Resveratrol is a naturally occurring phytoalexin produced by some higher plants in response to injury or fungal infection. Phytoalexins are chemical substances produced by plants as a defence against infection by pathogenic micro organisms, such as fungi. Alexin is from the Greek, meaning to ward off or to protect. Resveratrol may also have alexin-like activity for humans. Epidemiological, in vitro and animal studies suggest that a high Resveratrol intake is associated with a reduced incidence of cardiovascular disease, and a reduced risk for cancer.

Resveratrol is found in grapevines (Vitis vinifera L). It occurs in the vines, roots, seeds and stalks, but its highest concentration is in grape skins. Wine also contains resveratrol. The concentration of resveratrol in red wine is much higher than that of white wine. The main difference between red and white wine production, besides the grapes used, is that for red wine the skins and seeds are involved in the process, while white wine is mainly prepared from the juice, essentially avoiding the use of grape skins and seeds. During the wine making process, resveratrol, as well as other polyphenols, including quercetin, catechins, gallocatechins, procyanidins and prodelphidins (condensed tannins), are extracted from the grape skins via a process called maceration.

Resveratrol, as well as the other polyphenols in wine, is thought to account in large part for the so-called French Paradox. The French Paradox—the finding that the rate of coronary heart disease mortality in France is lower than observed in other industrialized countries with a similar risk factor profile—has been attributed to frequent consumption of red wine.

In addition to grapes and wine, dietary sources of resveratrol include peanuts and mulberries. Resveratrol is also found in significant amounts in the dried roots and stems of the plant Polygonium cuspidatum Sieb. Et Zucc., also known as the Japanese knotweed. The dried root and stem of this plant is used in traditional Chinese and Japanese medicine as a circulatory tonic, among other things. This traditional Chinese and Japanese remedy is also known as Hu Zhang, Hu Chang, tiger cane, kojo-kon and hadori-kon. Most of the resveratrol-containing supplements which are marketed in the U.S. contain extracts of the root of Polygonium cuspidatum. Darakchasava, an ayurvedic herbal remedy, has as its principal ingredient Vitis vinifera L, and therefore, contains resveratrol. It is mainly used in ayurvedic medicine as a cardiotonic.

Resveratrol, which is also known as 3,4',5 trihydroxystilbene and 3,4',5-stilbenetriol, exists in cis- and trans-stereoisomeric forms. Resveratrol is the parent molecule of a family of polymers called viniferins. Cis- and trans-resveratrol occur naturally as do their glucosides. Resveratrol-3-O-beta-D-glucoside is also known as piceid, and the respective cis- and trans-glucosides are called cis-piceid and trans-piceid. The molecular formula of resveratrol is C14H12O3 and its molecular weight is 228.25 daltons. It is represented by the following structural formula:

Resveratrol

The stereoisomer of resveratrol found in grapes and peanuts is the trans-form. Both cis- and trans-resveratrol are found in Polygonium cuspidatum. Therefore, dietary supplements containing resveratrol, which are principally derived from this plant, contain both stereoisomers. The amount of resveratrol (trans-resveratrol) in peanuts ranges from 0.02 to 1.79 micrograms per gram. Red wine contains from 0.6 to 0.8 micrograms per milliliter, and fresh grape skin, approximately 50 to 100 micrograms per gram. A glass of red wine delivers on the average, between 600 to 700 micrograms of resveratrol.

ACTIONS AND PHARMACOLOGY ACTIONS
Resveratrol may have cardioprotective and antiproliferative actions.

MECHANISM OF ACTION
Resveratrol has several activities that may account for its possible cardioprotective action. These include inhibition of the oxidation of low-density lipoprotein (LDL), inhibition of smooth muscle cell proliferation and inhibition of platelet aggregation. Resveratrol has also been found to reduce the synthesis of lipids in rat liver and to inhibit the production of proatherogenic eicosanoids by human platelets and neutrophils.

Resveratrol's antioxidant activity may play an important role in its possible cardioprotective action. Above, was mentioned its ability to inhibit the oxidation of LDL. Resveratrol also has been found to exert a strong inhibitory effect on superoxide anion and hydrogen peroxide production by macrophages stimulated by lipopolysaccharides or phorbol esters. It also has been demonstrated to decrease arachidonic acid release induced by lipopolysaccharides or phorbol esters, or by exposure to superoxide or hydrogen peroxide. It has hydroxyl-radical scavenging activity and has recently been found to possess glutathione-sparing activity.

In a rat study of the effect of resveratrol on ischemia-reperfusion, it was found that the substance had a dramatic effect against ischemia-reperfusion-induced arrhythmias and mortality. Resveratrol pretreatment both reduced the incidence and duration of ventricular dysrhythmias, including ventricular tachycardia and ventricular fibrillation. Resveratrol pretreatment also increased nitric oxide and decreased lactate dehydrogenase levels in the carotid blood. In this example, the cardioprotective effect of resveratrol may be correlated with its antioxidant activity, upregulation of nitric oxide synthesis and protection against endothelial dysfunction.

Resveratrol's possible phytoestrogenic activity may also contribute to its possible cardioprotective action. Resveratrol appears to act as a mixed agonist/antagonist for estrogen receptors alpha and beta. It has been found to bind estrogen receptor beta and estrogen receptor alpha with comparable affinity but with 7,000-fold lower affinity than estradiol. Resveratrol differs from other phytoestrogens, which bind estrogen receptor beta with higher affinity than they bind estrogen receptor alpha. Resveratrol also shows estradiol antagonistic behavior for estrogen receptor alpha with some estrogen receptors. It does not show estradiol antagonistic activity with estrogen receptor beta.

Resveratrol's possible antiproliferative activity also may be accounted for in several different ways. Resveratrol's antioxidant activity was discussed above. It also has antimutagenic activity, as illustrated by its dose-dependent inhibition of the mutagenic response induced by treatment of Salmonella typhimurium strain TM677 with 7,12-dimethylbenz(a)anthracene (DMBA). Resveratrol has been found to inhibit cellular events associated with tumor initiation, promotion and progression. It has been found to inhibit cyclooxygenase (COX) activities in different cancer models, suggesting an effect at the level of tumor promotion. It has also been found to reverse tumor-promoter-induced inhibition of gap-junctional intracellular communication in rat epithelial cells. Inhibition of gap-junctional intracellular communication is an important mechanism of tumor promotion.

Resveratrol has demonstrated inhibition of growth of several cancer cell lines and tumors, suggesting that it has an inhibitory effect on cancer promotion/progression. It has been found to inhibit ribonucleotide reductase, DNA polymerase, the transcription of COX-2 in human mammary epithelial cells and the activity of ornithine decarboxylase. Ornithine decarboxylase is a key enzyme of polyamine biosynthesis, which is enhanced in tumor growth.

Resveratrol has also been found to induce phase II metabolizing enzymes which are involved in the detoxification of carcinogens, to upregulate apoptosis, to inhibit the progression of cancer by inducing cell differentiation and to inhibit protein kinase D and possibly protein kinase C. Recently, resveratrol has been shown to inhibit both NF-kappaB activation and NF-kappaB-dependent gene expression via its ability to inhibit IkappaB kinase activity, the key regulator of NF-kappaB activation. This appears to upregulate apoptosis.

It is clear that resveratrol has a wide range of activities that may account for its possible antiproliferative action. It is also clear that the mechanism of this possible action is far from being understood.

PHARMACOKINETICS
From animal studies and from limited human studies, it appears that resveratrol is absorbed from the gastrointestinal tract following its ingestion. However, the efficiency of its absorption, as well as its distribution, metabolism and excretion, are not well understood. Much research needs to be done in order to elucidate the pharmacokinetics of resveratrol in its various forms.

INDICATIONS AND USAGE
Epidemiological, in vitro and animal studies suggest that resveratrol has anti-atherosclerotic activity and that it might have some immune-stimulating and anti-cancer effects. Human studies are few in number and inconclusive due to short duration and poor design.

RESEARCH SUMMARY
There has been a suggestion from epidemiological data for some time that moderate consumption of red wine is associated with a reduced incidence of mortality and morbidity from coronary heart disease. In vitro and animal work has strongly suggested that resveratrol and other polyphenols found in grapes and wines are at least partially responsible for often-observed anti-platelet aggregating anti-inflammatory and anti-oxidant effects.

Red wine has been shown, in some experiments, to be more effective than other alcoholic beverages in decreasing some of the risk factors of coronary heart disease. Compared, in one study, with ethanol, resveratrol had superior anti-platelet-aggregation effects; it was superior in this respect, as well, to catechin, epicatechin, alpha-tocopherol, hydroquinone and butylated hydroxytoluene. Resveratrol also inhibited the synthesis of thromboxane B2 and hydroxy- heptadecatrienoate from arachidonate in a dose-dependent manner.

Other studies, in animals and in vitro, have shown that resveratrol can inhibit the oxidation of LDL-cholesterol and, more recently, that it can reduce smooth-muscle-cell proliferation, believed to be one of the requisites of atherogenesis, by 70-90%, in a dose-dependent pattern. Red wine extract and resveratrol have shown equally significant cardioprotective effects in animal models of myocardial ischemic reperfusion injury.

Additional evidence suggests that resveratrol also has estrogenic effects that may also provide cardiovascular protection. Bearing a structural resemblance to diethylstilbestrol, trans-resveratrol is a phytoestrogen found to have variable degrees of estrogen-receptor agonisms in different test systems.

The clinical data that would confirm or refute the relevance of these findings are largely lacking. In one small, short-term study, 24 healthy human subjects aged 26-45 consumed red wine, white wine, commercial grape juice and the same grape juice fortified with resveratrol over periods of 4 weeks. Results were mixed and conflicting, suggesting some positive benefit from resveratrol while also suggesting lack of activity in other measures related to coronary heart disease. The researchers themselves acknowledged multiple weaknesses in their study design. Further, better-controlled, longer-term studies are needed to determine whether red wine, high-resveratrol grape juice, or resveratrol supplements are efficacious in preventing atherosclerosis or in ameliorating it once it is present.

More preliminary yet are findings of some resveratrol-related anti-cancer and immune-stimulating effects. In a number of mostly in vitro studies, resveratrol has demonstrated an ability to inhibit tumor initiation, promotion and progression. Some of its antiproliferative activity is attributed to its observed ability to inhibit ribonucleotide reductase and DNA synthesis in mammalian cells. It has been shown to induce apoptotic cell death in human leukemia cell lines, as well as in some breast carcinoma cells.

Its antiestrogenic activity is also believed to play a role in its inhibition of human breast cancer cells in vitro. A partial estrogen-receptor agonist itself, resveratrol is believed by some researchers to be an estrogen-receptor antagonist in the presence of estrogen, resulting in breast cancer inhibition.

Finally, resveratrol has recently shown activity against herpes simplex virus types 1 and 2 in a dose-dependent manner. It appears to disrupt a critical early event in the viral reproduction cycle. More research is needed.

CONTRAINDICATIONS, PRECAUTIONS, ADVERSE REACTIONS
CONTRAINDICATIONS
Resveratrol is contraindicated in those hypersensitive to any component of a resveratrol-containing product.

PRECAUTIONS
Pregnant women and nursing mothers should avoid the use of resveratrol-containing supplements. They should also avoid the use of wine as a resveratrol source. Purple grape juice is a good and safe source of resveratrol, as well as other polyphenolic antioxidants.

DOSAGE AND ADMINISTRATION
Resveratrol, marketed as a nutritional supplement, is typically an extract of Polygonum cuspidatum (see Description). Such an extract contains both cis- and trans-resveratrol. The extracts are usually standardized to deliver about 8% resveratrol in its various forms. Many of the products currently marketed have resveratrol in combination with other phytonutrients and vitamins. Some supplements deliver 16 milligrams per serving or higher. There is no typical dosage.

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