Oxidative Stress and Antioxidants in Neurodegenerative Disorders

Abstract

Neurodegenerative disorders constitute a substantial proportion of neurological diseases with significant public health importance. The pathophysiology of neurodegenerative diseases is characterized by a complex interplay of various general and disease-specific factors that lead to the end point of neuronal degeneration and loss, and the eventual clinical manifestations. Oxidative stress is the result of an imbalance between pro-oxidant species and antioxidant systems, characterized by an elevation in the levels of reactive oxygen and reactive nitrogen species, and a reduction in the levels of endogenous antioxidants. Recent studies have increasingly highlighted oxidative stress and associated mitochondrial dysfunction to be important players in the pathophysiologic processes involved in neurodegenerative conditions. In this article, we review the current knowledge of the general effects of oxidative stress on the central nervous system, the different specific routes by which oxidative stress influences the pathophysiologic processes involved in Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis and Huntington's disease, and how oxidative stress may be therapeutically reversed/mitigated in order to stall the pathological progression of these neurodegenerative disorders to bring about clinical benefits.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; free radicals; homeostasis; mitochondrial stress; reactive nitrogen species; reactive oxygen species.

Figure 1

Effects of ROS production by mitochondria. The generation of ROS as a by-product of cellular respiration via the electron transport chain in mitochondria can have deleterious effects in the cell and tissue involved. ROS can cause oxidative damage to mitochondrial DNA and protein, resulting in mutations and mitochondrial dysfunction that impair the ability of mitochondria to synthesize ATP, leading to disease. Reactive species can also lead to the induction of a permeability transition pore (PTP) in mitochondria, rendering the inner membrane of the mitochondria more permeable to small molecules during episodes of ischemia/reperfusion injury. ROS can also lead to the oxidative degradation of lipid molecules (lipid peroxidation), especially within the cell membrane, resulting in cell damage and death. Reactive species can also lead to the release of intermembrane proteins including cytochrome c (Cyt C) into the cytosol of the cell, which, in turn, can activate apoptotic machinery within a cell, leading to cell death.