseases. Research has revealed resveratrol’s ability to protect against some of the common HD complications by decreasing inflammation, combating oxidative stress, increasing the energy production in cells, and potentially reducing huntingtin protein aggregates. However, it is important to note that nearly all of the research on resveratrol has been done in cell culture and in mice, and this data may not necessarily apply to humans. As more studies are conducted regarding the mechanism of resveratrol, the amount necessary in human body in order to have protective effects, and the effects of resveratrol supplements in humans, we will have a better idea about how resveratrol works and whether it will be an effective treatment for patients with neurodegenerative diseases such as HD.
For further reading^
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- Duan W, Guo Z, Jiang H, Ware M, Li XJ, Mattson MP. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci U S A 2003 Mar 4;100(5):2911-6.
- Department of Pharmacology, University of Seville. Review: Resveratrol as an anti-inflammatory and anti-aging agent: Mechanisms and clinical implications. Molecular Nutrition and Food Research. 2005 February.
- Han Y., Zheng W., Bastianetto S., et al. Neuroprotective effects of resveratrol against β-amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C. British Journal of Pharmacology. 2004 March; 141(6): 997–1005.
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-D. McGee, 01/11/05, and P. Bakhai, 6/19/10