|Resveratrol and Huntington's||| Print ||
Resveratrol is a natural substance found in small quantities in the skin of grapes, blueberries, cranberries and most highly concentrated in red wine. This substance which is available as a dietary supplement has been shown to protect several types of cells and organisms from oxidative stress, and to prolong life in some organisms. In this article, Dr. Goodman reviews the preliminary evidence that may support its use in Huntington's.
Mechanism of Action: Resveratrol stimulates the activity (directly or indirectly) of an enzyme called SIRT1, which is known to up regulate key metabolic and anti-inflammatory pathways that protect cells. This is probably the same protective mechanism that is activated by calorie restriction. Both resveratrol and calorie restriction can increase mitochondrial number and improve mitochondrial energy function. Both can decrease inflammation and chronic oxidative DNA injury. All of these effects are important for Huntington's.
Evidence for Potential Benefit in HD: First, scientists showed that calorie restriction delays onset of symptoms and extends the life of a genetic HD mouse [Duan 2003]. Scientists have also studied resveratrol and found it to be neuroprotective in several models of HD. This includes a nematode (worm) model and neurons (in cell culture) derived from a genetic HD mouse [Parker 2005]. More scientists have shown its benefit in the toxin mouse model of HD [Kumar 2006]. Lending more support for resveratrol neuroprotection, a recent study shows that it gives benefit (when injected directly into ventricles in brain) in mouse models of Alzheimer's disease and Amyotrophic Lateral Sclerosis [Kim 2007].
Resveratrol is on the SET-HD list, but was not chosen as an agent for initial review; nor is it listed as an agent being studied at CHDI.
Should We Take this Supplement? The correct answer is not known. Resveratrol may be beneficial if enough of it can get to the right place. But there are at least two substantial problems.
First, there is disagreement about dose needed for people. Sirtris Pharmaceuticals Inc. is using high doses in phase I human trials (2500 mg and 5000 mg per day) in their clinical trial of this drug for diabetes. Dr. David Sinclair, whose laboratory performed resveratrol mouse studies, has stated that lower doses may be beneficial. In an interview in the New York Times, he stated that he is taking a resveratrol supplement in smaller doses (5 mg/kg/day) than that used in the clinical trial. This smaller dose translates to 300-400 mg a day for people of average weight.
While most scientists not directly involved in the study suggest it is premature to take more than that available in one or two glasses of wine (about 1 or 2 mg/5 oz), there is no evidence that this dosage is beneficial. The dosage used in the clinical trial or by Dr. Sinclair is not attainable from wine or any other natural source.
Second, resveratrol is degraded quickly when exposed to oxygen. For instance, it is no longer active in wine if the bottle has been opened 24 hrs. The same applies to supplement preparations exposed to air during manufacture or storage. Most likely, the majority of marketed preparations don't contain the advertised active form.
Supplement Information: Longevinex (Greenpower in Europe) claims its manufacturing technique prevents degradation and has published results from (outside) lab testing that shows continued activity in capsules stored for 10 months. Further, this company claims to be sponsoring a human clinical trial using this product, and if so, must meet a higher level of manufacturing standard than other companies. But it's pricey: a little more than a dollar per each 100 mg pill.
There is little information available on the bioactivity of other over the counter brands. Consumer Lab states they are testing resveratrol supplements with results expected later in 2007. If you choose to use this supplement, Longevinex is probably your best alternative. A review in World Science gives background on the politics of resveratrol development, lists food sources, and gives additional supplement information.
Comments: At HDDW, we don't give definitive recommendations on any supplement or drug because there is no definitive clinical trial evidence. But we do give proactive information on those that have greatest possibilty of benefit based on the limited evidence that is available. The evidence base for each supplement or drug varies greatly. Some have only test tube evidence. Up a notch are those that have model organism (worm, fly, mouse) evidence. Much further along are those that are in human clinical trial for other neurodegenerative diseases, or better, are planned for HD. This means that they have passed the first hurdles in people; human safety and some documentation that the agent gets into brain.
We clearly favor those that are highest on this list. But remember, this does not mean that others with lesser evidence won't be helpful. Should you use resveratrol? The answer is still out.
Duan W, Guo Z, Jiang H, Ware M, Li XJ, Mattson MP. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci U S A 2003 Mar 4;100(5):2911-6. PubMed abstract
Parker JA, Arango M, Abderrahmane S, Lambert E, Tourette C, Catoire H, Néri C. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet 2005 Apr;37(4):349-50. PubMed abstract
Kumar P, Padi SS, Naidu PS, Kumar A. Effect of resveratrol on 3-nitropropionic acid-induced biochemical and behavioural changes: possible neuroprotective mechanisms. Behav Pharmacol 2006 Sep;17(5-6):485-92. PubMed abstract
Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F, Rodgers JT, Delalle I, Baur JA, Sui G, Armour SM, Puigserver P, Sinclair DA, Tsai LH. SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis. EMBO J 2007 Jul 11;26(13):3169-3179. PubMed abstract
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