Simultaneous Activation of Nrf2 and Elevation of Dietary and Endogenous Antioxidants for Prevention and Improved Management of Parkinson’s Disease

Abstract

Parkinson disease (PD) is a slow progressive neurological disorder associated with abnormal functions of extrapyramidal system. Studies suggest that increased oxidative stress, chronic inflammation and glutamate play a dominant role in the initiation and progression of PD. Mitochondria are very sensitive to increased oxidative stress and damaged mitochondria produce more free radicals. Mutation in DJ-1, alpha-synuclein, PINK-1 or PARKIN gene associated with familial PD impairs mitochondrial functions which can increase oxidative stress. Oxidative damage initiates chronic inflammation, whereas excessive amounts of glutamate participate in neuronal death via free radicals. Thus, attenuation of oxidative stress, chronic inflammation and glutamate levels may reduce incidence, progression, and in combination with drug therapy, improve the management of PD. This review suggests that an elevation of the levels of antioxidant enzymes and phase-2-detoxifying enzymes, and dietary and endogenous antioxidants simultaneously are essential for attenuating these biochemical abnormalities optimally. The levels of dietary and endogenous antioxidants can be increased by supplementation; however, the levels of antioxidant enzymes and detoxifying enzymes requires an activation of a nuclear transcriptional factor Nrf2 and its binding with the antioxidant response elements (AREs) in the nucleus. This review discusses the regulation of Nrf2 activation, and identifies agents that activate Nrf2 by reactive oxygen species (ROS)-dependent and-independent mechanisms. This review also describes studies on individual antioxidants in PD to show that a single antioxidant cannot activate Nrf2 and enhance the levels of multiple antioxidants at the same time. It suggests a mixture of micronutrients that may accomplish the above goal.