37 replies to this topic

[maxwatt]

Resveratrol, Found in Red Wine, Worsens MS-Like Symptoms and Neuropathology in Mice


Researchers discourage supplemental use by patients with multiple sclerosis, according to report in The American Journal of Pathology
Philadelphia, PA, October 1, 2013
Resveratrol, a naturally occurring polyphenol compound produced by the skin of red grapes and peanuts, and found in red wine, has been touted as a beneficial supplement due to its anti-inflammatory and antioxidant properties. This has been supported by some experimental studies, whereas others suggest a lack of benefit. A new study using two multiple sclerosis (MS) models published in The American Journal of Pathology has found that resveratrol actually worsened MS-like neuropathology and inflammation and had no neuroprotective effects.

http://www.elsevier....(Elsevier News)


Interesting, but a pubmed search turns up

Resveratrol neuroprotection in a chronic mouse model of multiple sclerosis.

Fonseca-Kelly Z, Nassrallah M, Uribe J, Khan RS, Dine K, Dutt M, Shindler KS.
Front Neurol. 2012;3:84. doi: 10.3389/fneur.2012.00084.

PMID: 22654783 [PubMed]
Free PMC Article

Oral resveratrol reduces neuronal damage in a model of multiple sclerosis.

Shindler KS, Ventura E, Dutt M, Elliott P, Fitzgerald DC, Rostami A.
J Neuroophthalmol. 2010 Dec;30(4):328-39. doi: 10.1097/WNO.0b013e3181f7f833.

PMID: 21107122 [PubMed - indexed for MEDLINE]
Free PMC Article
Whether it's a matter of different doses or something else, I do not know,

[hav]

It amazes me how much coverage a study has gotten with little to no info released on methods used or dosages tested. And all the reports cite:

A new study using two multiple sclerosis (MS) models published in The American Journal of Pathology has found that resveratrol actually worsened MS-like neuropathology and inflammation and had no neuroprotective effects.

... but lack info on the publication month. The current October 2013 issue doesn't contain the article so its clearly not published yet. My favorite bit of hoopla is this YouTube video (2 views right now, one being mine), which strongly suggests to me that someone is really trying to hype this:



Fwiw, the full text of the previous study published in 2012 found resveratrol inhibited M-S in mice at a resveratrol dosage level of 250mg/kg but had no effect at 100 mg/kg dosage levels. Maybe the new study uses a dosage below that range. Also note that both of these studies employ an externally administered toxic peptide to initiate M-S symptoms... so there may be a relative dosage level where co-administered resveratrol helps to incrementally extend the life of the volatile peptide in the body but is below the level needed to provide neuroprotection. In which case, similar or more dramatic results may obtain from other antioxidants. Which would only be relevant in real life if M-S was usually caused by a peptide like that.

Howard

[cudBwrong]

Here is a link to the abstract:

http://www.journals....0527-0/abstract

I like to keep an open mind and evaluate everything on its merits. There is little information on methods
in the abstract, but it is interesting that they used 2 different models of the disease.

I've seen other cases where resveratrol makes pathology worse when the immune system is severely
compromised. These disease models clearly affect the immune system.

The previous study:

http://www.ncbi.nlm....cles/PMC3359579

(Fonseca-Kelly et. al) used one of the same models (EAE) in a different strain of mouse. I don't
know if the method of EAE induction was the same, and I don't know (as Howard stated) what the
dosage was. I don't know much about the immune systems of the 2 varieties of mice.

If time permits, I'll dig this up in the university library and explore additional details.

[cudBwrong]

Correction:

(Fonseca-Kelly et. al) used one of the same models (EAE) in a different strain of mouse.

Sorry, it's the same strain, I was confused by the font. This is a very common variety, said to have a somewhat weakened immune system but in general it is seen as immunocompetant.

[hav]

Looks like the abstract suggests they may have tested both MS induction methods: toxic peptides and injecting with virus-infected cells. Though its not absolutely clear since the following paper mentions the isolation of a peptide-like chain that can simulate the virus-induced model:

Mouse Models of Multiple Sclerosis: Experimental Autoimmune Encephalomyelitis and Theiler’s Virus-Induced Demyelinating Disease

TMEV-IDD is a useful model for understanding the possible viral etiology of MS. This section provides detailed information on the preparation of viral stocks and subsequent intracerebral infection of mice. Additionally, virus plaque assay and clinical disease assessment are discussed. Recently, recombinant TMEV strains have been created for the study of molecular mimicry which incorporate various 30 amino acid myelin epitopes within the leader region of TMEV.

If they relied solely on peptide induction, maybe resveratrol worsened the situation by helping protect the peptide and delay breakdown in the body thereby enhancing its activity.

Howard

[nowayout]

Is there any reason at all to even bother talking about resveratrol any more? It clearly doesn't prolong life in mammal models. It apparently may trigger or worsen various immune-related conditions. Even the original promoters of it have given up on it. This supplement is so two thousand and late...

[maxwatt]

But it does protect against the progression of arthritis, and PPAR activity enhances mitochondrial biogenesis and improves athletic performance.
Curcumin is also effective with arthritis, and Magnolia extract and bitter melon extracts are PPAR-delta agonists.

I know someone with several tons of resveratrol he'd like to sell. It does have its uses.

But it does protect against the progression of arthritis, and PPAR activity enhances mitochondrial biogenesis and improves athletic performance.
Curcumin is also effective with arthritis, and Magnolia extract and bitter melon extracts are PPAR-delta agonists.

I know someone with several tons of resveratrol he'd like to sell. It does have its uses.

[eon]

haven't tried resveratrol yet. I see a product called trans-resveratrol recently. Not sure if this is the "second coming" of the hype. Any clue?

[cudBwrong]

haven't tried resveratrol yet. I see a product called trans-resveratrol recently. Not sure if this is the "second coming" of the hype. Any clue?

Resveratrol occurs in 2 isomers (closely related chemical structures,) "cis" and "trans." It is the "trans" form that has been shown to have some positive effects. If you want to take resveratrol, I suggest you look for a product that has a high purity level of trans-resveratrol. Some products claim a 98 or 99% purity level, as verified by an independent lab. That way, you know what you are taking. Look through this forum, and/or search for pure resveratrol and read the fine print.

[eon]

thanks for the clarification. I see trans resveratrol 99% in bulk powder form. 100g about $40. Is that a good price? What should the dose be? I've seen this come in 500mg pills, so I guess 500mg a day is good enough?

[cudBwrong]

thanks for the clarification. I see trans resveratrol 99% in bulk powder form. 100g about $40. Is that a good price? What should the dose be? I've seen this come in 500mg pills, so I guess 500mg a day is good enough?

Both price and dose seem reasonable, but I'm not an expert. Search through the forums and you will find discussions on these topics.

I advise everyone starting resveratrol, or any supplement to discuss it with their doctor. There could be interactions with other medications. If you are interested in it because it may help treat or prevent a medical condition, partner with your doctor and share your research. You can educate one another.

You might want to start with a small dose and purchase, to check for bad reactions and side effects, before you make a big commitment.

[maxwatt]

That price is low enough, the product is probably not an herbal extract from Polygonum cuspidatum, but a 'synthetic', from GMO bacteria in a vat, a strain of E. coli or of yeast that has been genetically modified and optimized to make trans-resveratrol. The chemical purity is likely high, perhaps as high as the label claims, but we do not know what any impurities might be.

[eon]

you mentioned e. coli and isn't this a bad bacteria?

[niner]

That depends on the strain, and it's highly unlikely that they would use a pathogenic strain in a manufacturing process. At any rate, the bacteria don't make it into the final product.

Regarding cis and trans, you don't need to care about this, as all resveratrol on the market is trans. That's the most stable form, and if there was any cis, you would have to work to keep the majority of it from spontaneously converting to trans.

[hav]

Here's an interesting paper:

E Coli: Good, Bad, and Deadly

I also read somewhere else that the e coli strain normally found in the gut is one of the best probiotics for yielding the beneficial effects from eating broccoli sprouts.

Howard

[eon]

in what way does resveratrol fight cancer? I don't have cancer but have some mole looking thing that grew on my back. Another weird looking piece of skin under my chin I had for as long as I can remember. Non cancerous but curious what can resveratrol do to it? I noticed niacin seem to have made it look lighter in color since niacin works the skin as well. I use the real flush niacin, nicotinic acid. At my first observation of the skin while on niacin it sorta kinda turned white-ish as if I just put hydrogen peroxide on it, but it was niacin's work. curious if resveratrol will give some noticeable effect and not placeboic or "subtle".

Edited by eon, 18 January 2014 - 10:30 AM.

[cudBwrong]

in what way does resveratrol fight cancer? I don't have cancer but have some mole looking thing that grew on my back. Another weird looking piece of skin under my chin I had for as long as I can remember. Non cancerous but curious what can resveratrol do to it? I noticed niacin seem to have made it look lighter in color since niacin works the skin as well. I use the real flush niacin, nicotinic acid. At my first observation of the skin while on niacin it sorta kinda turned white-ish as if I just put hydrogen peroxide on it, but it was niacin's work. curious if resveratrol will give some noticeable effect and not placeboic or "subtle".

The literature on resveratrol and cancer is vast, so I'll focus on resveratrol and other polyphenols and skin cancer. There is a recent, free fulltext review article here:

http://www.ncbi.nlm....les/PMC3288507/

In addition, resveratrol, through a possibly related, possibly unrelated mechanism, can, at least in some cases, supress the synthesis of melanin, and has been used cosmetically to lighten the skin. This study reports on resveratrol and melanin:

http://www.ncbi.nlm....pubmed/24414332

I've been taking resveratrol for a couple of years as part of an experimental treatment of a rare disease of the retina. (Results: so far, so good.) One side effect I've noticed is that some discolorations on the backs of my hands ("liver spots") which were present for years have completely disappeared.

[eon]

what would happen if melanin is suppressed? Would it have any adverse effect when staying out int he sun for periods of time?

Is there anything about resveratrol that treats anything related to eyes or is this just a personal experiment? Did your "liver spots" have anything to do with your retina disease?

Edited by eon, 28 January 2014 - 04:29 AM.

[cudBwrong]

eon asks about possible adverse effects of melanin suppression. It's a good question, and I don't know the answer.

I always cover up and wear sunscreen even on cloudy days. I think if you do this it should not be a problem.

The positive effects on the retina are due to resveratrol's role as an antioxidant, and also, its ability to suppress angiogenesis, or the abnormal growth of blood vessels. In many diseases of the retina, the damage is caused by blood vessel growth which distorts the tissues. This may be new vessels, enlarged vessels, or existing vessels that grow in new directions. Resveratrol suppresses this by controlling VEGF -- vascular endothelial growth factor. The effect is similar to that of the drug Avastin.

Resveratrol has been effective, in most but not all experiments, against many kinds of tumors, which require a robust supply of blood vessels. Again, similar to Avastin. In some studies, however, resveratrol made tumors grow more quickly.

The spots on my hands -- Solar lentigo -- are a common effect of aging (I'm an old guy) and are thought to be harmless. However, I was surprised to see them disappear. I had them long before the retina disease showed up.

[eon]

curious to know what type of tumors resveratrol made grow quickly? That sounds like a bad adverse effect.

[cudBwrong]

curious to know what type of tumors resveratrol made grow quickly? That sounds like a bad adverse effect.

Howard and I discuss one set of experiments where 2 different studies show opposite effects in this thread:

http://www.longecity...mpromised-mice/

Here, it's not a different type of tumor -- it's actually the same cell line and the same group of researchers. The differences in the studies are the kind of mouse they used and the vehicle (carrier) of the resveratrol. I think the cancer growth in one experiment was due to the severely comprimised immune system of the mouse.

To me, it shows that resveratrol might not be a good idea in patients with a severely comprimised immune system, as may happen with radiation, chemotherapy, and other disorders.

[eon]

so resveratrol could only benefit those with the right immune system?

[cudBwrong]

so resveratrol could only benefit those with the right immune system?

I think it could be harmful if the patient's immune system was not working at all, or very much suppressed.

The study where resveratrol made tumors grow faster used a kind of mouse called an SCID mouse. Severe Combined Immunodeficiency. In humans, it is known as "bubble boy disease."

"complete inability of the adaptive immune system to mount, coordinate, and sustain an appropriate immune reponse."

What's going on here? You are trying to study cancer in a live animal (in vivo) instead of merely in the test tube (in vitro,) because you think the live animal study is more realistic.

You want to study a cancer tumor with known properties. This would be a cell line, a culture of living cells, taken from (most likely) a human patient who had cancer.

So the way it's often done is to graft some of the cells onto the skin of a lab animal, and then run the experiment, testing a drug or whatever.

The problem is that the animal's immune system will tend to attack the graft, as it is not a normal thing to be present on the animal's body. So you have to in some way turn down the animal's immune system so that it doesn't kill off the graft all by itself.

There are several ways to do this, but a common one is to use an animal that is genetically modified to have a weak immune system.

The case where the tumors grew faster used a mouse that had an unusually weak immune system. These mice basically had no immune system at all.

The case where resveratrol made the tumors grow slower used a different mouse that had a slightly stronger immune system. It also used a different kind of food oil to dissolve the resveratrol. You have to dissolve it in something to get it inside the mouse, they don't like to swallow pills.

The problem is that when you treat a patient for cancer, you give them radiation and or drugs (chemotherapy,) and both of these things temporarily suppress the immune system. So there might be a danger in this type of patient that resveratrol makes things worse. For a normal healthy patient, I don't think so.

There are other cases where the immune system is suppressed, such as active AIDS and patients taking immunosuppressive drugs after an organ transplant. Some have expressed concern that people with autoimmune diseases, for example, Multiple Sclerosis, might be at risk, but I don't think so because their immune systems actually are quite active, unless they are taking a drug to suppress it.

But there really is limited research about this, although I think it is clear that resveratrol is safe, usually, for people in generally good health. Some may be allergic to resveratrol, or to even tiny quantities of impurities which may be present in resveratrol prepared from plants, as most of it is. (On this forum, one of these patients reported joint pain which disappeared when the patient switched to a synthetic form of resveratrol).

I always advise people to talk to their doctor about this, and to use a highly purified resveratrol source, such as a 98% purified product, to minimize the chance of side effects from other stuff.

Edited by cudBwrong, 28 January 2014 - 02:02 PM.

[cudBwrong]

Here is a link to the abstract:

http://www.journals....0527-0/abstract

The previous study:

http://www.ncbi.nlm....cles/PMC3359579

(Fonseca-Kelly et. al) used one of the same models (EAE) in a different strain of mouse. I don't know if the method of EAE induction was the same, and I don't know (as Howard stated) what the dosage was. I don't know much about the immune systems of the 2 varieties of mice.

If time permits, I'll dig this up in the university library and explore additional details.

Correction:

(Fonseca-Kelly et. al) used one of the same models (EAE) in a different strain of mouse.

Sorry, it's the same strain, I was confused by the font. This is a very common variety, said to have a somewhat weakened immune system but in general it is seen as immunocompetant.

I have been able to consult the full text of the Sato et. al. article, "Resveratrol Exacerbates Both Autoimmune and Viral Models of Multiple Sclerosis" whose abstract can be found here:

http://www.journals....0527-0/abstract

I'm comparing the methods used in the experimental autoimmune encephalomyelitis (EAE) part of the study with the methods used by Fonseca et. al., cited above, who found an opposite, protective effect.

Here are some observations:

1). The mice are the same strain, and the same age, but obtained from different sources.

2). EAE was induced using the same substance, myelin oligodendroglial glycoprotein (MOG) peptide 35–55, but obtained from different sources. The exact methods are described in other references to which I have no access at the moment, so there may be differences here. In fact, Sato et. al. note that:

In MOG-induced EAE, different groups used different concentrations of MOG and pertussis toxin.

3). Both groups use resveratrol from Sigma-Aldrich.

4). There are differences in the methods of resveratrol preparation and administration. In particular, Sato et. al. heated the resveratrol. I am very interested in your comments on this.

Fonsecea et. al. suspend the resveratrol in phosphate buffered saline and administer it by oral gavage at 100 or 250 mg/kg.

The Sato et. al. method is described as follows:

Although an intake of resveratrol may be less constant via
chow than via oral gavage, resveratrol is more stable in chow
than in water, (13) and we therefore administered the resveratrol
in chow. A diet containing resveratrol (Sigma-Aldrich, St.
Louis, MO) was prepared according to Banerjee et al. (14) First,
50 g of a powder diet was weighed, then 55 mL of double-
distilled H 2 O were added to the powder diet and mixed
well. Next, 15 mL of 100% ethanol (control diet) or 100%
ethanol containing 0.02 g of resveratrol (for 0.04% in the
diet) was added to the chow and mixed well. For ethanol
evaporation, the chow was placed in a vacuum oven at 50 degrees C
overnight. Because resveratrol is sensitive to light, (15,17) the
chow was keptaway from light whenever possible and stored
in the dark at 4 degrees C.

I'm not sure what the "chow" is. In another reference, the "Bannerjee et. al." reference, it is described as a "common pellet diet" and a "pulverized rodent diet." See:

http://cancerres.aac...62/17/4945.long

Could the resveratrol be reacting under heat, in contact with "chow," and turning into something else?

Curiously, although the Sato group says they are following the Bannerjee method, Bennerjee et. al. do not heat the resveratrol:

Resveratrol was dissolved in 70% ethanol and then added into the diet 1 day in advance and left at room temperature for 1 day. After ethanol evaporation, food was then given to the rats.

There is no question that the (heated) resveratrol made the condition worse, the spinal cord images are very compelling.

Edited by cudBwrong, 03 April 2014 - 11:10 AM.

[cudBwrong]

There is an issue with self-oxidation of resveratrol under certain conditions, including heat, resulting in compounds that can be toxic to cells.

"Transport, stability, and biological activity of resveratrol"

http://onlinelibrary...10.05871.x/full

Redox reactions As with many other polyphenols, resveratrol may undergo an auto-oxidation process that occurs with many polyphenols, which leads to the production of O₂^.−, H₂O₂, and a complex mixture of semiquinones and quinines that may be cytotoxic²⁶. This has been particularly shown in culture media and may indicate a pitfall in the interpretation of in vitro results. The evaluation of resveratrol oxidation in vitro shows that 96% of 200 μM resveratrol was degraded, which produced 90 μM of H₂O₂ after 24 h at 37°C.²⁷ This degradation is markedly and dose-dependently enhanced by bicarbonate ions.²⁷ In contrast, Long et al. show that resveratrol degradation can occur without any H₂O₂ production.²⁸ Concerning crystalline resveratrol and its glucoside, a recent study shows that both molecules are stable up to three months with negligible degradation in various conditions (e.g., high temperature, ambient fluorescent light, UV/fluorescent light, and air).²⁹ These auto-oxidation or degradation events could be very important, because oxidized resveratrol could generate complexes with others molecules, such as copper ions. Indeed, the oxidative product of resveratrol is a dimer, and the initial electron transfer generates the reduction of Cu(II) to Cu(I). Thus, the copper-peroxide complex is able to bind DNA and to form a DNA-resveratrol-Cu(II) ternary complex.³⁰ These complexes would favor and give rise to internucleosomal DNA fragmentation, which is a hallmark of apoptosis.

This process seems to depend upon bicarbonate ions. A typical rat chow has lots of ingredients including various carbonates, perhaps they can generate bicarbonate ions under the right conditions, including ethanol, water, and heat.

"Evaluation of resveratrol oxidation in vitro and the crucial role of bicarbonate ions."

http://www.ncbi.nlm....pubmed/20057154

[eon]

I just saw an article about anti aging with a mention of resveratrol. Was Dr. David Sinclair the one responsible for its introduction to the world? There was a mention of NAD (nicotinamide adenine dinucleotide) as well. Is that supposed to be another potential anti aging serum? I think this is an "active" or conenzymated version of vitamin B3 (Niacin). Correct me if I'm wrong. 

 

http://news.yahoo.co...-035336385.html

Edited by eon, 20 August 2014 - 09:40 AM.

[APBT]

I just saw an article about anti aging with a mention of resveratrol. Was Dr. David Sinclair the one responsible for its introduction to the world? There was a mention of NAD (nicotinamide adenine dinucleotide) as well. Is that supposed to be another potential anti aging serum? I think this is an "active" or conenzymated version of vitamin B3 (Niacin). Correct me if I'm wrong. 

 

http://news.yahoo.co...-035336385.html

 

See the David Sinclair strikes again thread for further discussion.

[eon]

I'm only a bit familiar with NAD. There is NADH which I know little about and nicotinamide riboside (NR) which seems to be marketed as the better product of the 3. I doubt anyone ever bought it considering Thorne Research sells a 60 pill bottle for $59! Must be expensive for a reason.

[niner]

I'm only a bit familiar with NAD. There is NADH which I know little about and nicotinamide riboside (NR) which seems to be marketed as the better product of the 3. I doubt anyone ever bought it considering Thorne Research sells a 60 pill bottle for $59! Must be expensive for a reason.

 

Umm, you should probably check out some of the NR threads.  Longecity members have cut a deal with an NR vendor, and in total we've bought, I don't know, several hundred bottles?  The threads are extensive.  Read up.

Edited by niner, 24 August 2014 - 02:23 AM.

[eon]

so you are familiar with the use of NAD, NADH, and NR? You're saying NR is the better of the 3?