Resveratrol May Be Good for the Brain
Can Resveratrol Help
Preventing amyloid-beta neurotoxicity in
laboratory experiments is a promising sign
By Hyla Cass, M.D.
recent story on 60 Minutes outlined the career of Peter Salerno, a notorious American cat burglar. By all accounts, he was the best of his rare breed, a Houdini in reverse, a magician at breaking and entering the supposedly impregnable mansions of the superwealthy, whom he would skillfully relieve of their jewels. (This did not sit well with their insurance companies.)
Salerno and his accomplice (his brother-in-law, Dominick Latella, who was the lookout and logistics guy) were known as the Dinner Set Gang because of their daring MO: they would hit their victims while they were at home, having dinner—typically, an elegant, drawn-out dinner party with guests from the Social Register—which meant that the alarm system would be off and no one would be upstairs, where the jewels were.
Here, Kitty, Kitty . . .
Levitate up the outside wall, slip into the master suite, find the hidden jewels (Salerno had an uncanny knack for that), drop back down again, and disappear into the night. The time inside: 3 minutes max. The haul: usually hundreds of thousands, sometimes millions. Although their fence, a “reputable” broker on Manhattan’s diamond exchange, gave them only ten cents on the dollar, they and their twin-sister wives were still wallowing in money.
Salerno is currently indisposed (i.e., doing hard time), but he and Latella, who’s out now, eluded the police so masterfully for so many years that the detectives who were tracking the slippery duo were actually saddened when they finally nailed them—the chase was over, and there was no more excitement to look forward to. The cops’ succinct assessment of the situation: “This sucks.”
When Brain Is on the Menu
Something else that sucks (aha—the segue) is Alzheimer’s disease (AD), which strikes not boldly or quickly, but nonetheless like a thief in the night, quietly stealing your most precious jewels: your memories, your capabilities, your very personality, and, finally, your life. In cat burglar fashion, AD hits you “upstairs” while your alarm system is off and you’re too busy with life to notice that anything is amiss. By the time you do notice (or your family or friends notice), the damage is done, and you will never again be the same. You are destined to fade away in what Nancy Reagan so poignantly called “the long goodbye.” It’s a story written in tears and sweat for the caregivers, whose own lives are typically shortened by the crushing burdens they must carry.
A striking difference between cat burglary and AD is the fact that the “burglar” in AD doesn’t bother to make a getaway. Instead, he simply settles in upstairs and methodically eats you out of house and home. Certain portions of your brain will slowly be destroyed, resulting in the most conspicuous neuroanatomical hallmark of the disease at autopsy: a massive loss of brain tissue. It’s not a pretty sight (an example can be seen in the article
“Galantamine Suppresses Brain-Cell Suicide” in the February 2004 issue).
Amyloid-Beta, Meet Resveratrol
And just who is this audacious burglar with a taste for brain? It’s amyloid-beta, a molecular villain if there ever was one. Amyloid-beta is a small protein molecule (small, that is, by the standards of proteins, which are typically enormous). It constitutes the bulk of the destructive brain deposits called senile plaques, which kill neurons, causing progressive deterioration of memory and other cognitive functions. These plaques, which are extracellular (forming outside the neurons), are also visible at autopsy, albeit only under a microscope. They occur mainly in the hippocampus (the primary locus of memory and learning) and the cerebral cortex. Another pathological feature that can be observed under the microscope is intracellular neurofibrillary tangles, which are twisted, filamentary structures found inside the neurons of the hippocampus and cerebral cortex.
Together, senile plaques and neurofibrillary tangles wreak biochemical and anatomical havoc in the brains of Alzheimer’s victims. Since the plaques are considered to be the more destructive of the two, a key objective of medical science is to find ways to prevent the formation of amyloid-beta. In the November 2005 issue of Life Enhancement, we published a story (
“Resveratrol Fights Brain Plaque”) describing the efforts of a research team in New York to do just that, using the remarkable plant polyphenol resveratrol (rez-VEER-a-troll), a red-wine-derived compound already celebrated for its role in helping to prevent cancer and cardiovascular disease and, perhaps, to extend lifespan by slowing the aging process.*
Amyloid-beta deposits (senile plaques) in an Alzheimer’s brain.
Resveratrol Helps Destroy Amyloid-Beta . . .
The researchers were disappointed: in their experiments with cultures of human embryonal kidney cells, resveratrol failed to prevent the production of amyloid-beta molecules. Disappointment turned to gratification, however, when they discovered that resveratrol promoted the clearance of amyloid-beta molecules that had already formed. Resveratrol apparently does this by inducing the destruction of amyloid-beta, in a process that involves intracellular molecular “shredding machines” called proteasomes.
Wait a minute, you say—if senile plaques are extracellular, how can amyloid-beta molecules be destroyed by intracellular shredders? The answer is simple: all proteins are manufactured inside cells, but some proteins leave the cells to do their work (including dirty work, such as that of amyloid-beta) outside the cells. Thus, if amyloid-beta can be destroyed while it’s still inside the cells—or, better yet, if it can be prevented from forming in the first place—there will be no senile plaques and, therefore, no Alzheimer’s disease, at least not as we know it.*
. . . But Prevention Is the Holy Grail
So prevention remains the Holy Grail of Alzheimer’s research, and there is zero chance that scientists will give up on it. A recent effort in this regard has just been published by a research team at the Gladstone Institute of Neurological Disease, University of California, San Francisco. Using cultured cerebral cortex cells from newborn rats, the researchers sought to clarify the biochemical role of a protein called nuclear factor-kappa B (NF-kappa B) in amyloid-beta neurotoxicity and to determine whether agents (such as resveratrol) that inhibit this protein can protect against neurodegeneration caused by amyloid-beta.
NF-kappa B is a transcription factor, i.e., it’s a kind of protein that can regulate gene activity through its role in facilitating the transfer (transcription) of genetically coded information from DNA molecules to RNA molecules. That information subsequently becomes the basis for the synthesis of many thousands of different kinds of proteins, each of which owes its structure to a specific gene in our DNA. There was reason to believe that NF-kappa B, which mediates immune and inflammatory responses in our bodies, may be implicated in the development of AD. The UCSF experiments appeared to confirm this.
The researchers found, in fact, that activation of NF-kappa B plays a critical role in mediating amyloid-beta neurotoxicity in rat cortical cultures consisting of both neurons (nerve cells) and microglia. The latter are one of four types of glial cells, which are nonneuronal cells of the central and peripheral nervous systems; they vastly outnumber the neurons and play a variety of important roles in nervous system function. Microglia are debris-scavenging cells that are functionally related to similar but larger cells called macrophages. Like macrophages, they contribute to inflammation by secreting proinflammatory compounds, such as cytokines.
Neuroprotection Comes from a Longevity Gene . . .
It turns out—in the UCSF experiments, at least—that amyloid-beta neurotoxicity depends critically on the presence of microglia and that, as mentioned above, NF-kappa B plays a vital role in this process, which leads to the neurodegeneration so characteristic of AD. Thus, the researchers reasoned, it would be desirable to interfere with the ability of NF-kappa B to function in this manner. Using recombinant DNA technology (genetic engineering), they caused a gene called SIRT1 to be overexpressed, meaning that the synthesis of the protein for which it codes was enhanced beyond normal levels. Overexpression of SIRT1 strongly inhibited the amyloid-beta-stimulated activation of NF-kappa B, thus providing powerful neuroprotection against amyloid-beta neurotoxicity.
If the name SIRT1 rings a bell, it may because you recall that this is no ordinary gene. It is, in fact, the mammalian version of a class of longevity genes, called Sir2, that are intimately involved in regulating the lifespans of a vast range of organisms, from yeasts to roundworms to fruit flies to rodents—and, probably, to primates, including humans. The actual effects are brought about by the proteins, called sirtuins (sir-TWO-ins), that the Sir2 genes code for. (The great importance of these genes was discussed in the November 2003 resveratrol article mentioned above; a more recent discussion can be found in the article
“Can Nitric Oxide Increase Lifespan?” in the January 2006 issue.)
. . . Whose Action Is Stimulated by Resveratrol
So SIRT1 appears to play a role not just in regulating lifespan but also, perhaps, in providing neuroprotection—and it’s not hard to imagine that there may be a connection there, although this remains to be demonstrated. In any case, overexpression of SIRT1 through genetic engineering is not a viable option for human beings (at least not yet), so what we want is a more conventional means of stimulating the SIRT1 gene in our DNA to higher levels of activity. Enter resveratrol, which, among its other biochemical accomplishments, is known to do just that.
Sure enough, when the UCSF researchers added resveratrol to their cell cultures, they found that it strongly inhibited amyloid-beta neurotoxicity. An interesting twist on this result is that it applied only in the presence of microglia: when the experiment was conducted in cultures of neurons from which almost all microglia had been removed, resveratrol showed no protective effect whatever. Thus, neuroprotection depended on there being a mixture of neurons and microglia—as is the case, of course, in living brain tissue. The authors concluded,
Our study identified NF-kappa B signaling in microglia as a critical pathogenic pathway and SIRT1 as a potential target for blocking this pathway by drug treatment. Our findings highlight the potential therapeutic value of resveratrol and other sirtuin-activating compounds in protecting against neuronal loss in Alzheimer’s disease and related conditions.
Resveratrol for Law and Order
So there you have it: a compound found in grape skins and red wine (but obtained most reliably in optimal amounts as a nutritional supplement) stimulates the action of a gene that plays an important role in longevity and that also suppresses the function of a protein that kills brain cells. In laboratory experiments, anyway. We’re still a long way from knowing whether this works in actual human beings, but it’s encouraging to think that we may be on the right path toward arresting the “cat burglar” that would steal into our brains and rob us of our minds.
- Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S, Mucke L, Gan L. SIRT1 protects against microglia-dependent amyloid-ß toxicity through inhibiting NF-?B signaling. J Biol Chem 2005;280;40364-74.
Blood Vessels via Nitric Oxide
Resveratrol is still best known for its cardioprotective action, which was discovered in the aftermath of “The French Paradox,” the eye-opening 60 Minutes story in 1991 suggesting that wine—especially red wine—may account, at least in part, for the surprisingly low incidence of heart disease in France. Many laboratory and animal studies have shown that resveratrol promotes vasodilation (thereby reducing blood pressure and increasing blood flow), inhibits platelet aggregation (thereby reducing the tendency for blood clots to form), and suppresses the oxidation of LDL-cholesterol (thereby inhibiting the development of atherosclerosis).
Until recently, however, there had been no evidence of resveratrol’s actions in human blood vessels. A research group in Turkey rectified this problem, in experiments with small segments taken from human arteries and veins that were to be used in coronary artery bypass grafting operations. (There are always some leftovers when the healthy blood vessels are being prepared for grafting, so why not put them to good use?) The arterial and venous “rings” were 3–4 mm (0.12–0.16 in.) in length, and the endothelium—the layer of smooth, flat endothelial cells constituting the inner lining of the blood vessels—was intact.
Proper endothelial function is vital for our blood vessels, which must adapt to the body’s changing conditions and demands by expanding or contracting as needed. Conversely, endothelial dysfunction—especially a failure to provide vasodilation (expansion) when needed—is strongly implicated in various aspects of cardiovascular disease. Of key importance in the mechanism of endothelial function is nitric oxide, a vasodilating molecule formed by the enzymatic degradation of the amino acid arginine. Anything that affects the action of the enzyme in question (nitric oxide synthase) can therefore affect blood pressure and blood flow, as well as other vascular functions in which nitric oxide plays an important role.
In their experiments, the Turkish researchers pretreated the vascular rings with noradrenaline, which is a strong vasoconstrictor (it causes blood pressure to rise), and then treated them with resveratrol to see if they would dilate. Indeed they did, in a dose-dependent manner. It was assumed, based on prior animal studies, that this vasodilation was mediated by the endothelium and was dependent on nitric oxide. Assumptions are not facts, however, so the researchers conducted further experiments to make the case. Removing the endothelial cells from the vascular rings almost completely abolished resveratrol’s effect, as did the use of a strong nitric oxide inhibitor when the endothelium was still there. Thus, the assumptions were verified. The authors concluded (in less than perfect English),
. . . this study results showed that resveratrol has some beneficial effect on human vasculature. These effects of resveratrol on endothelial function and tone of human vessels could contribute to cardioprotective effect attributed to red wine.
In an unrelated study, researchers in India investigated the role of nitric oxide in the protective effects of resveratrol in a common form of tissue injury called ischemia/reperfusion injury. Ischemia means the lack of an adequate blood supply, which occurs when there is a temporary restriction or interruption of blood flow to a given area. This causes biochemical injury to the tissues served by the blood vessel in question (and to the blood vessel itself), owing in part to a lack of oxygen. Ironically, further injury occurs upon reperfusion, i.e., the resumption of normal blood flow, owing largely to the sudden release of massive amounts of reactive oxygen species (ROS), including free radicals, when cellular metabolism is re-energized. Too little oxygen, then too much, can cause various kinds of serious tissue damage.
In the Indian experiments, resveratrol provided significant and varied protective effects in ischemia/reperfusion injury in rat kidneys, apparently through its ability to maintain nitric oxide function, which is typically impaired in this scenario. (Another irony is that nitric oxide, which is vitally important in protecting tissues from free radical damage in ischemia/reperfusion, is itself a free radical.)
- Rakici O, Kiziltepe U, Coskun B, Aslamaci S, Akar F. Effects of resveratrol on vascular tone and endothelial function of human saphenous vein and internal mammary artery. Int J Cardiol 2005;105:209-15.
- Chander V, Chopra K. Protective effect of nitric oxide pathway in resveratrol renal ischemia-reperfusion injury in rats. Arch Med Res 2006;37:19-26.
Microencapsulized Resveratrol for Neuroprotection
For those who wish to avail themselves of the antioxidant, antimutagenic, anti-inflammatory, and apparently neuroprotective properties of the plant polyphenol resveratrol, it is important to consider a microencapsulized form such as PEGylated liposomes (a supplement-delivery vehicle formulated as a liquid suspension) for enhanced bioavailability. PEGylated liposomes are able to encase the resveratrol molecules within a lipid bilayer similar to that which constitutes the walls of natural cells. The PEGylated liposomes are able to penetrate readily into the system through the mucous membranes of the mouth, thus avoiding the digestive tract.
Dr. Hyla Cass is a nationally recognized expert in integrative medicine, an assistant clinical professor of psychiatry at the UCLA School of Medicine, and the author or coauthor of several popular books, including Natural Highs: Supplements, Nutrition, and Mind-Body Techniques to Help You Feel Good All the Time and 8 Weeks to Vibrant Health: A Woman’s Take-Charge Program to Correct Imbalances, Reclaim Energy, and Restore Well-Being.