Antioxidants and free radicals have become commonly used terms in modern discussions of disease mechanisms. Our cells have antioxidant mechanisms which can scavenge free radicals. It’s when these antioxidant systems become overwhelmed that we run into health problems.

Antioxidants – An antioxidant is a molecule stable enough to donate an electron to a rampaging free radical and neutralize it, thus reducing its capacity to damage.These low-molecular-weight antioxidants can safely interact with free radicals and terminate the chain reaction before vital molecules are damaged. Some of such antioxidants including glutathione, ubiquinol, and uric acid are produced during normal metabolism in the body. Other lighter antioxidants are found in the diet. The principle micronutrient antioxidants are vitamin E (α-tocopherol), vitamin C (ascorbic acid), and B-carotene. The body cannot manufacture these micronutrients, so these vitamins must be supplied in the diet.

Antioxidant Enzymes – Three of the most important enzymes of the cell antioxidant defense system are glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase.

Glutathione Peroxidase (GPx) is a selenium-dependent enzyme found not only in the cytosol (70%), but also in the mitochonrdria (30%). Requiring four selenium atoms per active molecule, GPx scavenges lipid peroxides through cell membranes and quenches hydrogen peroxide, the product of SOD, converting it to water. Hydrogen peroxide is a weak and relatively stable oxidant, at least in the absence of iron and copper. However, in their presence, hydrogen peroxide can convert to the highly reactive hydroxyl radical. As a result, GPx is irreplaceable in the antioxidant arsenal, especially in the mitochondria, which do not contain catalase for protection from peroxide. GPx also offers exclusive protection from organic hydroperoxides (implicated in changes of vascular wall lipids that promote atherogenesis), and helps regenerate reduced vitamin C. Imbalances in GPx have been observed with aging and a variety of disorders such as cancer, cardiovascular disease, diabetes, Alzheimer’s, alcohol-induced oxidative stress, cholecystitis, and urticaria.

Superoxide Dismutase (SOD) – SOD is critical for preventing the superoxide radical from generating other highly reactive species through its interactions with iron. These damaging molecules can initiate lipid peroxidation of fatty acids (a major cause of posttraumatic cell damage and death), form peroxyl radicals (implicated in colon cancer development in vitro), or react with nitric oxide to form another highly reactive compound, peroxynitrite (instrumental in the development of organ damage in circulatory shock). Because reduced SOD activity can result in the accumulation of intracellular superoxide, this SOD reaction constitutes a critical step in preventing oxidative stress. Imbalances in SOD have been noted in several disorders, such as familial ALS, Parkinson’s, Alzheimer’s, and other neurological diseases, Down’s syndrome, diabetes and impaired glucose tolerance, cataracts, and dengue fever.

Catalase – Catalase is a common enzyme found in nearly all living organisms, which are exposed to oxygen, where it functions to catalyze the decomposition of hydrogen peroxide to water and oxygen. Hydrogen peroxide is a harmful by-product of many normal metabolic processes: to prevent damage, it must be quickly converted into other, less dangerous substances. To this end, catalase is frequently used by cells to rapidly catalyze the decomposition of hydrogen peroxide into less reactive gaseous oxygen and water molecules.

Free Radicals or Reactive Oxygen Species (ROS) – From the moment we are first formed in our mother’s womb, our cells produce destructive particles called free radicals. They are also introduced into our body from the environment. A small number of free radicals are necessary for normal functioning of the body, for example, in the production of cellular signals and for the proper functioning of the immune system; yet any excess of these free radicals can slowly damage important components of the cells and surrounding tissues. Inadequate antioxidant protection allows these free radicals or ROS (specific types of free radicals) to alter cellular physiology, contributing to loss of function and the development of most chronic diseases. Over a lifetime, they chip away at our cells, like water wearing away a stone, until the cells are so weakened, they begin to malfunction. We call this process aging, and in extreme cases, degenerative disease.

Inflammation generates free radicals. Our brain, due to its high metabolic rate, is one of the most vulnerable organs to the damaging effects of ROS. This may explain ROS involvement in several neuropsychiatric diseases. ROS may play an active role in the pathophysiology of depression by various mechanisms such as tissue damage, inflammation, neurodegeneration, autoimmune mechanisms generated by tissue damage, and apoptosis (programmed cell death).

Mitochondria – In order for our organs to function properly, they require energy, and that energy is produced by the mitochondria which are tiny organelles. Their function is at the very heart of everything that occurs in our body. Mitochondrial oxidative phosphorylation is the major ATP-producing pathway, which supplies more than 95% of the total energy requirement in the cells throughout our body. However, that process also produces byproducts such as reactive oxygen species (ROS), which are damaging to our cells, and our mitochondrial DNA, which are then transferred to our nuclear DNA. So there’s a trade-off. In producing energy, our body also ages from the damaging aspects from the ROS that are generated. Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of psychiatric disorders.

The brain contains a large number of mitochondria, therefore, it is more susceptible to reduction of the aerobic metabolism. Mitochondrial dysfunction results from alterations in biochemical cascade and the damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neuropsychiatric disorders, such as bipolar disorder, depression and schizophrenia. Recent studies have demonstrated that important enzymes involved in brain energy are altered in bipolar disorder patients. Depressive disorders, including major depression, are serious and disabling. However, the exact pathophysiology of depression is not clearly understood. Several works have demonstrated that metabolism is impaired in some animal models of depression, induced by chronic stress, especially the activities of the complexes of mitochondrial respiratory chain. Alterations of mitochondrial oxidative phosphorylation in schizophrenia have been reported in several brain regions and also in platelets.

Oxidative Stress – Oxidative stress is a consequence of excessive production of free radicals and also due to the failure of the antioxidant defense mechanism that protects the cells by removing free radicals. When prolonged or severe, oxidative stress eventually results in tissue damage and increased risk of disease. Oxidative stress is a well-established finding and may be playing a role in the pathogenesis of depression due to having an integral relationship with the inflammatory cascade. The brain with its extensive capacity to consume large amounts of oxygen and production of free radicals, is considered especially sensitive to oxidative damage. Therefore, it is not surprising that oxidative stress is implicated in several disorders of the brain including neurodegenerative disorders and psychiatric ailments. This association is largely due to the high vulnerability of brain to oxidative load. Individuals with depression or anxiety are deficient in antioxidants, indicative of increased oxidative stress.

Resources

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3964745/

https://www.hindawi.com/journals/omcl/2014/430216/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249911/http://onlinelibrary.wiley.com/doi/10.1002/ddrr.115/epdf?r3_referer=wol&tracking_action=preview_click&show_checkout=1&purchase_referrer=searchttp://link.springer.com/article/10.1007/s11064-008-9865-8

http://link.springer.com/article/10.1007/s11064-008-9865-8

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249911/