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How the world got lost on
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August 2, 2012: by Bill Sardi
Georgetown University researchers are widely publicizing their planned study of the red wine molecule resveratrol (rez-vair-ah-trol) among adults over 50 years of age with early signs of Alzheimer’s disease.
Alzheimer’s patients have already flocked to retail stores to purchase resveratrol pills, having heard of the planned study. And while it is indeed a very promising molecule for Alzheimer’s disease (one report called it a “boon for treating” the disease), there is justifiable concern that the study design, namely the dosage of resveratrol to be used in the study, may produce a negative result, produce unwanted side effects and more importantly, doom the future of resveratrol for years to come.
The investigators are working under the assumption that resveratrol is not very “bioavailable” and that it may not cross what is called the blood-brain barrier. Resveratrol is a small molecule (228 Daltons molecular weight) that must make it past the liver detoxification system to reach the brain. After a few passes through the liver via the arterial system, virtually all resveratrol is attached (conjugated) to detox proteins (glucuronate, sulfate). However, then resveratrol complexed with these detox molecules is too large to pass through the blood-brain barrier.
Most resveratrol researchers seem unaware that at sites of inflammation or infection an enzyme called glucuronidase is abundantly active and unzips resveratrol from its carrier molecule, glucuronate. This is nature’s drug delivery system and results in unbound (free) resveratrol being delivered at the right time and place. Such a natural “drug” delivery system would obviate the need for high-dose resveratrol.
The brain is protected from germs or toxins by capillaries (connectors) between arteries that supply the brain with nutrients and oxygen that are transported to the fluid the surrounds the brain. It is interesting to learn that resveratrol produces adenosine which is the controlling molecule that opens capillaries for passage of large molecules past the blood-brain barrier.
However, a published examination of whether resveratrol enters brain tissue directly concludes it is “not very likely” that resveratrol-like molecules have direct antioxidant effects in the human brain, but a number of studies do show resveratrol positively affects brain function. Is the positive effect indirect?
The authors of the paper that examines whether resveratrol-like molecules enter the brain describe a phenomenon known as hormesis, that is, where exposure to a low-dose mild toxin induces a beneficial effect by activating antioxidant defenses. This hormesis effect is controlled by a gene transcription factor known as Nrf2. Resveratrol is perceived by the body as a mild toxin and switches on Nrf2 which in turn increases the activity of glutathione, catalase, superoxide dismutase, three powerful internal antioxidants. To achieve this hormesis effect, low-dose resveratrol is required.
The dosage range of resveratrol that produces a hormesis effect in humans has not been precisely determined, but in rodents the human equivalent of 175-350 milligrams produced a protective effect in heart tissue whereas 10-times that much resveratrol, 1750-3500 mg, was cell-killing (cytotoxic), turned from being an antioxidant to promote oxidation, and actually increased the area of damage to the heart. (Resveratrol doesn’t cause heart attacks, but at high doses could possibly worsen them.)
The study protocol for Alzheimer’s patients calls for doses beginning at 500 mg and then rising to 1000 mg twice a day, 2000 mg total. That would theoretically push the dose into the pro-oxidant range!
A subsequent study in humans reveals a 150-milligram dose of resveratrol, a 200-fold lower dose than used in prior animal studies, resulted in the same blood concentration produced in laboratory animals. So humans need far less resveratrol than laboratory rats, and the low dose had a huge effect upon the genes. The 150-mg dose of resveratrol significantly altered 469 genes in calf muscle within 30 days.
Antioxidant researchers who explored whether resveratrol-like molecules pass through the blood-brain barrier said: “lacking a precise definition of hormesis,” that molecules like resveratrol may produce “significant beneficial or detrimental effects….even at low dose.”
Many elderly patients with Alzheimer’s dementia (memory loss) take other medications. Resveratrol negates some of the protective detoxification processes in the liver (inhibits what are called cytochrome p450 enzymes). Therefore, resveratrol could magnify the effects of other drugs, which could be deleterious, for example, by causing blood pressure drugs to work too well, resulting in dizziness. Researchers in Europe have recently warned that mega-doses of resveratrol may produce serious drug interactions. It is unlikely that Alzheimer’s patients aren’t going to be taking prescription medications. Low-dose resveratrol would appear to be more prudent.
This would not be the first time resveratrol appears to have been intentionally overdosed to produce negative results in a study. The very same researchers who claimed that low-doses of molecules like resveratrol in plants can produce a beneficial hormesis effect (called xenohormesis, from xenos, the Greek word for stranger, and hormesis, the term for health benefits provided by mild biological stress, such as cellular damage or a lack of nutrition), then used mega-dose resveratrol (1565 mg equivalent human dose) in subsequent studies involving laboratory rats which were unsuccessful at prolonging lifespan. This appears as if the life extension study with lab rats was designed to intentionally fail. Certainly, the researchers were talking out of two sides of their mouths (suggesting low-dose, using high-dose).
In humans, resveratrol combined with other synergistic molecules has been demonstrated to abolish the first sign of blood vessel disease and to rescue patients with sight-robbing macular degeneration, at a 100-mg dose of resveratrol. The human eye has a protective barrier (blood-ocular barrier) similar to the blood-brain barrier. So it would be assumed that if resveratrol demonstrably affecting the human eye, it will do so in the brain. The resveratrol product that produced beneficial effects in the human eye is specially made (micronized, microencapsulated) and exhibited a genomic effect that was 6-times greater than plain resveratrol. There were no side effects reported. Strangely, those published studies didn’t create greater public demand for resveratrol pills.
One thing is for sure. A positive study among Alzheimer’s patients would likely result in billions of dollars of sales of resveratrol pills worldwide. A null study, or a study that resulted in side effects that had to be stopped for safety reasons, would thrust resveratrol into an infamy similar to thalidomide, the anti-nausea drug that resulted in so many birth defects.
© 2012 Bill Sardi, ResveratrolNews.com
Bill Sardi has a commercial interest in resveratrol pills.
Indeed, it is widely recognized that a challenge to treatment for Alzheimer’s disease is passage of medications past the tightly regulated blood-brain barrier, which is located at the level of the capillaries between the blood circulation and brain tissue and is characterized as having tight junctions during a state of health and loose junctions in states of inflammation and infection. The blood-brain barrier is said to prevent 98% of all small molecules and 100% of large molecules from reaching the brain. Since every brain cell is located within 20 nanometers (millionth of a meter) from a capillary, and capillaries are where oxygen, nutrients and cellular debris enter and exit the brain, it is clear that capillaries are of importance in controlling inflammation and entry of toxins to the brain that are involved in Alzheimer’s disease.
In general, for molecules to penetrate the blood-brain barrier they must be dissolve in fats or oil (be lipophilic) and be less than 500 Daltons in size (molecular weight).
The red wine molecule resveratrol has a molecular weight of 228 Daltons and should therefore pass through the blood-brain barrier. Similar-sized red wine molecules (catechin/290 Daltons, quercetin/ 302 Daltons, and cyanidin-3-glucoside/ 484 Daltons) have been shown to pass through brain capillaries grown in a lab dish.