Thyroid hormone activation brain

Like steroid hormones, thyroid hormones interact with receptors to alter genomic activity and affect the synthesis of specific proteins during development [25-28], As with testosterone and progesterone, metabolic transformation of thyroxine (T4) is critical to its action [25-28]. Moreover, as with steroid hormones, thyroid hormones alter brain functions in adult life in ways that both resemble and differ from their action during development [25-28]. 

The alterations in morphological organization of the brain resulting from hypothyroidism have been documented [10-13]. Numerous biochemical parameters are affected by altered thyroid states (for review see 14-16). Recent biochemical data on the effect of thyroid hormones on nerve cell differentiation indicate that they regulate microtubule assembly by changing the concentration and/or the activity of MAPS (tau fraction) [17]. The critical period of effectiveness of thyroid hormones in brain maturation raises a special problem. The correct organization of... 

Ph. De Nayer and B. Dozin. Thyroid hormones and brain development modulation of the binding activity of the T3 nuclear receptor by chromatin-associated factors. Molec. Physiol. 7 303-310 (1985). 

Hormonal actions occur during sensitive periods in development, in adult life during natural endocrine cycles and in response to experience as well as during the aging process (see Ch. 30). As a result of their fundamental actions on cellular processes and genomic activity and of the control of their secretion by environmental signals, steroid and thyroid hormone actions on the brain provide unique insights into the plasticity of the brain and behavior (see also Ch. 50). 

The transport of amino acids at the BBB differs depending on their chemical class and the dual function of some amino acids as nutrients and neurotransmitters. Essential large neutral amino acids are shuttled into the brain by facilitated transport via the large neutral amino acid transporter (LAT) system [29] and display rapid equilibration between plasma and brain concentrations on a minute time scale. The LAT-system at the BBB shows a much lower Km for its substrates compared to the analogous L-system of peripheral tissues and its mRNA is highly expressed in brain endothelial cells (100-fold abundance compared to other tissues). Cationic amino acids are taken up into the brain by a different facilitative transporter, designated as the y system, which is present on the luminal and abluminal endothelial membrane. In contrast, active Na -dependent transporters for small neutral amino acids (A-system ASC-system) and cationic amino acids (B° system), appear to be confined to the abluminal surface and may be involved in removal of amino acids from brain extracellular fluid [30]. Carrier-mediated BBB transport includes monocarboxylic acids (pyruvate), amines (choline), nucleosides (adenosine), purine bases (adenine), panthotenate, thiamine, and thyroid hormones (T3), with a representative substrate given in parentheses [31]. 

Figure 5 is a model of the peripheral metabolism of thyroid hormone in normal humans which places the production of plasma T3 and the clearance of plasma rT3 predominantly in tissues with PTU-sensitive, type I deiodinase activity. Although the role of the liver is emphasized, contribution of the kidneys is not excluded. Clearance of plasma T3 and production of plasma rT3 is located mainly in tissues such as brain and perhaps skin with PTU-insensitive, type III deiodinase activity. 

Type III deiodinase catalyzes the conversion of T4 to reverse T3, and the conversion of T3 to T2- These steps constitute 5 -deiodination reactions. The enzyme occurs in the brain and skin of rats. The physiological role of the type III enzyme is thought to be to protect the brain from possible toxic effects of active thyroid hormone (T3). The placenta is distinguished in that it contains both type II and type III deiodinases (Glinoer, 1997). 

Selenium is a component of all three members of the deiodinase enzyme family, the enzymes responsible for deiodination of the thyroid hormones (Kohrle 1994 St. Germain and Galton 1997). The deiodinases contain a selenocysteine at the active site, which is required for catalytic activity. There are three types of deiodinases and they differ in terms of tissue distribution, reaction kinetics, efficiency of substrate utilization, and sensitivity to inhibitors. The first to be recognized as a selenoprotein was type I iodothyronine 5 -deiodinase which converts the prohormone thyroxine (T4) to the active form, triiodothyronine (T3) and to date, studies of the effects of excess selenium have focused on this protein. Under normal circumstances the human thyroid produces only 20-30% of its hormone as T3 the remainder is T4 (a minute amount of reverse T3 (rT3) is also produced), which is largely converted to active T3 by type I deiodinase located within the liver, euthyroid pituitary, kidney, thyroid, and brain. Type I deiodinase is a membrane bound protein and, thus, its activity has not been directly measured in studies of humans supplemented with selenium. Human studies have instead measured serum levels of T3, rT3, T4, and TSH. 

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