Oxidative Stress and the Central Nervous System

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Abstract

Biochemical integrity of the brain is vital for normal functioning of the central nervous system (CNS). One of the factors contributing to cerebral biochemical impairment is a chemical process called oxidative stress. Oxidative stress occurs upon excessive free radical production resulting from an insufficiency of the counteracting antioxidant response system. The brain, with its high oxygen consumption and lipid-rich content, is highly susceptible to oxidative stress. Therefore, oxidative stress-induced damage to the brain has a strong potential to negatively impact normal CNS functions. Although oxidative stress has historically been considered to be involved mainly in neurodegenerative disorders such as Alzheimer disease, Huntington disease, and Parkinson disease, its involvement in neuropsychiatric disorders, including anxiety disorders and depression, is beginning to be recognized. This review is a discussion of the relevance of cerebral oxidative stress to impairment of emotional and mental well-being.

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Free radicals and antioxidants in normal physiological functions and human disease.

Marian Valko, Dieter Leibfritz, Jan Moncol … (2007)

Reactive oxygen species (ROS) and reactive nitrogen species (RNS, e.g. nitric oxide, NO(*)) are well recognised for playing a dual role as both deleterious and beneficial species. ROS and RNS are normally generated by tightly regulated enzymes, such as NO synthase (NOS) and NAD(P)H oxidase isoforms, respectively. Overproduction of ROS (arising either from mitochondrial electron-transport chain or excessive stimulation of NAD(P)H) results in oxidative stress, a deleterious process that can be an important mediator of damage to cell structures, including lipids and membranes, proteins, and DNA. In contrast, beneficial effects of ROS/RNS (e.g. superoxide radical and nitric oxide) occur at low/moderate concentrations and involve physiological roles in cellular responses to noxia, as for example in defence against infectious agents, in the function of a number of cellular signalling pathways, and the induction of a mitogenic response. Ironically, various ROS-mediated actions in fact protect cells against ROS-induced oxidative stress and re-establish or maintain "redox balance" termed also "redox homeostasis". The "two-faced" character of ROS is clearly substantiated. For example, a growing body of evidence shows that ROS within cells act as secondary messengers in intracellular signalling cascades which induce and maintain the oncogenic phenotype of cancer cells, however, ROS can also induce cellular senescence and apoptosis and can therefore function as anti-tumourigenic species. This review will describe the: (i) chemistry and biochemistry of ROS/RNS and sources of free radical generation; (ii) damage to DNA, to proteins, and to lipids by free radicals; (iii) role of antioxidants (e.g. glutathione) in the maintenance of cellular "redox homeostasis"; (iv) overview of ROS-induced signaling pathways; (v) role of ROS in redox regulation of normal physiological functions, as well as (vi) role of ROS in pathophysiological implications of altered redox regulation (human diseases and ageing). Attention is focussed on the ROS/RNS-linked pathogenesis of cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases (Alzheimer's disease and Parkinson's disease), rheumatoid arthritis, and ageing. Topics of current debate are also reviewed such as the question whether excessive formation of free radicals is a primary cause or a downstream consequence of tissue injury.