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Mitigating Effects of Oxidation in Aging and Diseases M. Shchepinov, R.J. Molinari *, V. Shmanai , C.Clarke , A. Manning-Bog March 5, 2010 ASENT Pipeline Session. * Presentor. Background & Hypothesis.

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  1. Mitigating Effects of Oxidation in Aging and DiseasesM. Shchepinov, R.J. Molinari *, V. Shmanai, C.Clarke, A. Manning-Bog March 5, 2010ASENT Pipeline Session * Presentor

  2. Background & Hypothesis • Many CNS disease etiologies have recently been associated with oxidation damage of mitochondrial membranes, • Such oxidation occurs at a very few, weak-link chemical bonds in polyunsaturated fatty acids, • Isotope effect can stabilize target bonds in well-understood ways, with little, if any, toxicity. Supplementing isotope-‘fortified’ components into essential fatty acids will increase resistance to oxidation, and may mitigate disease.

  3. Oxidation by ROS and Simplest Isotope Protection ROS abstract hydrogens from PUFAs Some specific stabilization schema.

  4. Preliminary Data: • D-4 Linolenic Acid Co-enzyme Q10 deficient yeast oxidative stress models. • Complete replacement of dietary PUFA with d-PUFA, • Treatment of MPTP mice with dietary PUFAs. .

  5. Yeast Co-Q10 minus Oxidative Stress ModelLinolenic Acid vs. D-4 Linolenic Acid * Clarke Lab, UCLA

  6. MPTP Mouse Study • Primary goal: • Does dietary D-PUFA protect nigrostriatal dopamine from MPTP-induced depletion? • Secondary goals: • -Do dietary D-PUFAs incorporate into the brain ? • -Are they toxic ? • -Does dietary D-PUFA decrease nigrostriatal lipid hydroperoxide formation (HNE) due to MPTP challenge ?

  7. Study Design: • Dietary PUFA dosing: • Fat-free chow (5-6g/mouse) supplemented with saturated fats, oleic acid, and H-PUFA or D-PUFA (30 mg linolenic and 30 mg linoleiccoated on pellets) for 6 days + 6 days post MPTP • Toxicant challenge: • Single injection of MPTP (40 mg/kg) or saline vehicle, i.p. Cohorts (4) were: H-PUFA-saline; H-PUFA-MPTP; D-PUFA-saline; D-PUFA-MPTP • Readouts: • Striatal dopamine levels • 4-HNE immunohistochemistry/nigral stereology • Remaining brain for total deuterium levels

  8. Nigrostriatal dopamine levels * p = 0.0077 Striatal DA (ng/mg protein) n=3 n=3 n=4 n=4 Manning-Bog Lab, Stanford Research Institute

  9. Additional Observations • Brain tissues in treated, saline samples were highly enriched in deuterium. • No observed mortality or side effects from dietary dosing, normal weight gain in all mice except as noted below. • MPTP produced marked dopamine depletion of >75% with abnormally high mortality in the untreated, MPTP cohort (3/7) vs. 1/7 in D-PUFA cohort. • Study Notations: Less than 1 in 7 were removed due to dissected protein amounts in excess of two std. deviations (n=2), or failure to thrive (n=1)

  10. Further Strategies Focus on diseases in which oxidation products of PUFAs (e.g. 4-HNE) are directly implicated (PD, AMD, ALS, ALZ, CHF) Expand POC efficacy and toxicity of PUFA reinforcement in predictive cellular models & mammals Retrotope supplies materials/expertise for trials, work done by disease model experts Triage and accelerate disease programs with new funding / partners when POC established Develop early regulatory Tox Approach

  11. Acknowledgments This work was funded by the Michael J. Fox Foundation for Parkinson’s Research

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