Stay Sharp with Resveratrol & Curcumin

Resveratrol and Curcumin
Protect Against
Neurodegenerative Diseases

Among the most beneficial of all polyphenols, these
compounds combat the factors that destroy our brains
By Will Block

Let food be thy medicine and medicine be thy food.
— Hippocrates, ca. 400 B.C.

o keep your car running smoothly and reliably, you—or, more likely, your auto mechanic—have to feed it all kinds of stuff, mostly fluids (i.e., liquids or gases). Besides gasoline, there’s motor oil, brake fluid, transmission fluid, power steering fluid, radiator fluid, windshield washer fluid, Freon® for the air conditioner, distilled water for the battery (maybe), and air for the tires. And, of course, there’s grease for the wheel bearings and other parts.

All these substances can be thought of as car foods whose “nutrient” value serves specific functions that allow your car to run safely and efficiently—or just to run, period. And let’s not forget the additives (supplements, in nutritional parlance), such as STP® or Armor All®, that are designed to optimize certain of your car’s functions or to protect parts of it from deterioration (some people use nitrogen in the tires to avoid oxidative damage to the rubber).

It requires some knowledge of automobile “physiology” to decide what “foods” to put into our cars, and when to add them, and for what purposes. We don’t like having to do it, of course, because it costs money that we’d rather spend on other things, including food for our bodies.* Now there’s something that’s not just necessary but also downright enjoyable (unlike, say, transmission fluid). But food is costly too, even if some of it does grow on trees.


*Believe it or not, gas at $4 per gallon (which may be history by the time you read this) is still a bargain compared with most of the fancy bottled waters—costing $5 to $10 per gallon—that consumers buy. Bottling tap water (that’s what most of it really is), giving it a highfalutin name, and selling it at a colossal premium was perhaps the greatest stroke of marketing genius in history. What next, canned “Alpine air”?


Functional Foods—An Ancient Concept

So why are many people not too particular about what they put into their bodies? Why don’t they give their food more careful thought, educating themselves about the specific functions that foods fulfill and weighing the cost/benefit ratio for all the different categories of food available to them? There are many reasons, but let’s not get into psychotherapy here.

Let’s instead just concentrate on the concept of functional foods, i.e., foods that go beyond mere nutrition, providing chemical “tools” with which to help prevent new disease or retard the progression of existing disease. The term is relatively new (it was introduced by the Japanese in the 1980s), but the concept of food as medicine is ancient, as we saw from the opening quotation.

What makes foods “functional” in the medicinal sense is, of course, the presence of certain chemical compounds with prophylactic (preventive) or therapeutic effects. Obvious examples are the antioxidant vitamins C (ascorbic acid) and E (consisting of four tocopherols and four tocotrienols), whose many benefits include protection against cardiovascular and neurodegenerative diseases. No one thinks twice about taking these vitamins as part of a multivitamin supplement, because it’s widely understood that optimal amounts of them are difficult or impossible to obtain through food alone, even with a very good diet.

Polyphenols Combat Oxidative Stress and Inflammation

It’s not nearly as widely known—but it should be—that polyphenols are the active ingredients in many functional foods and that it’s probably beneficial to supplement our diets with a number of them too, because of the many health benefits attributed to them. Plant-based polyphenols are a large class of compounds (about 10,000 are known so far) that include, among others, the flavonoids found in many fruits and vegetables as well as in red wine and tea.

It would take a big, fat book to do justice to this subject. We’ll just scratch the surface by mentioning two extremely important and closely related phenomena for which polyphenols are especially beneficial, namely, oxidative stress and inflammation. Both of these physiological pariahs can promote disease or exacerbate existing disease, including neurodegenerative diseases, such as Alzheimer’s and Parkinson’s. They often go hand in hand, because each one can (in some circumstances) induce the other. Thus it’s not surprising that some of the polyphenols that have been found to be helpful against one are also helpful against the other, even if only indirectly.

In a recent review of dietary polyphenols for brain aging and Alzheimer’s disease published by a team of biologists from the University of Rome, the authors stated,1

Mounting evidence suggests that lifestyle factors, and especially the diet, may counteract oxidative damage contributing to the onset of many diseases, including cardiovascular ones, cancer, or neurodegenerative diseases. Nowadays, many plants and fruits are considered “functional food,” because, when regularly consumed, they protect from the onset or slow the progression of a disease. It is possible that the onset of brain diseases during aging is partially due to the failure of protective factors, especially in weak, elderly people, improperly fed, and at risk of dietary deficiencies. . . .

Therefore, a healthy diet, including the Mediterranean one, is highly recommended throughout the entire life, and the use of food additives is becoming increasingly common to prevent the onset and to slow down development of aging-associated neuropathies [nervous system disorders].

Resveratrol—Polyphenol Extraordinaire

Also increasingly common, of course, is the use of nutritional supplement formulations containing the same chemical compounds to which the health benefits of functional foods are attributed. In the form of supplements, many of these compounds can be more readily and conveniently obtained in the amounts that scientific research suggests may be optimal for providing the benefits in question.

A notable case in point is the polyphenol resveratrol, the red wine compound that has taken the scientific world by storm because, in relatively large supplemental amounts, it can protect the health and greatly increase the longevity of a wide variety of organisms. The results of these experiments have been so extraordinary that it’s easy to forget that resveratrol’s original claim to fame came from its ability to reduce the risk for cardiovascular disease in humans.

Of equally great interest is resveratrol’s potential for protecting us from neurodegenerative diseases, such as Alzheimer’s, in which oxidative stress and inflammation play key roles. (It’s worth remembering that, although the adult human brain weighs only about 3 lbs, it consumes about 20% of the body’s energy intake and is thus our richest source of harmful free radicals, which not only cause direct damage to cellular components but are also potent inducers of inflammation.)

Resveratrol Protects Brain Neurons

The Italian researchers discussed evidence in the literature regarding resveratrol’s neuroprotective effects in laboratory studies. These benefits are due primarily to its ability to promote degradation of the infamous protein amyloid-beta, which is the principal constituent of the plaques found in the brains of Alzheimer’s victims at autopsy. Resveratrol also helps protect the brain from amyloid-beta-mediated neuronal death, another striking feature seen at autopsy.

Also mentioned by the authors were the results of several epidemiological studies indicating that moderate consumption of wine is associated with a reduced risk for Alzheimer’s disease—this despite the very small (and highly variable) amounts of resveratrol found in a glass of red wine. It’s incomparably easier (and safer) to obtain substantial amounts of resveratrol through supplementation than by drinking wine.

Resveratrol Protects Against Parkinson-like Condition

A new indication of resveratrol’s neuroprotective capacity comes from a study by researchers in Quebec, who investigated its effects on mice in which a condition similar to Parkinson’s disease had been induced.2 The chief neuroanatomical feature of Parkinson’s is the destruction of brain cells that produce the neurotransmitter dopamine, in a small region of the brain called the substantia nigra; this results in the characteristic tremors, muscular rigidity, and other symptoms of the disease.*


*It should be noted that Parkinson’s, unlike Alzheimer’s, is not a dementia. The normal course of the disease does, however, usually lead to dementia as a consequence (not a primary feature) of the neurodegeneration involved. This condition is called dementia of Parkinson’s disease.


In mice, a Parkinson-like condition can be induced by a neurotoxic compound called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), which reduces dopamine levels and the numbers of dopaminergic neurons in the substantia nigra. The mice do not display the outward symptoms of Parkinsonism, however.

The researchers studied the effects of pretreatment with resveratrol (administered orally, daily for 8 or 15 days) on MPTP-treated mice that were on a special diet free of the soy products found in standard mouse chow. Soy is particularly rich in phytoestrogens, which are plant-based, nonsteroidal, polyphenolic compounds with biological activities similar to those of estrogens. Phytoestrogens (most of which are flavonoids) are believed to be beneficial against a variety of diseases, including cancer, cardiovascular and neurodegenerative diseases, and osteoporosis. (The researchers pointed out, by the way, that conventional estrogen replacement therapy in postmenopausal women is now recognized to reduce the risk of neurodegenerative diseases.)

So why minimize phytoestrogens in the mouse diet? Because resveratrol is a phytoestrogen (it’s not a flavonoid, however), and the researchers wanted to observe its effects independently of those of other phytoestrogens, which are known to modify the course of Parkinson’s disease. What they found, when they examined the mouse brains at autopsy 5 days after the MPTP treatment, was that the resveratrol pretreatment maintained normal dopamine levels in the substantia nigra and that it provided substantial (but not complete) protection against the loss of neurons. This indicates a strong neuroprotective effect, in line with the results of other studies.

The authors stated,2

Overall, our findings clearly demonstrate that resveratrol is an efficient protective molecule against MPTP-induced brain lesions and may serve as a complementary and/or preventive therapy in neurodegenerative diseases.

Curcumin Is Neuroprotective

In their paper on dietary polyphenols for brain aging and Alzheimer’s disease, the Italian researchers mentioned above singled out two other compounds, besides resveratrol, for special mention. One was curcumin, which is the principal biologically active constituent (along with several related curcuminoids) of the Indian spice turmeric. Turmeric is the main ingredient in curry powder, and it gives many mustards their yellow color. It has a millennia-old tradition of use in Indian folk medicine. (Like resveratrol, by the way, curcumin is a polyphenol but not a flavonoid.)

Modern medicine has verified the therapeutic value of curcumin, particularly as an anti-inflammatory agent with strong antioxidant properties. This makes it potentially useful in neurodegenerative diseases, in which both oxidative stress and inflammation play important roles. Curcumin acts as a neuroprotectant, shielding the brain’s neurons from some of the damage for which such diseases are notorious. Among the numerous specific actions that have been observed (in laboratory cell cultures) are the inhibition of amyloid-beta and the induction of heme oxygenase-1, an enzyme that protects against oxidative stress.1

Curcumin Deactivates Iron and Copper Ions

Also important in neurodegenerative diseases is the role played by certain transition metals, especially iron and copper, which can instigate oxidation-reduction (“redox”) reactions leading to the formation of harmful reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the brain.* Excessive levels of these metal ions in the brain are, in fact, characteristic of neurodegenerative diseases.


*Transition metals are those that occupy the central portion of the periodic table of the elements. Their electronic structures are distinctly different from those of the other metals and give them certain properties, such as multiple valences (combining capacities) and the ability to form stable complex ions with many kinds of molecules, that result in great chemical versatility. At least seven of them (chromium, cobalt, copper, iron, manganese, molybdenum, and zinc) play vital roles in our physiology.


Some polyphenolic compounds, including curcumin, are able to deactivate transition metal ions by a chemical reaction called chelation, in which the ion forms a complex with two or more groups of atoms (having certain molecular-electronic properties) from a single molecule. In chelating iron or copper ions, curcumin curtails their ability to act as pro-oxidants; it thus acts, indirectly, as an antioxidant.

What We Don’t Know About Polyphenols

A major impediment to our understanding of the health benefits of polyphenols has been the fact that the great majority of studies to date have been done with cell cultures in the laboratory or with experimental animals, neither of which can provide reasonable assurance that the effects observed will translate to human beings. It is well known, for example, that the bioavailability of these compounds tends to be very low, mainly because they’re extensively metabolized to derivative compounds in the intestines and liver.

Thus it’s mainly the derivatives that exert whatever biological activity is ascribed to the parent compounds. This calls into question the relevance of studies done with the latter—and in cell cultures rather than living organisms. Such apparent misdirection of research is a matter of increasing concern to some scientists. Also of concern is the realization that dosages can be problematic: at high levels, some polyphenols are reversed from antioxidant status to pro-oxidant status, with inhibition of enzymes responsible for cell survival or activation of enzymes that lead to cell death. (Cooking can also cause a reversal in the activity of some polyphenols.)


“Resveratrol is an efficient protective
molecule against MPTP-induced brain
lesions and may serve as a comple-
mentary and/or preventive therapy in
neurodegenerative diseases.“


Furthermore—and of paramount importance where brain disorders are concerned—is the key question of whether or not the compounds in question can cross the blood-brain barrier, thereby gaining access to the brain. In most cases, the answer to that question is still unknown. For resveratrol and curcumin, however, we do know the answer: it’s yes.

Curcumin—First Clinical Trial for Alzheimer’s

Thus it’s very important that clinical trials with humans be done to verify the results—almost all of which have been positive in terms of potential health benefits—found in preclinical research. Recently a group of researchers in Hong Kong undertook the first clinical trial (a small pilot trial, placebo-controlled and double-blind) of curcumin in patients with Alzheimer’s disease (AD).3

There were 34 patients, aged 50 or older, in varying stages of dementia, who were randomized to receive 0, 1, or 4 g of curcumin daily for 6 months. They also received, as a “standard treatment,” 120 mg/day of a standardized extract of Ginkgo biloba leaf because it had shown moderate benefit in previous studies. And they were allowed to continue (or to change at any time) any treatment deemed appropriate by their personal physicians.

These features of the study did not bode well for obtaining clear results concerning the effectiveness of curcumin, and, indeed, no clear results were observed, either physiologically or cognitively. Basically, the trial was a bust, and the authors acknowledged various limitations that probably contributed to this outcome. Based on a lack of adverse effects, they were, however, able to say that “. . . longer and larger trials to test the efficacy of curcumin for treating AD may be safely commenced.” One hopes that this will soon come to pass.

EGCG Too Is Neuroprotective

The other compound highlighted by the Italian researchers was the flavonoid EGCG (epigallocatechin gallate), the principal biologically active constituent of green tea, which is a champion among functional foods. EGCG belongs to the family of compounds called catechins (one of the many types of flavonoids), which are known to cross the blood-brain barrier. It’s known for its strong antioxidant and anticancer effects, among others, and it’s an effective chelator of transition metal ions.

In laboratory and animal studies, EGCG has been shown to exert a neuroprotective effect by inhibiting the formation of amyloid-beta plaques. It’s not just Alzheimer’s disease for which EGCG may helpful, however. In other studies cited by the Italian researchers, EGCG was shown to be protective against Parkinson’s disease, and it specifically protects against the neurotoxic effects of MPTP, which we discussed above in connection with resveratrol.

How Is Your Self Doing?


Hippocrates

© iStockphoto.com/
Phil Sigin

The more we learn about medicine and nutrition, the clearer it becomes how intimately they’re linked. It’s humbling to realize that Hippocrates, a genius who was far ahead of his time on many medical matters, intuited more than two millennia ago what we are now confirming in our laboratories. (For all of his great accomplishments as a physician, by the way, there’s one thing Hippocrates did not do: he did not author the Hippocratic oath, which is falsely attributed to him.)

It’s useful to think of our nutrition in terms of functional food—a concept that might more aptly have been called medicinal food—because it reminds us that food, at its best, serves not only to nourish us but also to protect us from disease. And some of the best “essences” of food are available in the form of nutritional supplements so that we can obtain them in optimal amounts. The question is, are you taking as good care of yourself—especially your brain—as you are of your car?

References

  1. Rossi L, Mazzitelli S, Arciello M, Capo CR, Rotilio G. Benefits from dietary polyphenols for brain aging and Alzheimer’s disease. Neurochem Res 2008 [online preprint].
  2. Blanchet J, Longpré F, Bureau G, Morissette M, DiPaolo T, Bronchti G, Martinoli MG. Resveratrol, a red wine polyphenol, protects dopaminergic neurons in MPTP-treated mice. Prog Neuro-Psychopharmacol Biol Psychiatry 2008 [online preprint].
  3. Baum L, Lam CWK, Cheung SKK, Kwok T, Lui V, Tsoh J, et al. Six-month randomized, placebo-controlled, double-blind, pilot clinical trial of curcumin in patients with Alzheimer disease. J Clin Psychopharmacol 2008;28:110-3.

Galantamine Improves Mood in Depression

Dementia is one thing, depression is another. They do have some things in common, though, including the occurrence of delusions and hallucinations. Although neither of these is characteristic of Alzheimer’s disease (the most common of all dementias), they occur fairly often in Lewy body dementia (the second most common) and, to a lesser extent, in dementia of Parkinson’s disease.

In those dementias, delusions tend to be loosely organized and readily changed or forgotten; the themes may include theft, fears, misidentification of people or places, and spousal infidelity. In depression, by contrast, the delusions tend to center on death, guilt, money, illness, self-reproach, and feelings of worthlessness; there may be some basis in reality here (we all have our failings, after all), but the perceptions are exaggerated to a pathological degree.

Dementia-related hallucinations, when they do occur, are more often visual than auditory, and they may be attributable in part to environmental factors. In depression, hallucinations are typically auditory and of a derogatory nature.

The relationship between dementia and depression may be due in part to their linkage via a certain feature of neuroanatomy, namely, the brain’s nicotinic acetylcholine receptors. These vitally important protein complexes, embedded in the cell wall at the synaptic junctions of many neurons, are activated by the neurotransmitter acetylcholine and by nicotine (hence the name), which is known to improve both cognition and mood. Their function is degraded and their numbers diminished in Alzheimer’s disease. These effects are counteracted, however, by the plant alkaloid galantamine—which is the main reason why galantamine is an effective treatment for the disease.

Knowing this, and based on reports that galantamine might be beneficial for a variety of psychiatric conditions, researchers in Ontario undertook a small pilot study (randomized, placebo-controlled, double-blind) of the effects of galantamine on both cognition and mood in patients with major depressive disorder.1 To their knowledge, it was the first study of this kind.

They recruited 20 patients, average age 52, who were already taking a variety of prescription antidepressants and who were in a stable, not acutely depressed, state at the time. (It can be dangerous to experiment with depressed, unstable individuals when one is not sure what kind of outcome to expect.) The patients received either placebo for 8 weeks or galantamine, 8 mg/day for the first 4 weeks and 16 mg/day for the next 4 weeks.

At baseline and again after 8 weeks, they were given a battery of neuropsychiatric tests to evaluate their cognitive function and their mood. Although there was a tendency toward improvement in cognition, the changes were not statistically significant. Evaluations of mood, however, showed a significant improvement in 4 of the patients in the galantamine group, vs. none in the control group.

Acknowledging the limitations of their study but encouraged by the positive tendencies, the authors recommended that further studies be undertaken on a larger scale and with patients in a more depressed state.

Reference

  1. Elgamal S, MacQueen G. Galantamine as an adjunctive treatment in major depression. J Clin Psychopharmacol 2008;28:357-9.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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