Resveratrol Fights Brain Plaque

Resveratrol is a Natural Wonder

Resveratrol Fights
Brain Plaque

In laboratory experiments, the star molecule of
red wine helps remove the infamous amyloid-beta
By Dr. Hyla Cass

istening to advice on good health—let alone taking that advice and living accordingly—will never make anyone’s top ten list of fun things to do. It usually entails, after all, the avoidance of things we love, such as Häagen-Dazs and French fries, or the doing of things we hate, such as exercise (actually, exercise can be fun, if you do it right). Occasionally, however, a ray of light pierces the gloom, such as the news that chocolate, despite its high sugar and fat content, contains antioxidant bioflavonoids that are good for your heart, or that pizza, despite its high salt and fat content, contains lycopene, which is good for the prostate gland and which may also be protective against the recurrence of breast cancer.

Of course, overindulging in chocolate or pizza will quickly wipe out any potential health benefits and replace them with definite health liabilities—not to mention that bioflavonoids and lycopene are much more widely available in fruits and vegetables—so let’s be prudent, shall we?

Does Mother Nature Discriminate Against Women?

Another ray of light is that alcohol is good for you (which gives a new double meaning to “Cheers!”)—in moderation, of course, and if ever the word moderation applied with a vengeance, this is the place. By now you’ve probably often heard medical experts recommend that, for cardiovascular health, up to two drinks per day may be beneficial for men (abstaining all week so you can have 14 on Saturday night doesn’t count), and up to one drink per day for women.

But why the gender disparity? Is it because women’s hearts don’t need as much tender liquid care as men’s hearts (no, that’s not it), or is it simply that women are smaller than men, so it takes less alcohol to have an effect? It’s partly that, but the main reason is that (newsflash!) women are biochemically different from men. Specifically, on a pound for pound basis, women have substantially less than men do of the enzyme alcohol dehydrogenase, which metabolizes alcohol in the gut and liver. The result is that, when a woman has a drink, she winds up with disproportionately more alcohol in her bloodstream than a man does. You know the rest of that story.

Another Paradox—This One French

It sounds as though this article is going to be all about alcohol, doesn’t it? But it’s not. (For that subject, see the article “Going to a Party? Be Prepared!” on page 24 of this issue.) Here, alcohol is just a way of easing into the real subject of this article: resveratrol. That ungainly word (pronounced rez-VEER-ah-troll) denotes a chemical compound found most abundantly in the skins of red grapes and, therefore, in red wine. So to get plenty of resveratrol, you could drink plenty of red wine—but I don’t recommend that, for obvious reasons and for the nonobvious reason that the resveratrol content of red wines is highly variable. The only way to get the optimal amount of resveratrol reliably on a daily basis, therefore, is to take it as a supplement.

Now, why should anyone want to do that? There are numerous reasons, the most familiar of which is that resveratrol is the compound believed to be primarily responsible for explaining the “French Paradox,” the much publicized fact that the rate of cardiovascular disease in France is lower than one would expect, based on the well-known predilection of the French for sinfully rich, fatty foods. Along with those foods, the French regularly drink a good deal of red wine, which contains … resveratrol. (Contrary to a misconception, by the way, resveratrol is not a bioflavonoid, but, like all bioflavonoids, it is a polyphenolic compound, and it’s a strong antioxidant.)

Resveratrol: Antioxidant, Antimutagen, Anti-inflammatory … and Neuroprotectant?

Red wine also contains many hundreds of other chemical compounds, some of which—including alcohol itself (in moderation)—are also beneficial to our health. Since 1992, however, scientists have zeroed in on resveratrol as having a particularly strong protective effect against cardiovascular disease—and against cancer too. In fact, the respected American Heritage Dictionary says that resveratrol “may protect against cancer and cardiovascular disease by acting as an antioxidant, antimutagen, and anti-inflammatory.” When statements such as that make it into the dictionary, it’s a safe bet that they have been widely accepted by the scientific community.

Growing evidence suggests that future editions of the dictionary will say that resveratrol “may protect against cancer, cardiovascular disease, and neurodegenerative disease by acting as an antioxidant, antimutagen, anti-inflammatory, and neuroprotectant. It may also promote longevity by stimulating a gene-silencing mechanism that extends the lifespan of many organisms.” That last statement got your attention, didn’t it? It’s a fascinating aspect of resveratrol’s multifaceted capabilities, but it’s not the subject of this article. (For a discussion of the lifespan effect, see “Resveratrol May Be a Longevity Molecule” in the November 2003 issue of Life Enhancement.)


The type of amyloidosis called
“amyloidosis of aging” affects mainly
nervous tissue, the heart (where it
can lead to intractable congestive
heart failure), and the pancreas.


Here we are interested in research suggesting that resveratrol helps protect against Alzheimer’s disease, which is by far the most prevalent of the neurodegenerative diseases affecting mankind. It already afflicts about 4.5 million Americans, according to the Alzheimer’s Association, and that number could soar to 16 million by 2050 if no cure is found. Next best to a cure would be retardation of the disease’s progress and alleviation of its symptoms, but best of all would be prevention.*


*Prominent in the retardation and alleviation of Alzheimer’s disease (and perhaps in its prevention, although that is speculative) is the nutritional supplement galantamine, which has been the subject of many articles in this magazine over the past five years. For the most recent such article, see page 4 of this issue. Also important are the neuroprotective effects of omega-3 fatty acids, especially DHA; for an article on that subject, see page 19 of this issue.


Alzheimer’s Means Amyloid-Beta (Senile Plaques)

The effects of Alzheimer’s disease on the human brain are devastating. At autopsy, the most obvious sign is the massive loss of neurons in certain regions of the brain, especially the cerebral cortex and the hippocampus (the primary seat of memory function). Microscopic examination reveals the chief neuroanatomical signs of Alzheimer’s: neurofibrillary tangles and senile plaques, which are found inside and outside the neurons, respectively, in affected regions of the brain. The senile plaques are composed chiefly of a small protein called amyloid-beta (also called beta-amyloid), a nasty substance with no redeeming qualities.

Amyloid-beta molecules are initially formed inside the neurons as degradation products of a larger protein aptly called amyloid precursor protein (APP). Why our bodies produce APP is not known, but it’s unfortunate that they do, because this can lead to a process called amyloidosis, which is the accumulation of amyloid deposits (not necessarily amyloid-beta) outside the cells in many different organs and tissues. The type of amyloidosis called “amyloidosis of aging” affects mainly nervous tissue, the heart (where it can lead to intractable congestive heart failure), and the pancreas.

Amyloids are produced by the cleavage (breakdown) of APP molecules by certain enzymes. This process, which appears to be induced in part by oxidative stress caused by free radicals, undoubtedly begins long before any symptoms of Alzheimer’s disease become apparent; it may even begin before the symptoms of mild cognitive impairment (a common precursor condition to Alzheimer’s) become apparent. In any case, the cleavage of APP molecules produces a variety of fragments, two of which are the ones that form the destructive amyloid-beta plaques in Alzheimer’s brains.

Resveratrol Helps Remove Amyloid-Beta …

A prime objective of Alzheimer’s research is to find ways in which to prevent amyloid-beta from forming in the brain. Toward that end, studies with resveratrol were conducted recently by scientists at the Litwin-Zucker Research Center for the Study of Alzheimer’s Disease and Memory Disorders at the North Shore-Long Island Jewish Institute for Medical Research in Manhasset, New York, and reported in a not-yet-finished paper.1 Using a variety of sophisticated biochemical techniques with cultures of human embryonal kidney cells, they were able to establish that resveratrol did not affect the production of amyloid-beta molecules inside the cells.


Amyloid formation may even begin
before the symptoms of mild
cognitive impairment (a common
precursor condition to Alzheimer’s
disease) become apparent.


That was disappointing. But wait—they discovered something else, namely, that resveratrol promoted the clearance of amyloid-beta molecules that had already formed. That was exciting, and the next question, obviously, was how? The researchers thought that resveratrol might somehow accomplish this through the action of certain proteins called metalloendopeptidases, of which there are at least four that are known to degrade amyloid-beta in living organisms. Their results showed, however, that this was not the case.


They discovered that resveratrol
promoted the clearance of
amyloid-beta molecules that had
already formed. That was exciting.


… By Means of an Awesome Molecular Machine

The researchers were finally able to identify the mechanism as being mediated via large (by molecular standards) cellular-protein disposal units called proteasomes, which themselves consist of a complex assembly of specialized proteins. One way in which they were able to confirm this mechanism was by the observation that when known proteasome inhibitors were used, resveratrol ceased to be effective. Another way was by suppressing the gene that codes for one of the critical protein subunits of the proteasome; when the cells were thereby made deficient in this protein, the effectiveness of resveratrol was again strongly curtailed. (See the sidebar “Demolition Derby with Proteasomes” for how these molecular machines work.)

Demolition Derby with Proteasomes


The basic structure of a human proteasome. Each sphere represents a large, complex protein molecule. The four maroon and blue rings of proteins constitute the channel where proteins to be disposed of are dismembered by intermolecular forces. The multicolored protein complex (shown here at one end only) is one of the two gatekeeping “lids” that open to allow amino acid chains to enter the channel.
A proteasome is a kind of molecular shredding machine found in the cells of all organisms, from fungi and bacteria to plants and animals. Its function is to chop up a great variety of cellular proteins that, for one reason or another, need to be disposed of so that their constituent amino acids can be recycled into new proteins. This is a never-ending process.

Proteasomes are themselves made of proteins (28 different kinds in the human version), and their basic architecture—cylindrical, with an open channel—is the same in all species. In the human proteasome, the cylinder consists of four stacked protein rings. At each end of the stack is a movable protein structure that serves as a kind of gatekeeping “lid” for the channel.

Before the molecular demolition can begin, the target protein must be identified and captured. This critical task is performed by hosts of small proteins called ubiquitins (because they’re everywhere). They then deliver their hapless victim to a proteasome, where the protein is uncoiled (most proteins are normally coiled up in very complicated ways) by “lid” proteins called ATPases. Then the lid opens, and the now long, skinny chain of amino acids is pulled by intermolecular forces down the proteasome channel, like a strand of spaghetti being threaded through a stack of Cheerios. As the chain disappears down the channel … chop chop chop. [No, there are no tiny knife blades—all the action occurs through intermolecular forces that are governed (as are all chemical reactions everywhere) by the laws of quantum mechanics.]

In this way, thanks to resveratrol, the amyloid-beta molecules in the study described in the accompanying article met their doom. The question is, how did resveratrol make amyloid-beta look like a target to the ubiquitins, or how did it induce the proteasomes to devour the amyloid-beta? We have no idea, but it will certainly be worth finding out. Stay tuned.

Although the mechanism by which resveratrol induces the proteasomes to destroy amyloid-beta remains unknown, the authors pointed out the intriguing fact that a decrease in proteasome activity occurs in the brains of Alzheimer’s disease victims (it is not clear, however, whether this decline coincides with increased amounts of amyloid-beta). It has even been proposed that amyloid-beta itself may be responsible for inhibiting proteasome activity, thereby creating a vicious cycle that spawns ever more amyloid-beta.

Here’s to Resveratrol!

Although the laboratory research described above tells us very little about what resveratrol might do to amyloid-beta in the aging brains of living organisms (namely, ourselves), it does encourage us to think that its action may indeed be beneficial. That hope seems justified in light of all the other benefits of resveratrol that are already well established. Whether you’re a man or woman, a teetotaler or one who enjoys a glass of wine with dinner, you might be doing yourself a lot of good by supplementing with resveratrol.

Cheers!

Reference

  1. Marambaud P, Zhao H, Davies P. Resveratrol promotes clearance of Alzheimer’s disease amyloid-b peptides. J Biol Chem 2005 [unedited online preprint].

Resveratrol Inhibits Genital Herpes

Anyone who has ever had cold sores caused by the herpes simplex virus can probably appreciate how painful it must be to have similar sores on the genitals. Worldwide, about 86 million people know what it’s like from firsthand experience, because they have the virus for genital herpes.1 Once you get it, it never goes away. It can remain dormant for years, only to flare up again for a new round of lesions when triggered by some event, such as fever, physical or emotional trauma, or suppression of the immune system—or it can strike for no apparent reason. Fortunately, each episode lasts only about a week.


Computer-generated image of the basic structure of a herpes simplex virus. The protein coat shown here encloses the nucleic acid core.
Actually, there are two types of herpes simplex virusHSV-1 and HSV-2—and both are contagious. Type 1 is associated mainly with lesions on the lips, and type 2 with lesions on the genitals, although type 1 can affect the genitals as well. Either way, the epi- sodes are most unpleasant, and the infection, even when apparently dormant, can be dangerous in a pregnant woman. That’s because it can be transmitted to the infant during delivery, resulting in serious illness or even death.

The standard treatment is with the synthetic drug acyclovir or its derivatives, taken orally or topically. Researchers have been trying, however, to find safe and effective treatments using natural plant products, and positive results have been achieved with a variety of plant extracts. One such success entailed the use of resveratrol against HSV-1 skin infections in mice.2

Recently the same research team investigated whether resveratrol was also effective against HSV-2 (and HSV-1) female genital infections.3 After inducing infections in the vaginas of mice, they tried a variety of topical treatments, using different resveratrol concentrations (in a polyethylene glycol cream), different times of administration after the infection, and different numbers of treatments per day. The trials lasted for 11 days.

The results depended strongly on all the factors above, including the virus type, and some were quite good: the researchers found that, in general, a 19% resveratrol cream could significantly reduce morbidity and mortality in the mice, as well as replication of the virus in their vaginas. In one trial, resveratrol was tested against acyclovir, and the two agents were similarly effective.

The mechanism by which resveratrol worked in this study is unknown, but the authors stated, “Its low toxicity, ready availability, anti-HSV properties, anti-inflammatory properties, and ease of use make it a viable candidate for a new and novel anti-HSV agent.”

References

  1. Halioua B, Malkin JE. Epidemiology of genital herpes—recent advances. Eur J Dermatol 1999;9:177-84.
  2. Docherty JJ, Smith JS, Fu MM, Stoner T, Booth T. Effect of topically applied resveratrol on cutaneous herpes simplex virus infection in hairless mice. Antiviral Res 2004;61:19-26.
  3. Docherty JJ, Fu MM, Hah JM, Sweet TJ, Faith SA, Booth T. Effect of resveratrol on herpes simplex virus vaginal infection in the mouse. Antiviral Res 2005;67:155-62.


Hyla Cass, M.D., is assistant clinical professor of psychiatry at UCLA and chair of the Dept. of Complementary and Alternative Medicine at the American University of Complementary Medicine. She has written several books on herbal supplements.

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