Oxidative stress plays a major role in the development of Parkinson’s disease (PD). Essential (available from diet only) polyunsaturated fatty acids (PUFAs) are one of the first targets of oxidation. The toxic products formed inflict PD-associated damage on other cellular components, and this damage cannot be neutralized by antioxidants. We propose to chemically reinforce PUFAs making them more resistant to oxidation. The essential nature of PUFAs ensures they are distributed throughout the body from diet.
Well-established MPTP and paraquat pre-clinical models of Parkinson’s will be used to test the efficiency of the proposed approach. Mice will be fed on a diet containing either reinforced PUFAs, or normal PUFAs (control group). Incorporation of PUFAs into the brain will be measured. When adequate levels are achieved, the mice will be treated with either MPTP or paraquat to induce symptoms of PD. Following this treatment, biochemical and histological analysis of the brain will be carried out to: measure levels of dopamine, oxidative stress, toxic PUFA oxidation products such as 4-hydroxynonenal; estimate stereologically nigral dopaminergic neurons; and assess other indicators of PD associated degeneration such as microglial activation.
Relevance to Diagnosis/Treatment of Parkinson's’s Disease:
Reinforcement of PUFAs could be an entirely new and a potentially safe, easy (via supplementation), and effective method of preventing or slowing progression of PD. Replacing essential PUFAs with forms less prone to oxidation may prevent/diminish oxidative injury and nigrostriatal toxicity. This novel approach may apply also to prevention and mitigation of other neurodegenerative diseases triggered by oxidation
Antioxidants have been extensively studied, but no attempts were made to make the oxidized molecules themselves more resistant. We believe this approach will show additional benefit in pre-clinical pre-clinical models of PD complementary to other forms of treatment and prevention. If our hypothesis that reinforcing essential nutrients will prevent/diminish oxidative injury and nigrostriatal toxicity in pre-clinical pre-clinical models is proved correct, we will initiate additional experimental models of alpha-synuclein over-expression and aggregation, and other preclinical testing.
These studies represent a completely novel therapeutic approach targeting a mechanism that has long been a major focus of Parkinson’s disease (PD) research - oxidative stress. Our strategy is to stabilize PUFAs by substituting deuterium for hydrogen at oxidation-prone bisallylic sites of these essential fatty acids. Because deuterium-carbon bond is more stable, this substitution dramatically reinforces the carbon-hydrogen bond that is first broken in lipid peroxidation. We propose that “reinforcing” essential PUFAs with isotopic replacement via dietary intake will reduce lipid peroxidation and decelerate hydroperoxide-mediated toxic cascades that contribute to neuronaldegeneration in PD. Following 6 days of dietary deuterated PUFA (D-PUFA) intake, we observed robust incorporation in brain tissue vs. animals fed hydrogenated PUFA (H-PUFA). Furthermore, after subsequent exposure to MPTP, mice fed D-PUFA vs. H-PUFA demonstrated marked neuroprotection at the striatal level as evidenced by partial-to-full attenuation of depletion of dopamine and TH immunoreactivity. These data support the hypothesis that “molecular stabilization” is a novel strategy to reduce cellular injury underlying PD.