Chapter 31 - Deuterium Protection of Polyunsaturated Fatty Acids against Lipid Peroxidation: A Novel Approach to Mitigating Mitochondrial Neurological Diseases

Abstract

Oxidative stress is associated with numerous neurological disorders. Mitochondrial malfunction contributes to generation of reactive oxygen species (ROS) in proximity to mitochondrial membranes rich in polyunsaturated fatty acids (PUFAs). ROS initiate PUFA autoxidation, a chain reaction that alters membrane fluidity and promotes toxic reactive carbonyl products (RCP) that damage proteins and DNA. Due to the stochastic nature of ROS generation, increased antioxidants cannot prevent such injury. However, deuterium-for-hydrogen substitution at bis-allylic sites reduces the rate-limiting step of autoxidation and results in inhibition of the subsequent PUFA oxidation chain reaction, decreasing toxic RCP levels. We propose a novel approach, using such isotopic reinforcement, to alleviate oxidative injury and have pre-clinical evidence demonstrating neuroprotection in an oxidative stress model of Parkinson’s disease. We hypothesize that site-specific PUFA deuteration will mitigate progression of degeneration in other disorders that manifest oxidative injury either as a primary or secondary insult.