Selenium is an essential trace element that is the foundation of the antioxidant defence system in the brain and in all other tissues — it is present in the active site of the glutathione peroxidase (GPx) enzymes, which are the primary enzymes that detoxify the hydrogen peroxide and the lipid hydroperoxides that are the reactive oxygen species (ROS) that are generated as byproducts of normal cellular metabolism and as products of the inflammatory response. The brain is particularly vulnerable to oxidative stress — it consumes approximately 20% of the total body oxygen consumption despite accounting for only 2% of the body weight, it has a high proportion of polyunsaturated fatty acids in its membrane lipids (which are the preferred targets of the lipid peroxidation chain reaction), and it has a relatively low activity of the antioxidant enzymes (including the catalase, the superoxide dismutase, and the glutathione peroxidase) compared to other organs. The selenium-dependent glutathione peroxidase system is therefore particularly important for the brain — it provides the primary defence against the ROS that are generated by the high metabolic activity of the brain and that are the primary drivers of the neurodegenerative process that underlies the Alzheimer disease, the Parkinson disease, and the other neurodegenerative conditions that are associated with the ageing process.
Glutathione Peroxidase and the Antioxidant Defence System
Glutathione peroxidase (GPx) is the selenium-dependent enzyme that catalyses the reduction of hydrogen peroxide (H2O2) and of organic hydroperoxides (ROOH) to water and to the corresponding alcohols, respectively, using the reduced glutathione (GSH) as the electron donor. This reduction reaction is the primary mechanism by which the cells detoxify the H2O2 that is produced by the superoxide dismutase reaction and by the oxidases, and it is essential for the prevention of the oxidative damage to the proteins, the lipids, and the DNA. There are several GPx isoforms — GPx1 is the cytosolic isoform that is present in all cells, GPx2 is the gastrointestinal isoform that protects the gut epithelium from the oxidative damage of the ingested toxins and pathogens, GPx3 is the extracellular isoform that is secreted by the kidney and that circulates in the plasma, and GPx4 is the phospholipid hydroperoxide isoform that is particularly important for the protection of the cell membranes from the lipid peroxidation. All of these GPx isoforms require selenium (as selenocysteine, the 21st amino acid that is incorporated into the GPx protein at theUGA codon) as an essential cofactor, and without adequate selenium, the GPx activity falls, the H2O2 accumulates, and the oxidative damage to the cells is unchecked — producing the tissue damage, the inflammation, and the degeneration that are the clinical manifestations of the selenium deficiency.
The clinical importance of the selenium-dependent GPx system for the brain is underscored by the observation that selenium deficiency is associated with the cognitive decline, the neurodegenerative changes, and the increased risk of the Alzheimer disease and the Parkinson disease. In the Alzheimer brain, the GPx activity is reduced (consistent with the low selenium status that has been documented in Alzheimer patients in several studies), the oxidative damage markers are elevated (including the 4-hydroxynonenal, the malondialdehyde, and the protein carbonyls), and the amyloid-beta plaques and the neurofibrillary tangles are surrounded by the evidence of the oxidative stress. In the Parkinson brain, the GPx activity is reduced in the substantia nigra (the brain region that is most affected by the dopaminergic neuronal loss), the oxidative damage markers are elevated, and the Lewy bodies (the intracellular aggregates of the alpha-synuclein protein) are the evidence of the oxidative stress and of the proteostasis failure. Selenium supplementation has been shown to increase the GPx activity, to reduce the oxidative damage markers, and to slow the progression of the cognitive decline in older adults — these findings are consistent with the hypothesis that selenium deficiency contributes to the neurodegenerative process and that selenium supplementation may be protective against the age-related neurodegenerative diseases.
Selenium and the Thyroid Function
Selenium is also essential for the thyroid function — the thyroid gland has the highest selenium content per gram of any organ in the body, and it is required for the function of the iodothyronine deiodinase enzymes that convert the thyroxine (T4) to the triiodothyronine (T3) and that regulate the peripheral metabolism of the thyroid hormones. The type 1 deiodinase (D1) and the type 2 deiodinase (D2) are selenium-dependent enzymes — they contain selenocysteine at the active site and require selenium for their catalytic activity. When selenium is deficient, the conversion of T4 to T3 is impaired (particularly in the peripheral tissues where D2 is the primary deiodinase), and the thyroid hormone metabolism is disrupted — producing the hypothyroidism that is one of the clinical manifestations of the severe selenium deficiency. The combination of the iodine deficiency and the selenium deficiency in the goitrous regions of central Africa and of the Himalayas produces the more severe form of the cretinism syndrome (called the neurological cretinism), which is characterised by the severe mental retardation, the deaf mutism, the spasticity, and the growth failure that are the hallmark of this devastating condition.
Practical Application
For general selenium supplementation, the evidence-based approach is to supplement with 100-200mcg of selenium daily (as selenomethionine or as selenite, the two most common supplemental forms). The RDA of selenium is 55mcg daily for adults, and the tolerable upper intake level is 400mcg daily for adults (above which the selenium can produce the selenosis — the toxicity syndrome that includes the hair loss, the nail brittleness, the gastrointestinal symptoms, and the neurological abnormalities). The selenomethionine form is preferred for the long-term supplementation because it is more bioavailable and because it is incorporated into the body proteins in place of the methionine (providing a storage form of selenium that is not toxic at the recommended doses). For comprehensive antioxidant and neurological support, selenium pairs well with the vitamin E (which works synergistically with the GPx system in the protection of the cell membranes from lipid peroxidation), with the CoQ10 (which is required for the function of the electron transport chain and which reduces the production of the ROS at the source), with the NAC (which provides the cysteine that is required for the synthesis of the glutathione, the co-substrate for the GPx reaction), and with the omega-3 fatty acids (which provide the polyunsaturated fatty acids that are the preferred targets of the lipid peroxidation and which are protected by the adequate selenium status).
Leave a Reply