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Endocrinology

Neurons in slow motion

Hypothyroidism protects the brain from attacks such as strokes

MARIANA SAMPAIOWhen attacked, the human brain can sometimes react in a fascinating way. In certain cases, not yet well understood, it manages to shift the control of vital functions, which used to be commanded by now damaged areas, to regions with neuronal connections that are still preserved. This is not the only self-preservation effort of the organ when threatened. Studies coordinated over the past two years by the Brazilian scientist Antonio Bianco, head of the Division of Endocrinology, Diabetes and Metabolism of the University of Miami Medical School focus on another type of brain plasticity that is much less well known but equally manifest in situations of danger: the capacity to regulate the amount of the thyroid hormone that acts locally on its cells and thus to speed up or slow down the functioning rate in accordance with its needs. Other organs, such as the heart, muscles and nerves, also have this ability, but none of them in such a refined way as the brain.

In recent work with human brain cells grown in vitro, published in June in the Journal of Clinical Investigation (JCI), Bianco describes the complex cellular mechanism that allows the brain to decrease the rate of functioning of these hormones when a health problem such as a stroke occurs. The researcher’s interpretation is that the slow-down is part of an adaptive effort of the organ to curb its metabolism and, thus, to try to minimize the harmful effects of the clinical condition. “The brain increases or decreases the level of thyroid hormone because it is exposed to situations of illness or health”, says endocrinologist. “A stroke causes hypothyroidism in localized brain tissue, which, by all indications, is beneficial to the organism”.

The cerebral vascular accident, the technical name for a stroke, causes hypoxia. There is a lack of blood and oxygen for the proper functioning of neurons. If deprived of these elements for a long time, brain tissue dies. Faced with this threat, the brain reduces the local levels of thyroid hormones and starts using less energy, so that the neurons require less oxygen. Adapting the metabolism to a slow-running mode is a means of fighting the harmful effects of the stroke. Two other Brazilians also took part in the JCI study: Rui Maciel, from the Federal University of São Paulo and the PhD candidate Beatriz Freitas.

Transformation
Understanding how the brain modulates the local impact of the thyroid hormone involves knowledge of the entire metabolic process of this substance. Located in the lower part of the neck front, the thyroid gland uses iodine from food to produce not one, but two hormones: thyroxine (T4) and triiodothyronine (T3). In a normal person, approximately 80 percent of the hormone secreted is T4 and the rest is T3. The thyroid makes these two forms of hormones and releases them into the bloodstream, which distributes them to body tissue. Technically, T4 is a pro-hormone, a less active form of the thyroid hormone that, in order to influence metabolism, needs to be converted by an enzyme into T3, its active version. Therefore, what matters in practical terms is the amount of T3 present in any specific organ.

Double effect
Bianco is one of the world’s leading experts in the field of deiodinases, a set of three enzymes (D1, D2 and D3) that activate or deactivate the thyroid hormones, and he has found a very peculiar expression pattern of these proteins in the brain. According to the model proposed in the JCI, the D2 enzyme acts on the brain’s abundant glial cells, which support and nourish neurons. This enzyme converts T4 into T3, raising the level of the active form of thyroid hormone in the organ. T3 resulting from the action of D2 is transported to neuronal cells adjacent to the glials. In a stroke, the lack of oxygen reduces the production of T3 in the glial cells while the neurons increase the expression of another deiodinase, D3, which deactivates the T3. “Hypoxia causes the expression of the D3 enzyme to increase in the neurons around sevenfold”, explains Bianco. In other words, in isolation, it places the brain in a condition that is analogous to that of an individual with hypothyroidism. The organ starts functioning in slow motion, consuming less energy and minimizing the damage caused by the lack of oxygen. There are also signs that hypothyroidism in certain tissues stimulates cell proliferation and so helps in the regeneration and cure of diseases.

In medical practice, endocrinologists are concerned about the concentration of the active thyroid hormone that circulates in the blood. It is this substance that determines if a person has hypothyroidism or hyperthyroidism, two abnormal conditions that can cause health problems if left untreated. However, looking at the levels of this hormone in specific tissues in conditions associated with diseases as well as in situations of full health may also supply important information. “Some studies have shown that in individuals close to death, an increased amount of the D3 enzyme reappears in tissues like the liver, the muscles and the heart”, says Bianco. As has been seen, the increased production of D3 in tissue drastically reduces the presence of the active form of the thyroid hormone. In these terminal cases, hypothyroidism is apparently the ultimate trump card of the body to slow down the amount of energy expended as much as possible and, perhaps, stay alive. The strategy seems to make sense. After all, cells of hypothyroid patients may consume about half the energy of the cells of normal individuals and a quarter of those people with hyperthyroidism.

Scientific article
FREITAS, B. C. et al. Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells. Journal of Clinical Investigation. v. 120, p. 2.206-17. Jun. 2010.

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