From the Editors Perspective: Rational Approaches for Radical Entities

Kenneth      Maiese

doi:10.2174/1567202052773526

Abstract

It is estimated that almost 400 million individuals suffer from nervous system disorders in the world. These disorders consist of both acute and chronic neurodegenerative diseases that include stroke, traumatic brain injury, presenile dementia, Alzheimer's disease, and Parkinson's disease. In addition, environmental toxin exposure also has become increasingly prominent as a precipitant of degenerative disease in the nervous system. Intimately coupled to each of these disorders is the generation of reactive oxygen species (ROS) in the brain. ROS consist of oxygen free radicals and other chemical entities that include superoxide free radicals, hydrogen peroxide, nitric oxide, and peroxynitrite. Under normal physiological conditions, these species are produced at low levels and are scavenged by endogenous antioxidant systems of the body that include superoxide dismutase, glutathione peroxidase, and catalase.

Yet, oxidative stress in the brain occurs when the generation of ROS overrides the ability of the endogenous antioxidant system to remove excess oxygen free radicals. Oxidative stress is a formidable factor for injury in the nervous system, since it leads to the dysfunction of both neuronal and vascular cells as well as inciting inflammatory cellular demise. Oxidative stress leads to the peroxidation of cellular membrane lipids, cleavage of genomic DNA, and the oxidation of a variety of cellular proteins. The generation of ROS also can block complex enzymes in the electron transport chain of the mitochondria to halt mitochondrial respiration. During the release of free radicals in the brain, microglia also become activated to begin the process of phagocytosis for the removal of injured cells. As a result, microglia are believed to lead to cellular damage of neighboring neurons and vascular cells, partly through the generation of ROS products as well as through the production of cytokines.

In consideration of the significant risks free radical generation can present to the nervous system, it is surprising to learn that the brain is highly susceptible to oxidative stress injury and has only limited capacity to avert cellular injury. A variety of observations support this premise. For example, the brain possesses the highest oxygen metabolic rate of any organ in the body, consuming twenty percent of the total amount of oxygen in the body and enhancing the possibility for the aberrant generation of free radicals. In addition, the brain is composed of significant amounts of unsaturated fats that can readily serve as a source of oxygen free radicals. Interestingly, given the increased risk factors for the generation of elevated levels of ROS in the brain, the brain also may suffer from an inadequate defense system against oxidative stress. Catalase activity in the brain, an endogenous antioxidant, has been reported to exist at levels markedly below other organs of the body, sometimes approaching catalase levels of ten percent in other organs such as the liver.