Resveratrol Protects Against Flu Virus

Each fall, as flu season approaches, we are treated to a new round of scare stories about potential epidemics and pandemics of influenza.


Orally taken resveratrol may offer little value.
Ordinary flu kills 36,000 Americans each year, but a pandemic (a worldwide outbreak), should it occur, could kill more than 10 times that number and cause unprecedented social disruption and economic loss.

In 1918, the Spanish flu pandemic killed 700,000 people in the United States and nearly 40 million worldwide. It's true that general health and medical care are much improved today, but even if they could reduce the mortality by 75%, which is optimistic, that still leaves 175,000 American deaths (10 million worldwide), five-fold more than an ordinary flu.

Pandemics are caused by the sudden appearance of a new strain of influenza A virus in the human population, the result of an "antigenic shift" in virus DNA. The Centers for Disease Control and Prevention (CDC) suggests that a "medium level" pandemic could affect up to a third of the population and cause between 89,000 and 207,000 deaths in the United States alone.

Scientists are currently keeping their eye on a particularly lethal strain of avian (bird) flu (H5N1) that has crossed over into humans in Asia, a rare event among avian viruses. While human-to-human transmission of H5N1 does not readily occur at the moment, should an antigenic shift occur such that people could pass on the virus more easily to other people, the consequences could be disastrous. The reported mortality rate for this virus is 50%, and there is currently no vaccine. You can see why the experts are worried.


Resveratrol’s oral bioavailability in vivo is likely to be grossly insufficient to furnish agent levels compatible with those which modulate carcinogenesis (and produce other therapeutic actions) in vitro.
Antiviral drugs may offer some protection against flu viruses, but in a major outbreak affecting tens of millions of people, the virus — which readily mutates — would probably develop resistance to these agents quickly.1 Ordinary viruses are most lethal to people whose immune systems may be compromised, including the very young, the very old, and the very sick. But with some viruses, even strong immunity may be of little help. During the 1918 Spanish flu pandemic, nearly half the deaths occurred in healthy, young adults.

In the absence of effective vaccines and antiviral drugs, there hasn't been a whole lot we could do to protect ourselves once flu season rolls around. However, recent research suggests an option that might greatly improve the odds. It's called resveratrol, which is a chemical found naturally in the skin of red grapes and some other foods, and is also available in nutritional supplements. According to the results of a study by researchers from the Institute of Neurobiology and Molecular Medicine of the Italian Research Council in Rome, resveratrol blocks influenza A virus replication both in vitro (test tube studies) and in flu-infected mice.2

Resveratrol is a remarkable member of a remarkable class of naturally occurring substances called polyphenols. Polyphenols are synthesized in plants in such places as grape skin and tea leaves in response to physiologic stimuli and environmental stress.3 In humans, polyphenols have been shown to have a wide range of health benefits, including protecting against heart disease, cancer, and neurologic diseases.4-7 Resveratrol has also been shown to inhibit the replication of Herpes simplex virus and to synergistically enhance the effects of known anti-HIV drugs.8-10

In the Italian Research Council in vitro study, flu virus was grown in a lab dish for 24 hours before being exposed to a range of doses of resveratrol. As shown in Figure 1, viral inhibition was dose-related, with the highest dose almost completely inhibiting replication.


Resveratrol Inhibits Replication of Influenza A Virus in Vitro


Figure 1. Results of an in vitro study showing that as the dose of resveratrol increases, the percent viral replication rate (yield) relative to the untreated control decreases. Adapted from Palamara et al, 2005.2

In the mouse portion of the study, 20 mice were given a dose of flu virus known kill 80% of them within 10 days. An hour after inoculation with the virus, half the mice began receiving resveratrol and half a placebo. Treatment continued for 7 days.

As shown in Figure 2, the protection offered by resveratrol was impressive. Within 10 days, 80% of the placebo-treated mice had died, compared with only 40% of the resveratrol-treated mice. Further examination revealed that the resveratrol-treated mice had 98% lower levels of the virus in their lungs. Resveratrol caused no significant toxicity.


Resveratrol Increases Survival in
Flu-Infected Mice


Figure 2. Mice were infected with flu virus and treated 1 hour later with either resveratrol or placebo daily for 7 days. Survival of the resveratrol-treated mice was significantly increased (P<0.05) compared with the placebo treated group. Adapted from Palamara et al, 2005.2

The authors remind us that all currently approved anti-flu drugs target essential viral functions and/or structures. While this approach can sometimes be effective, it has one major drawback: the virus will eventually adapt to the drug by developing resistance, at which point the drug will become useless.

Resveratrol differs in its approach because, instead of going after the virus directly, it inactivates functions of the host cell that the virus uses to help it replicate. This approach offers two major advantages over conventional anti-viral drugs: 1) the virus is less likely to develop resistance to resveratrol; and 2) resveratrol's inhibitory effects are independent of the virus' type, strain, and antigenic properties.1

Getting the Most Out of Resveratrol

Although evidence suggests that using resveratrol may be very beneficial for our health, how we use it can make all the difference. You could, of course, drink red wine, which is the best natural source of resveratrol. In fact, some evidence suggests that regular red wine consumption may be responsible for the "French paradox," whereby the cardiovascular dangers of a high fat diet appear to be neutralized by drinking red wine with dinner.

There is, however, a better way to obtain resveratrol on a daily basis, namely, through supplementation. It may not be as tasty, for sure, but it is much more reliable (the resveratrol content of most red wines is quite low as well as highly variable) and less expensive. But not all supplements are created equal, a principle that is especially true when applied to resveratrol.


When taken orally, virtually no unmetabolized resveratrol survives to make it into the bloodstream.
For a nutrient to be beneficial, it must be bioavailable, which means it must be readily absorbed from the digestive tract into the bloodstream, where it must survive long enough to reach the cells that need it. For all resveratrol's benefits, getting it to where it is needed poses an extraordinary problem, because even though resveratrol taken orally is well absorbed by the gut (at least 70%), its bioavailability turns out to almost zero. This apparent "paradox" can be traced to its rapid and extensive metabolism to two types of chemical derivatives: sulfates and glucuronides.11-14 Most resveratrol is converted into these metabolites in the gut, and the metabolites are readily absorbed into the bloodstream. The process is completed by the liver within about half an hour. As a result, virtually no unmetabolized resveratrol survives to make it into the bloodstream.

Given these facts of life, some researchers have suggested that the large body of laboratory research on which the therapeutic reputation of resveratrol largely rests may be irrelevant, because the agent used may have been the wrong agent, namely, resveratrol rather than its metabolites.11, 12, 14, 15 We simply don't know yet whether these metabolites would produce similar beneficial effects. Only hard experimental facts will tell, and experts in this field are suggesting that the research focus be shifted from resveratrol to its metabolites.


Researchers agree that the oral bioavailability of resveratrol is near zero.
But all is not lost. Because resveratrol is so extensively metabolized in the gut before it even has a chance to reach the bloodstream, it's tempting to think that it might be possible to improve its bioavailability by bypassing the digestive tract in favor of a more direct route to the bloodstream. This helps to some degree, but even if resveratrol were delivered directly to the bloodstream via intravenous (IV) injection or other more convenient "parenteral" routes (eg, transdermal or transmucosal application), it is still subject to destruction in the bloodstream by immune agents such as phagocytes.

However, clever scientists have developed a method of administration that employs a kind of "stealth technology" to encapsulate the resveratrol molecules in manmade "cells" called PEGylated liposomes. Encapsulating resveratrol in PEGlyated liposomes enables resveratrol to pass readily into the bloodstream and then protect it from agents that might alter them, thus allowing excellent bioavailability. Formulated as a liquid suspension, the liposomes can be easily absorbed through the mucous membranes of the mouth by holding the liquid in your mouth without swallowing it.

PEGylated liposome technology has been under development since the 1970s and first came into clinical use for delivering drugs and nutritional supplements in the 1990s. It doesn't matter what the payload is. Water-soluble nutrients dissolve in the aqueous interior, and fat-soluble nutrients may be suspended (as fine particles) in the interior or dissolved in the liposomal membrane itself.

Once in the bloodstream, phagocytes, the cell-eating cells whose mission it is to seek out and destroy potentially harmful cellular matter and foreign substances,


By entering directly in the bloodstream, PEGysomal resveratrol prevents premature breakdown of resveratrol while keeping it intact as it is distributed throughout the body.
give a free pass to PEGylated liposomes, despite the fact that PEG (polyethylene glycol) is a synthetic polymer. With a superb safety record, PEG is rated GRAS (generally recognized as safe) and is harmless in the human body.

Because this technique promises superior delivery of free (unmetabolized) resveratrol to the blood, it can produce higher blood levels of resveratrol, and, thanks to PEGylation, sustain those levels because the resveratrol isn’t released all at once or in the same area. While resveratrol will still be rapidly metabolized when released by the liposomes and passed through liver, there is still far more time for resveratrol to work its benefits. In one study,13 following oral delivery of resveratrol, no free resveratrol was detectable in the blood at any time (although its metabolites were readily detectable). However, after IV delivery, there were measurable levels initially, but they dropped quickly and were gone after about half an hour. However, PEGylation has been found to extend the life of other payloads (drugs and nutrients), and it is reasonable to conclude that it can do the same for resveratrol, thus sustaining its usefulness.

References

  1. Nicholson KG, Wood JM, Zambon M. Influenza. Lancet. 2003;362:1733-1745.
  2. Palamara AT, Nencioni L, Aquilano K, et al. Inhibition of influenza a virus replication by resveratrol. J Infect Dis. 2005;191:1719-1729.
  3. Dercks W, Creasy L. The significance of stilbene phytoalexins in the Plasmopara vitiocola-grapevine interactions. Physiol Mol Plant Pathol.1989;34:189-202.
  4. Yu R, Hebbar V, Kim DW, Mandlekar S, Pezzuto JM, Kong AN. Resveratrol inhibits phorbol ester and UV-induced activator protein 1 activation by interfering with mitogen-activated protein kinase pathways. Mol Pharmacol. 2001;60:217-224.
  5. Wu JM, Wang ZR, Hsieh TC, Bruder JL, Zou JG, Huang YZ. Mechanism of cardioprotection by resveratrol, a phenolic antioxidant present in red wine (review). Int J Mol Med. 2001;8:3-17.
  6. Sun AY, Simonyi A, Sun GY. The "French paradox" and beyond: Neuroprotective effects of polyphenols. Free Radic Biol Med. 2002;32:314-318.
  7. Jang M, Cai L, Udeani GO, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 1997;275:218-220.
  8. Heredia A, Davis C, Redfield R. Synergistic inhibition of HIV-1 in activated and resting peripheral blood mononuclear cells, monocyte-derived macrophages, and selected drug-resistant isolates with nucleoside analogues combined with a natural product, resveratrol. J Acquir Immune Defic Syndr. 2000;25:246-255.
  9. Docherty JJ, Smith JS, Fu MM, Stoner T, Booth T. Effect of topically applied resveratrol on cutaneous herpes simplex virus infections in hairless mice. Antiviral Res. 2004;61:19-26.
  10. Docherty JJ, Fu MM, Stiffler BS, Limperos RJ, Pokabla CM, DeLucia AL. Resveratrol inhibition of Herpes simplex virus replication. Antiviral Res. 1999;43:145-155.
  11. Wenzel E, Soldo T, Erbersdobler H, Somoza V. Bioactivity and metabolism of trans-resveratrol orally administered to Wistar rats. Mol Nutr Food Res. 2005;49:482-494.
  12. Wenzel E, Somoza V. Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food Res. 2005;49:472-481.
  13. Walle T, Hsieh F, DeLegge MH, Oatis JE, Jr., Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos. 2004;32:1377-1382.
  14. Gescher AJ, Steward WP. Relationship between mechanisms, bioavailability, and preclinical chemopreventive efficacy of resveratrol: A conundrum. Cancer Epidemiol Biomarkers Prev. 2003;12:953-957.
  15. Yu C, Shin YG, Chow A, et al. Human, rat, and mouse metabolism of resveratrol. Pharm Res. 2002;19:1907-1914.

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