Resveratrol, neuroprotection and SIRT1

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Resveratrol, neuroprotection and SIRT1

Postby dignan » Tue Jul 24, 2007 11:53 am

Interesting stuff if they can figure out how to get around that pesky brain-blood barrier...



Saving Neurons and Memories

Physicians can treat the symptoms of Alzheimer's disease and other neurodegenerative disorders, but there is no way to prevent or reverse the underlying degeneration and death of neurons that characterize these diseases. Now research by scientists at Harvard and MIT suggests a potential new therapeutic approach.

The scientists have shown that a gene called SIRT1 and a plant compound found in red wine called resveratrol can protect against neuron degeneration in a mouse model of Alzheimer's disease and amyotrophic lateral sclerosis. The researchers demonstrated that activating SIRT1 and injecting resveratrol, which have both been previously associated with life-span extension in lower organisms, can also prevent cognitive problems in the mice.

The mice used in the study develop an approximation of human neurodegenerative disease over a period of weeks. As neurons in their brains die and lose connections, their spatial learning is impaired, and the mice develop difficulty associating cause and effect. Treatment with resveratrol reduced the death and degeneration of neurons in these mice and also restored their learning abilities to a level comparable to that of normal mice not suffering neurodegeneration. "Thus, resveratrol is not only neuroprotective, it also improves cognitive function after severe neurodegeneration," says Li-Huei Tsai, the professor of neuroscience at MIT who led the research with David Sinclair, a professor of pathology at Harvard. Tsai says this improvement in function suggests that resveratrol has potential for treating human neurodegenerative diseases.

Sinclair cofounded Sirtris, a company based in Cambridge, MA, that's developing resveratrol-like therapies for a range of diseases, including type 2 diabetes and another metabolic disorder, called MELAS syndrome. Tsai is a scientific advisor to Sirtris.

The study is the first to suggest that resveratrol could actually improve cognitive function in patients with neurodegenerative diseases. "Generally, SIRT1 has been observed to be neuroprotective," says Leonard Guarente, the professor of biology at MIT who uncovered the connection between life span and the yeast equivalent to SIRT1 about 10 years ago. What's new about Tsai and Sinclair's work, he says, is its demonstration that activating SIRT1 prevents cognitive decline in mice with neurodegenerative disease. The study shows that "resveratrol can protect against memory loss and learning decline," says Guarente, who was not involved with the research.

Guarente says the study suggests that compounds that can activate SIRT1 could be used to treat neurodegenerative disease in humans as long as they can pass through the blood-brain barrier. This membrane surrounding and protecting the brain from chemicals in the blood presents a major challenge to any researcher developing drugs that target the brain. Mice in the study received injections of resveratrol directly into blood vessels in their brains, which would not be practical in human patients.

The Harvard/MIT study could also shed light on the mechanisms behind Alzheimer's. Most studies of Alzheimer's disease focus on the toxic, malformed proteins that build up in afflicted neurons; Tsai and Sinclair's study did not. "This research takes a path less traveled," says Stephen Snyder, director of the Etiology of Alzheimer's Disease Program at the National Institute on Aging.

For the rest of the article:
http://www.technologyreview.com/Biotech/19080/
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Postby scoobyjude » Tue Jul 24, 2007 6:14 pm

The scientists have shown that a gene called SIRT1 and a plant compound found in red wine called resveratrol can protect against neuron degeneration in a mouse model of Alzheimer's disease and amyotrophic lateral sclerosis.

Guess it's time to start drinking up :D
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Postby viper498 » Wed Jul 25, 2007 6:42 am

Merlot anyone?
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Postby BioDocFL » Wed Jul 25, 2007 7:52 am

SIRT1 is a histone deacetylase. Histones are proteins that bind and package DNA and can help sequester genes, suppressing the gene expression. Histones have a lot of positive charges on them which helps them bind the negatively charged DNA. When histones are acetylated, the acetylation is a negative charge so it reduces the overall binding of the histone to the DNA, loosening the histones' hold somewhat (but not necessarily releasing the histones from the DNA). This allows for an increased possibility for the underlying gene to be expressed.
So if a histone deacetylase is active or overactive, it will remove the acetyl group from the histone (usually lysine 9 on histone H3 I believe), leaving the histone with the higher positive charge and therefore the histone will bind tighter and increase overall gene suppression.
I am involved in a screening project on SIRT1 where we are trying to find new inhibitors and enhancers of SIRT1 activity for cancer drugs. I am especiallly interested in this because increases in polyamine synthesis lead to increases in acetylation activity, including acetylation of histones. This all goes along with my thoughts that increased polyamine expression is involved in MS and other autoimmune diseases.

Wesley
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Re: Resveratrol, neuroprotection and SIRT1

Postby NHE » Wed Jul 25, 2007 5:51 pm

viper498 wrote:Merlot anyone?

A recent episode of Nova Science Now on my local PBS station discussed resveratrol and the sirtuin gene family. They noted that for a person to get the same dosage that was given to the mice you would need to drink 1000 glasses of red wine per day. Even if that were physically possible, I think you would be dead from alcohol poisoning long before you finished.

You can watch the show segment here:
http://www.pbs.org/wgbh/nova/sciencenow/3401/01.html

They also had a recent show which discussed the effects of diet and environment on epigenetics. That segment can be found here:
http://www.pbs.org/wgbh/nova/sciencenow/3411/02.html

NHE
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Postby mjs » Wed Jul 25, 2007 6:59 pm

viper498 wrote:Merlot anyone?


You obviously haven't see the movie Sideways. :D
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Postby Abe » Thu Jul 26, 2007 1:00 am

Thanks for the interesting research.

I've been taking 6 Reveratrol caps a day. They contain 100mg trans-reseratrol and 80mg Polyphenols.

I began taking them because of Reveratrol anti viral effects.

Does this seem like a sensible dosage? Are there any dangers of taking too much Reveratrol?
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Postby viper498 » Thu Jul 26, 2007 9:31 am

LOL! Well of course I was kidding about the merlot... and also I may actually be able to drink 1000 glasses of wine? I am pretty big (330 lbs!) ;-)

I've seen the movie Sideways also. Very funny movie. Not sure what he has against merlot though.. I think its pretty good!

You know whats funny. After that movie, sales of merlot went down. That goes to show you how feeble and pretentious people in America are becoming. Thats a generalized statement of course...
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Postby mjs » Thu Jul 26, 2007 4:23 pm

I agree, Merlot can be very drinkable. :)
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Postby jackD » Fri Jul 27, 2007 5:21 am

The how and why part of it. MMP-9s cut hole in BBB and cut Myelin up ito little pieces.

http://home.ix.netcom.com/~jdalton/Yongrev.pdf
(fig 2 page 505)

jackD

1: Acta Pharmacol Sin. 2003 Nov;24(11):1167-71.Links
Resveratrol inhibits matrix metalloproteinase-9 transcription in U937 cells.Li YT, Shen F, Liu BH, Cheng GF.
Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

AIM: To examine the inhibitory effect of resveratrol on matrix metalloroteinase-9 (MMP-9) and explore its mechanism. METHODS: MMP-9 activity was analyzed by gelatin zymography; MMP-9 protein was detected by Western blot; MMP-9 mRNA expression was investigated by RT-PCR. Activation of activator protein -1 (AP-1) was measured by electrophoretic mobility shift assay (EMSA). RESULTS: MMP-9 activity in U937 cells increased significantly after exposed to PMA at 10 nmol/L for 24 h without FCS (P<0.01). Resveratrol at 1 and 10 micromol/L showed significant inhibition on MMP-9 activity (P<0.05 and P<0.01, respectively). Western blot and RT-PCR experiments displayed that MMP-9 protein (P<0.01) and mRNA expression (P<0.01) increased significantly in PMA-treated U937 cells. Resveratrol at 1 and 10 micromol/L showed inhibitory effects on MMP-9 protein production and MMP-9 mRNA expression (P<0.05). The activation of AP-1 induced by PMA was also extensively inhibited by resveratrol at 0.1, 1, and 10 micromol/L.

CONCLUSION: The inhibitory effect of resveratrol on MMP-9 activity may be partly through suppression of activation of nuclear transcription factor AP-1, and inhibition of MMP-9 mRNA expression and MMP-9 protein production.

PMID: 14627504 [PubMed - indexed for MEDLINE]


Since lots of MS folks think that taking "Grape Seed Extract" is good and I feel the opposite I will provide my reason for having my opinion.

IF and ONLY if we accept that increasing GAMMA INTERFERON is BAD for MS folks will my argument prove sound.

I would hope that everyone can accept this as a fact.

Some Gamma Interferon at low levels is necessary for good health and myelin repair.

The medical literature shows that ADDING/INCREASING Gamma Interferon has worsened MS folks in clinical studies.

The problem with GRAPE SEED EXTRACT is it RAISES ---*** GAMMA INTERFERON *** ```!!!!! (see abstract below)

jackD


: Clin Diagn Lab Immunol 2002 Mar;9(2):470-6

Grape seed extract activates Th1 cells in vitro.

Nair N, Mahajan S, Chawda R, Kandaswami C, Shanahan TC, Schwartz SA.

Division of Allergy, Immunology, and Rheumatology, Department of Medicine, State University of New York at Buffalo and Kaleida Health, 14203, USA.

Although flavonoids manifest a diverse range of biological activities, including antitumor and antiviral effects, the molecular mechanisms underlying these activities await elucidation. We hypothesize that the flavonoid constituents of a proprietary grape seed extract (GSE) that contains procyandins exert significant antiviral and antitumor effects, by inducing production of the Th1-derived cytokine gamma interferon (IFN-gamma) by peripheral blood mononuclear cells) from healthy donors. Our results show that GSE significantly induced the transcription of IFN-gamma mRNA as demonstrated by reverse transcription-PCR but had no effect on the Th2-derived cytokine interleukin-6. The enhancing effect of GSE on IFN-gamma expression was further supported by a concomitant increase in the number of cells with intracytoplasmic IFN-gamma as well as the synthesis and secretion of IFN-gamma.

Our results demonstrate that the potentially beneficial immunostimulatory effects of GSE may be mediated through the induction of IFN-gamma.

PMID: 11874895 [PubMed - indexed for MEDLINE
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Postby TwistedHelix » Fri Jul 27, 2007 11:36 am

The blood brain barrier may not be as insurmountable as we think: it's the subject of a lot of research at the moment. Nanotechnology is being explored for its potential to carry drugs, genes etc. in so called " nanocontainers":

Nanotechnology involves the design, synthesis, and characterization of materials and devices that have a functional organization in at least one dimension on the nanometer (ie, one billionth of a meter) scale. One area in which nanotechnology may have a significant clinical impact in neuroscience is the selective transport and delivery of drugs and other small molecules across the blood brain barrier that cannot cross otherwise. Using a variety of nanoparticles composed of different chemical compositions, different groups are exploring proof-of-concept approaches for the delivery of different antineoplastic drugs, oligonucleotides, genes, and magnetic resonance imaging contrast agents. This review discusses some of the main technical challenges associated with the development of nanotechnologies for delivery across the blood brain barrier and summarizes ongoing work.


Also, there are many transporter molecules we know very little about at the moment, which deserve further investigation, plus large molecules like insulin and leptin use a technique called RMT to trigger their own transport across the barrier. So do some monoclonal antibodies and it may be possible to use these as Trojan horses to ferry useful substances across into the brain:

if neurotrophins such as BDNF or FGF-2 are coupled to BBB molecular Trojan horses, such as a mAb to the transferrin receptor (TfR), then neuroprotection with intravenous administration of low doses is possible.


There are, as usual, some large obstacles in the way before such a technique becomes routine, but at least some progress is being made,
Both quotes:© 2005, The American Society for Experimental NeuroTherapeutics, Inc
Dom
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Postby CureOrBust » Fri Jul 27, 2007 5:27 pm

TwistedHelix wrote:...and it may be possible to use these as Trojan horses to ferry useful substances across into the brain
On a related note, I remember a few years ago where doctors were being troubled in treating brain tumours because the medication wasn't making it past the BBB. They found that injecting sugars before the medication opened up the BBB, and thereby produced considerably better results.
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Postby jackD » Fri Jul 27, 2007 5:37 pm

Cell phones/radiation are very good at opening up the BBB. Great for getting Cancer meds into the brain but those cell phones held next to the head do not seem to be a good idea for most MSers.

jackD
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Postby TwistedHelix » Sun Jul 29, 2007 7:55 am

A bit more about SIRT 1 and ON...

SIRT1 Activation Confers Neuroprotection in Experimental Optic Neuritis.

Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3602-9

Authors: Shindler KS, Ventura E, Rex TS, Elliott P, Rostami A

PURPOSE: Axonal damage and loss of neurons correlate with permanent vision loss and neurologic disability in patients with optic neuritis and multiple sclerosis (MS). Current therapies involve immunomodulation, with limited effects on neuronal damage. The authors examined potential neuroprotective effects in optic neuritis by SRT647 and SRT501, two structurally and mechanistically distinct activators of SIRT1, an enzyme involved in cellular stress resistance and survival. METHODS: Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, was induced by immunization with proteolipid protein peptide in SJL/J mice. Optic neuritis developed in two thirds of eyes with significant retinal ganglion cell (RGC) loss detected 14 days after immunization. RGCs were labeled in a retrograde fashion with fluorogold by injection into superior colliculi. Optic neuritis was detected by inflammatory cell infiltration of the optic nerve. RESULTS: Intravitreal injection of SIRT1 activators 0, 3, 7, and 11 days after immunization significantly attenuated RGC loss in a dose-dependent manner. This neuroprotective effect was blocked by sirtinol, a SIRT1 inhibitor. Treatment with either SIRT1 activator did not prevent EAE or optic nerve inflammation. A single dose of SRT501 on day 11 was sufficient to limit RGC loss and to preserve axon function. CONCLUSIONS: SIRT1 activators provide an important potential therapy to prevent the neuronal damage that leads to permanent neurologic disability in optic neuritis and MS patients. Intravitreal administration of SIRT1 activators does not suppress inflammation in this model, suggesting that their neuroprotective effects will be additive or synergistic with current immunomodulatory therapies.
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Postby dignan » Sun May 04, 2008 12:49 pm

There's some interesting research being done on resveratrol and MS...

link
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