Posted 23 June 2007 - 04:10 PM
"Can resveratrol kill brain cells?"
This is the heading of a post by Thomas Carter on sci.life-extension.
He dug up some clues as how this could happen. It depends on 2 big
ifs.
1) If resveratrol besides activating SIRT1 can also activate SIRT2.
2) If SIRT2 can somehow harm neurons.
Then, resveratrol -> SIRT2 -> some neurons dead.
1A) According to PMID: 15749705 [PubMed - indexed for MEDLINE]
resveratrol only activates SIRT1. So we don't have to worry.
!B) But, according to other researchers resveratrol can enhance some
effects of SIRT2:
Biochem Biophys Res Commun. 2007 Aug 3;359(3):665-71. Epub 2007 Jun 4.
Resveratrol abolishes resistance to axonal degeneration in slow Wallerian degeneration (Wld(S)) mice: Activation of SIRT2, an NAD-dependent tubulin deacetylase.Suzuki K, Koike T.
Molecular Neurobiology Laboratory, Division of Integrated Life Science, Hokkaido University Graduate School of Life Science, Sapporo 060-0810, Japan.
Resveratrol is a natural polyphenol having a wide range of biological and pharmacological activities. Here we have investigated the effect of resveratrol on neurodegeneration in cultured cerebellar granule cells from slow Wallerian degeneration (Wld(S)) mice, characteristic of substantial delay of degeneration in the distal stump of transected axons. Resveratrol diminished resistance of Wld(S) neurons to axonal degeneration induced by colchicine, a microtubule depolymerizing drug. Resveratrol also decreased the level of tubulin acetylation in Wld(S) neurons and their homogenates. This promoting effect on tubulin deacetylation was mimicked by NAD, suggesting the involvement of SIRT2, an NAD-dependent tubulin deacetylase. Indeed, resveratrol promoted tubulin deacetylation in the presence of GFP-SIRT2 but not GFP-SIRT2 N168A, a catalytically inactive mutant. Moreover, SIRT2 silencing restored the resistance to axonal degeneration in resveratrol-treated Wld(S) neurons. These results suggest that resveratrol abolishes the resistance of Wld(S) mice to axonal degeneration by enhancing SIRT2-mediated tubulin deacetylation.
PMID: 17560549 [PubMed - in process]
2)
Source: Massachusetts General Hospital
Date: June 23, 2007
Novel Parkinson's Disease Drug Target Identified
Science Daily — Researchers at the Massachusetts General Institute for Neurodegenerative Disease (MGH-MIND) have identified a potential new drug target for the treatment of Parkinson's disease and possibly for other degenerative neurological disorders. In an upcoming issue of the journal Science, the investigators describe finding, in cellular and animal models, that blocking the action of an enzyme called SIRT2 can protect the neurons damaged in Parkinson's disease from the toxic effects of alpha-synuclein, a protein that accumulates in the brains of Parkinson's patients
The study, which also suggests that inhibiting this pathway could help in the treatment of other conditions in which abnormal proteins accumulate in the brain, is receiving early online release on the Science Express.
"We have discovered a compelling new therapeutic approach for Parkinson's disease, which we expect will allow our scientists -- as well as those at pharmaceutical and biotech companies -- to pursue innovative new drugs that will treat and perhaps even cure this disorder," says Aleksey Kazantsev, PhD, director of MGH-MIND Drug Discovery Laboratory, who led the Science study. "Since the same sort of aggregation of misfolded proteins has been reported in Huntington's and Alzheimer's diseases - as well as Lewy body dementia, which also involves alpha-synuclein deposits - we plan to test this approach in those conditions as well."
Parkinson's disease -- characterized by tremors, rigidity, difficulty walking and other symptoms -- is caused by the destruction of brain cells that produce the neurotransmitter dopamine. In recent years researchers at several centers have been studying the role of alpha-synuclein accumulations in dopamine-producing neurons, observed in patients with both inherited and sporadic Parkinson's disease. MGH-MIND investigators have discovered that, in Parkinson's, the alpha-synuclein molecule folds abnormally and form aggregates called inclusion bodies. Such inclusions of other abnormal proteins are seen in several disorders, but whether inclusions are toxic or protective to neurons has been controversial.
In a paper published last year in the Proceedings of the National Academy of Sciences, a research team led by Kazantsev analyzed ways to reduce the size of inclusions containing misfolded versions of alpha-synuclein or of the Huntington's disease-associated protein huntingtin. They found that a compound called B2, which promotes the formation of larger inclusions, paradoxically appeared to reduce toxicity in cellular disease models, possibly by reducing the overall number of inclusions.
In the current study, the investigators began by seeking the mechanism underlying the observed effects of B2. Assays of the compound's activity against a panel of key enzymes identified only one significant association -- a weak but selective inhibition of SIRT2, which is known to regulate the cell cycle and may have a role in aging. An experiment using RNA interference to suppress SIRT2 and a related enzyme in human cell lines expressing alpha-synuclein confirmed that only the inhibition of SIRT2 reduced alpha-synuclein toxicity.
Kazantsev's team then developed and identified more powerful inhibitors of SIRT2, based on the structure of B2. One of these novel inhibitors called AGK2 had 10 times the potency of B2 and was shown to protect dopamine-producing neurons from alpha-synuclein toxicity in cultured rat neurons and in an insect model of PD. Several additional compounds that act on the SIRT2 pathway have been identified, some which may be even better than AGK2 as candidates for drug development.
SIRT2 is known to act on a major protein component of microtubules, cellular structures that help move objects within cells, among other functions. The researchers theorize that inhibiting SIRT2 might promote microtubule-dependent transportation of alpha-synuclein into large aggregates; or it could strengthen microtubules that have been destabilized by misfolded alpha-synuclein.
Kazantsev explains, "For Parkinson's disease, we can now pursue a straightforward drug development process by identifying potent and selective candidates from this class of compounds that can be tested in animal studies and eventual human trials. One of the most satisfying aspects is how this discovery validates our approach to drug discovery, which incorporates both the most advanced tools for screening candidate compounds and outstanding collaboration with our clinical and scientific experts in human disease." Kazantsev is an assistant professor of Neurology at Harvard Medical School.
Co-authors of the Science report are first author Tiago Outeiro, PhD, and co-authors Steve Altman, Allison Amore, Michele Maxwell, PhD, Pamela McLean, PhD, Anne Young, MD, PhD, and Bradley Hyman, MD, PhD, of MGH-MIND; Eirene Kontopoulos and Mel Feany, MD, PhD, Brigham and Women's Hospital; Irina Kufareva, PhD, and Ruben Abagyan, PhD, Scripps Research Institute; and Katherine Strathearn, Catherine Volk, and Jean-Christophe Rochet, PhD, Purdue University. The study was supported by private donations to MGH-MIND and grants from the National Institutes of Health and the Massachusetts Biomedical Research Corporation.
If 1A) and 2) are right there is something to worry about.
Sinclair and Kazantsev, please start talking to each other. After all
you both work for Harvad. Invite Suzuki and Koike and have a serious
chat. PLEASE!!!
