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CURATOR
A pinboard by
Ran Furman

Post doctorate fellow, University of Pennsylvania

PINBOARD SUMMARY

Testing novel molecules that incorporate and reduce oxidation in neurodegenrative diseases

Oxidative stress is frequently observed in Alzheimer’s disease (AD) as well as in most age-related diseases, but its pathological significance is poorly understood. Polyunsaturated fatty acids (PUFA) like arachidonic (omega 6) and docosahexaenoic (omega 3) acids are concentrated in the brain, and are likely the most vulnerable compounds to oxidative damage. PUFA oxidation leads to the accumulation of many neurotoxic molecules but their impact on AD onset and progression is unclear. We now have an unprecedented opportunity to pursue a unique strategy that combines early intervention and an entirely novel antioxidant compounds with direct therapeutic potential through their extraordinary abilities to inhibit oxidative stress. These novel compounds, known as “stabilized fatty acids” are PUFA derivatives that have been modified by selective deuterium substitutions to be highly resistant to oxidative damage, and to inhibit the free-radical mediated processes that damage ordinary PUFAs. They dramatically inhibit lipid oxidation in vitro, and are already in human clinical trials for other indications. However, they have not yet been tested in relevant animal models of AD, and differ in ways that must be understood before human trials can be designed. We have obtained these compounds in forms that may be fed to mice and have already collected preliminary data from animal testing. This therapy combined with advanced analytical methods that we developed and that can rapidly quantify the concentrations of hundreds of oxidatively-damaged molecules will provide an unprecedented insight into the extent and localization of oxidative stress and assess the efficacy of this promising treatment. In addition our research will evaluate the effects of the intervention time. Our latest studies revealed a correlation between maternal diet low on omega 3 and propensity for AD-like symptoms in adult mice; therefore, an early administration as well as late administration of these compounds will be tested and will address their efficacy as both a preventative and a therapeutic solution.
Overall, we are aiming at a more comprehensive and sophisticated understanding of oxidative stress in the brain, and at novel therapeutic approaches to inhibiting oxidative stress in Alzheimer’s disease. The research will lay the foundations for clinical trials in a drug that is already in advanced clinical stages for other diseases.

6 ITEMS PINNED

Isotope-reinforced polyunsaturated fatty acids protect mitochondria from oxidative stress.

Abstract: Polyunsaturated fatty acid (PUFA) peroxidation is initiated by hydrogen atom abstraction at bis-allylic sites and sets in motion a chain reaction that generates multiple toxic products associated with numerous disorders. Replacement of bis-allylic hydrogens of PUFAs with deuterium atoms (D-PUFAs), termed site-specific isotope reinforcement, inhibits PUFA peroxidation and confers cell protection against oxidative stress. We demonstrate that structurally diverse deuterated PUFAs similarly protect against oxidative stress-induced injury in both yeast and mammalian (myoblast H9C2) cells. Cell protection occurs specifically at the lipid peroxidation step, as the formation of isoprostanes, immediate products of lipid peroxidation, is drastically suppressed by D-PUFAs. Mitochondrial bioenergetics function is a likely downstream target of oxidative stress and a subject of protection by D-PUFAs. Pretreatment of cells with D-PUFAs is shown to prevent inhibition of maximal uncoupler-stimulated respiration as well as increased mitochondrial uncoupling, in response to oxidative stress induced by agents with diverse mechanisms of action, including t-butylhydroperoxide, ethacrynic acid, or ferrous iron. Analysis of structure-activity relationships of PUFAs harboring deuterium at distinct sites suggests that there may be a mechanism supplementary to the kinetic isotope effect of deuterium abstraction off the bis-allylic sites that accounts for the protection rendered by deuteration of PUFAs. Paradoxically, PUFAs with partially deuterated bis-allylic positions that retain vulnerable hydrogen atoms (e.g., monodeuterated 11-D1-Lin) protect in a manner similar to that of PUFAs with completely deuterated bis-allylic positions (e.g., 11,11-D2-Lin). Moreover, inclusion of just a fraction of deuterated PUFAs (20-50%) in the total pool of PUFAs preserves mitochondrial respiratory function and confers cell protection. The results indicate that the therapeutic potential of D-PUFAs may derive from the preservation of mitochondrial function.

Pub.: 13 Jan '15, Pinned: 25 Aug '17

Deuterium-reinforced polyunsaturated fatty acids protect against atherosclerosis by lowering lipid peroxidation and hypercholesterolemia.

Abstract: Oxidative modification of lipoproteins is a crucial step in atherosclerosis development. Isotopic-reinforced polyunsaturated fatty acids (D-PUFAs) are more resistant to reactive oxygen species-initiated chain reaction of lipid peroxidation than regular hydrogenated (H-)PUFAs. We aimed at investigating the effect of D-PUFA treatment on lipid peroxidation, hypercholesterolemia and atherosclerosis development.Transgenic APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism, were pre-treated with D-PUFAs or control H-PUFAs-containing diet (1.2%, w/w) for 4 weeks. Thereafter, mice were fed a Western-type diet (containing 0.15% cholesterol, w/w) for another 12 weeks, while continuing the D-/H-PUFA treatment.D-PUFA treatment markedly decreased hepatic and plasma F2-isoprostanes (approx. -80%) and prostaglandin F2α (approx. -40%) as compared to H-PUFA treatment. Moreover, D-PUFAs reduced body weight gain during the study (-54%) by decreasing body fat mass gain (-87%) without altering lean mass. D-PUFAs consistently reduced plasma total cholesterol levels (approx. -25%), as reflected in reduced plasma non-HDL-cholesterol (-28%). Additional analyses of hepatic cholesterol metabolism indicated that D-PUFAs reduced the hepatic cholesterol content (-21%). Sterol markers of intestinal cholesterol absorption and cholesterol breakdown were decreased. Markers of cholesterol synthesis were increased. Finally, D-PUFAs reduced atherosclerotic lesion area formation throughout the aortic root of the heart (-26%).D-PUFAs reduce body weight gain, improve cholesterol handling and reduce atherosclerosis development by reducing lipid peroxidation and plasma cholesterol levels. D-PUFAs, therefore, represent a promising new strategy to broadly reduce rates of lipid peroxidation, and combat hypercholesterolemia and cardiovascular diseases.

Pub.: 29 Jun '17, Pinned: 25 Aug '17