Thyroid Hormones, T3 and T4, in the Brain

Abstract

Thyroid hormones (THs) are essential for fetal and post-natal nervous system development and also play an important role in the maintenance of adult brain function. Of the two major THs, T4 (3,5,3′,5′-tetraiodo-l-thyronine) is classically viewed as an pro-hormone that must be converted to T3 (3,5,3′-tri-iodo-l-thyronine) via tissue-level deiodinases for biological activity. THs primarily mediate their effects by binding to thyroid hormone receptor (TR) isoforms, predominantly TRα1 and TRβ1, which are expressed in different tissues and exhibit distinctive roles in endocrinology. Notably, the ability to respond to T4 and to T3 differs for the two TR isoforms, with TRα1 generally more responsive to T4 than TRβ1. TRα1 is also the most abundantly expressed TR isoform in the brain, encompassing 70–80% of all TR expression in this tissue. Conversion of T4 into T3 via deiodinase 2 in astrocytes has been classically viewed as critical for generating local T3 for neurons. However, deiodinase-deficient mice do not exhibit obvious defectives in brain development or function. Considering that TRα1 is well-established as the predominant isoform in brain, and that TRα1 responds to both T3 and T4, we suggest T4 may play a more active role in brain physiology than has been previously accepted.

Hormony tarczycy w ośrodkowym układzie nerwowym (OUN) i ich wpływ na nowotworzenie, zwłaszcza na rozwój i przebieg glioblastoma multiforme — hipoteza badawcza

“…Further studies showed that an effect similar to that of T4 can be evoked by administration of rT3, previously considered an inactive product of T4 monodeiodination catalysed on the periphery by D-1 and in the brain by D3. At present it is believed that only D-2 and D-3 are present in the brain [3,5]. Thus, part of the rT3 present in the brain probably originated from the circulation and organs containing D1.…”

“…Also, throughout the life of a human being thyroid hormones have an impact on the broadly understood brain activity and can modulate pathological processes occurring in the brain, including hyperplastic processes [5][6][7]. In recent years attention has been paid to the effect of thyroid hormones on the properties and activity of microglial cells [8][9][10].…”

“…Due to paracrine signalling, T3 is transferred from astrocytes to neural cells, where the hormone binds to THRs [33]. THRs in turn react with the triiodothyronine response element (TRE) of genes sensitive to thyroid hormones and activate or inhibit the gene transcription process depending on whether the TRE is positive or negative [34,35]. On the other hand, there is accumulating evidence that THRs are also present in intact glial cells and gliomas [10,36].…”

“…From the second trimester and then after birth and in adult life THRA1 constitutes about 70% of receptor protein in the brain while THRB1 constitutes 20% and THRB2 constitutes 10% of this protein in the brain [45]. The effect of thyroid hormones in every period of foetal life has been thoroughly investigated and discussed in recent years [1][2][3][4][5][6]. This paper focuses only on such aspects of thyroid hormone activity and brain development that might affect, in future, the development of neoplasms, mainly gliomas.…”

“…Również przez całe życie TH mają wpływ na szeroko pojętą czynność mózgu, a również mogą modulować zachodzące w nim procesy patologiczne w tym rozrostowe [5][6][7]. W ostatnich latach zwrócono uwagę na wpływ TH na właściwości i czynność komórek mikrogleju [8][9][10].…”