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, 52 (7), 737-750

The Role of Oxidative Stress in Anxiety Disorder: Cause or Consequence?


The Role of Oxidative Stress in Anxiety Disorder: Cause or Consequence?

Alessandra das Graças Fedoce et al. Free Radic Res.


Anxiety disorders are the most common mental illness in the USA affecting 18% of the population. The cause(s) of anxiety disorders is/are not completely clear, and research in the neurobiology of anxiety at the molecular level is still rather limited. Although mounting clinical and preclinical evidence now indicates that oxidative stress may be a major component of anxiety pathology, whether oxidative stress is the cause or consequence remains elusive. Studies conducted over the past few years suggest that anxiety disorders may be characterised by lowered antioxidant defences and increased oxidative damage to proteins, lipids, and nucleic acids. In particular, oxidative modifications to proteins have actually been proposed as a potential factor in the onset and progression of several psychiatric disorders, including anxiety and depressive disorders. Oxidised proteins are normally degraded by the proteasome proteolytic complex in the cell cytoplasm, nucleus, and endoplasmic reticulum. The Lon protease performs a similar protective function inside mitochondria. Impairment of the proteasome and/or the Lon protease results in the accumulation of toxic oxidised proteins in the brain, which can cause severe neuronal trauma. Recent evidence points to possible proteolytic dysfunction and accumulation of damaged, oxidised proteins as factors that may determine the appearance and severity of psychotic symptoms in mood disorders. Thus, critical interactions between oxidative stress, proteasome, and the Lon protease may provide keys to the molecular mechanisms involved in emotional regulation, and may also be of great help in designing and screening novel anxiolytics and antidepressants.

Keywords: Antioxidants; Lon protease; Nrf2; anxiety disorder; inflammation; oxidative stress; proteasome; psychiatric disorders.


Figure 1.
Figure 1.. Neurotoxic effects of oxidative stress.
Neurotoxicity may occur through an elevation of superoxide anion (O2•−) by mitochondria, by autoxidation of neurotransmitters such as Dopamine (DA), or by inappropriately activated microglia, any or all of which may result in increased H2O2 levels, increased formation of the highly reactive hydroxyl radical (HO) and superoxide (O2•−). Phospholipids and proteins, sugars, RNA and DNA are all susceptible to damage by HO as are cell membranes, and both nuclear and mitochondrial chromosomes. These factors closely link hypotheses involving mitochondrial dysfunction, neuro-inflammation, oxidative stress, and the essential role of Nrf2 in protein degradation, through activation of the 20S Proteasome that selectively degrades oxidized proteins, and modulating macrophage activation in response to neuro-inflammation.
Figure 2.
Figure 2.. Damaging Effects of Oxidative Stress on Cell Structures and its Relation to Disease initiation/Progression, Ageing, and Senescence.
Oxidative stress arising (largely) from O2•− and H2O2 generated by mitochondria; by environmental and medical sources; by phagocytes such as astrocytes, glia, neutrophils, macrophages, monocytes, etc.; and by autoxidation of metabolites such as dopamine can damage cell structures. Phospholipids, both soluble and membrane-bound proteins, and nuclear and mitochondrial DNA, are easily damaged by oxidation which can lead to subsequent cellular malfunction, tissue dysfunction, and even organ failure. Ultimately, such molecular damage is thought to contribute to the initiation and/or progression of many age-related disorders and diseases that are among the major causes of morbidity and mortality in ageing populations (some of the major ones are shown at the bottom of the figure), and in the very processes of aging and senescence.
Figure 3.
Figure 3.. Formation and Neutralization of Reactive Oxygen Species in the Mitochondrial Electron Transport Chain (ETS).
The Krebs cycle is a series of enzymatic reactions that provide electrons (from pyruvate via acetyl CoA) to the ETS in the form of NADH and FADH2. These electrons then undergo vectorial transport along the ETS, generating an electrochemical energy gradient by which ADP can be phosphorylated to ATP at complex V. In order to maintain electron flow (and ATP generation) electrons must ultimately be ‘removed’ from the ETS, and this is accomplished at Complex IV (cytochrome oxidase) where the electrons reduce oxygen to water in four consecutive (but concerted) one-electron steps. Although the whole process is really rather efficient, some 1–2% of the molecular oxygen consumed during normal physiological respiration is reduced in one-electron side reactions (mostly at Complex ‘s I and III) into the superoxide anion radical, O2•- (also commonly just called ‘superoxide’). The O2•- so generated is almost immediately dismutated to hydrogen peroxide (H2O2) by superoxide dismutase (SOD) and, H2O2 can then be removed by the enzyme, glutathione peroxidase (GPX).

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