The Role of Oxidative Stress in Parkinson's Disease

Abstract

Parkinson's disease (PD) is caused by progressive neurodegeneration of dopaminergic (DAergic) neurons with abnormal accumulation of α-synuclein in substantia nigra (SN). Studies have suggested the potential involvement of dopamine, iron, calcium, mitochondria and neuroinflammation in contributing to overwhelmed oxidative stress and neurodegeneration in PD. Function studies on PD-causative mutations of SNCA, PRKN, PINK1, DJ-1, LRRK2, FBXO7 and ATP13A2 further indicate the role of oxidative stress in the pathogenesis of PD. Therefore, it is reasonable that molecules involved in oxidative stress, such as DJ-1, coenzyme Q10, uric acid, 8-hydroxy-2'-deoxyguanosin, homocysteine, retinoic acid/carotenes, vitamin E, glutathione peroxidase, superoxide dismutase, xanthine oxidase and products of lipid peroxidation, could be candidate biomarkers for PD. Applications of antioxidants to modulate oxidative stress could be a strategy in treating PD. Although a number of antioxidants, such as creatine, vitamin E, coenzyme Q10, pioglitazone, melatonin and desferrioxamine, have been tested in clinical trials, none of them have demonstrated conclusive evidence to ameliorate the neurodegeneration in PD patients. Difficulties in clinical studies may be caused by the long-standing progression of neurodegeneration, lack of biomarkers for premotor stage of PD and inadequate drug delivery across blood-brain barrier. Solutions for these challenges will be warranted for future studies with novel antioxidative treatment in PD patients.

Keywords: Parkinson’s disease; antioxidant; coenzyme Q10; creatine; desferroxamine; iron; melatonin; mitochondria; neuroinflammation; oxidative stress; pioglitazone; radical oxidative species; vitamin E.

Figure 1

Schematic diagram representing the mechanisms of reactive oxygen species (ROS) production, antioxidative stress pathways and potential drugs with different targets for Parkinson’s disease (PD). Boxes shaded in red are indicative of genetic and environmental factors involved in the production of ROS. The drugs/proteins with potential in treating PD by reducing oxidative stress are indicated in boxes shaded in yellow. CoQ10: coenzyme Q10; CART: cocaine- and amphetamine-regulated transcript; GSH: glutathione; GSH-Px: glutathione peroxidase; NRF2: nuclear factor erythroid-2-related factor 2; PGC-1α: PPARγ coactivator-1α; ROS: radical oxidative species; SOD: superoxide dismutase.