Toxicology Letters 207 (2011) 97– 103
Isotopic reinforcement of essential polyunsaturated fatty acids diminishes nigrostriatal degeneration in a mouse model of Parkinson’s disease
Mikhail S. Shchepinov, Vivian P. Chou, Erik Pollock, J. William Langston, Charles R. Cantor,
Robert J. Molinari, Amy B. Manning-Bog
Oxidative damage of membrane polyunsaturated fatty acids (PUFA) is thought to play a major role in mitochondrial dysfunction related to Parkinson's disease (PD). The toxic products formed by PUFA oxidation inflict further damage on cellular components and contribute to neuronal degeneration. Here, we tested the hypothesis that isotopic reinforcement, by deuteration of the bisallylic sites most susceptible to oxidation in PUFA may provide at least partial protection against nigrostriatal injury in a mouse model of oxidative stress and cell death, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Mice were fed a fat-free diet supplemented with saturated acids, oleic acid and essential PUFA: either normal, hydrogenated linoleic (LA, 18:2n − 6) and α-linolenic (ALA, 18:3n − 3) or deuterated 11,11-D2-LA and 11,11,14,14-D4-ALA in a ratio of 1:1 (to a total of 10% mass fat) for 6 days; each group was divided into two cohorts receiving either MPTP or saline and then continued on respective diets for 6 days. Brain homogenates from mice receiving deuterated PUFA (D-PUFA) vs. hydrogenated PUFA (H-PUFA) demonstrated a significant incorporation of deuterium as measured by isotope ratio mass-spectrometry. Following MPTP exposure, mice fed H-PUFA revealed 78.7% striatal dopamine (DA) depletion compared to a 46.8% reduction in the D-PUFA cohort (as compared to their respective saline-treated controls), indicating a significant improvement in DA concentration with D-PUFA. Similarly, higher levels of the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were detected in MPTP-exposure mice administered D-PUFA; however, saline-treated mice revealed no change in DA or DOPAC levels. Western blot analyses of tyrosine hydroxylase (TH) confirmed neuroprotection with D-PUFA, as striatal homogenates showed higher levels of TH immunoreactivity in D-PUFA (88.5% control) vs. H-PUFA (50.4% control) in the MPTP-treated cohorts. In the substantia nigra, a significant improvement was noted in the number of nigral dopaminergic neurons following MPTP exposure in the D-PUFA (79.5% control) vs. H-PUFA (58.8% control) mice using unbiased stereological cell counting. Taken together, these findings indicate that dietary isotopic reinforcement with D-PUFA partially protects against nigrostriatal damage from oxidative injury elicited by MPTP in mice.
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Free Radical Biology & Medicine 50 (2011) 130–138
Isotope-reinforced polyunsaturated fatty acids protect yeast cells from oxidative stress
S. Hill, K. Hirano, V.V. Shmanai, B.N. Marbois, D. Vidovic, A.V. Bekish, B. Kay, V. Tse, J. Fine, C.F. Clarke, M.S. Shchepinov
The facile abstraction of bis-allylic hydrogens from polyunsaturated fatty acids (PUFAs) is the hallmark chemistry responsible for initiation and propagation of autoxidation reactions. The products of these autoxidation reactions can form cross-links to other membrane components and damage proteins and nucleic acids. We report that PUFAs deuterated at bis-allylic sites are much more resistant to autoxidation reactions, because of the isotope effect. This is shown using coenzyme Q-deficient Saccharomyces cerevisiae coq mutants with defects in the biosynthesis of coenzyme Q (Q). Q functions in respiratory energy metabolism and also functions as a lipid-soluble antioxidant. Yeast coq mutants incubated in the presence of the PUFA α-linolenic or linoleic acid exhibit 99% loss of colony formation after 4 h, demonstrating a profound loss of viability. In contrast, coq mutants treated with monounsaturated oleic acid or with one of the deuterated PUFAs, 11,11-D2-linoleic or 11,11,14,14-D4-α-linolenic acid, retain viability similar to wild-type yeast. Deuterated PUFAs also confer protection to wild-type yeast subjected to heat stress. These results indicate that isotopereinforced PUFAs are stabilized compared to standard PUFAs, and they protect coq mutants and wild-type yeast cells against the toxic effects of lipid autoxidation products. These findings suggest new approaches to controlling ROS-inflicted cellular damage and oxidative stress.
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Bioorganic & Medicinal Chemistry Letters 21 (2011) 255–258
Control of lysyl oxidase activity through site-specific deuteration
N.B. Pestov, I.A. Okkelman, V.V. Shmanai, A.L. Hurski, A.J. Giaccia, M.S. Shchepinov
Lysyl oxidase (LOX) is implicated in several extracellular matrix related disorders, including fibrosis and cancer. Methods of inhibition of LOX in vivo include antibodies, copper sequestration and toxic small molecules such as β-aminopropionitrile. Here, we propose a novel approach to modulation of LOX activity based on the kinetic isotope effect (KIE).We show that 6,6-D2-lysine is oxidised by LOX at substantially lower rate, with apparent deuterium effect on Vmax/Km as high as 4.35 ± 0.22. Lys is an essential nutrient, so dietary ingestion of D2Lys and its incorporation via normal Lys turnover suggests new approaches to mitigating LOX-associated pathologies.
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Do ‘‘heavy’’ eaters live longer?
A new hypothesis is put forward, linking cellular endurance
with dietary consumption of stable heavy isotopes.
Due to the isotope effect, biomolecules that incorporate
heavier isotopes give rise to more stable molecular
structures with increased resistance to damages associated
with aging and age-related disease. The inclusion
of heavy isotopes might be either active (selection for
heavier isotopes) or passive (incorporation reflecting the
existing abundance). The hypothesis links consumption
of foods relatively rich in heavy isotopes (such as 13C and
D, derived from C4-plants), especially at the early stages
of the organism’s development, with enhanced longevity.
Implications of diets and intestinal microflora are also
discussed. BioEssays 29:1247–1256, 2007.
2007 Wiley Periodicals, Inc.
Read more here: http://www3.interscience.wiley.com/
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Reactive Oxygen Species, Isotope Effect, Essential
Nutrients, and Enhanced Longevity
A method is proposed that has the potential to lessen detrimental damages caused by reactive
oxygen species (ROS) to proteins, nucleic acids, lipids, and other components in living
cells. Typically, ROS oxidize substrates by a mechanism involving hydrogen abstraction in a
rate-limiting step. The sites within these (bio)molecules susceptible to oxidation by ROS can
thus be “protected” using heavier isotopes such as 2H (D, deuterium) and 13C (carbon-13). Ingestion
of isotopically reinforced building blocks such as amino acids, lipids and components
of nucleic acids and their subsequent incorporation into macromolecules would make these
more stable to ROS courtesy of an isotope effect. The implications may include enhanced
longevity and increased resistance to cancer and age-related diseases.
Read more here: http://www.liebertonline.com/
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Heavy isotopes to avert ageing?
Oxidative modifications of cellular components by free
radicals are thought to be the cause of ageing nd ageassociated
diseases. Extensive prior research has aimed
to lessen such damage by ounteracting the free-radical
oxidizers with antioxidants, but there have been no
attempts to protect the oxidizer-targeted biomolecules
by making them more stable against oxidation. A recent
paper escribes an original and promising method based
on the use of non-radioactive heavy isotopes, hich
ight enable living cells to resist the free-radical oxidation
and consequently allow us to live a ealthier,
Read more here: http://www.sciencedirect.com/science
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