Factors and Mechanisms of Thyroid Hormone Activity in the Brain: Possible Role in Recovery and Protection.

Thyroid hormones (THs) are essential in normal brain development, and cognitive and emotional functions. THs act through a cascade of events including uptake by the target cells by specific cell membrane transporters, activation or inactivation by deiodinase enzymes, and interaction with nuclear thyroid hormone receptors. Several thyroid responsive genes have been described in the developing and in the adult brain and many studies have demonstrated a systemic or local reduction in TH availability in neurologic disease and after brain injury. In this review, the main factors and mechanisms associated with the THs in the normal and damaged brain will be evaluated in different regions and cellular contexts. Furthermore, the most common animal models used to study the role of THs in brain damage and cognitive impairment will be described and the use of THs as a potential recovery strategy from neuropathological conditions will be evaluated. Finally, particular attention will be given to the link observed between TH alterations and increased risk of Alzheimer's Disease (AD), the most prevalent neurodegenerative and dementing condition worldwide.

Regulators of thyroid hormone availability and action in embryonic chicken brain development.

Thyroid hormones (THs) are crucial elements in vertebrate brain development. They exert their action mainly through binding of 3,5,3'-triiodothyronine (T3) to nuclear receptors that directly influence the expression of TH-regulated genes. Intracellular TH action is therefore dependent on both the availability of T3 and its receptors. TH uptake in cells is regulated by specific TH transporters and local activation and inactivation is regulated by deiodinases. This review provides an overview of the general expression pattern of TH transporters, deiodinases and receptors during embryonic chicken brain development and compares it to the situation in mammals. It is clear that THs and their regulators are present in the embryonic brain from the early stages of development, long before the onset of embryonic thyroid gland functioning. The mechanism of TH uptake across the brain barriers during development is only partly understood. At the developing blood-brain-barrier expression of the TH-activating type 2 deiodinase is closely associated with the blood vessels, but contrary to the situation in (adult) mammals no expression of MCT8 or OATP1C1 TH transporters is found at that level in the developing chicken. At the blood-cerebrospinal fluid-barrier co-expression of the TH-inactivating type 3 deiodinase and MCT8 and OATP1C1 is found in birds and mammals. These comparative data show overlapping patterns, pointing to general mechanisms, but also indicate specific interspecies differences that may help to understand species-specific responses to regulator gene knockout/mutation.

Effect of the Fetal THRB Genotype on the Placenta.

CONTEXT: Pregnant women with mutations in the thyroid hormone receptor beta (THRB) gene expose their fetuses to high thyroid hormone (TH) levels shown to be detrimental to a normal fetus (NlFe) but not to an affected fetus (AfFe). However, no information is available about differences in placental TH regulators. OBJECTIVE: To investigate whether there are differences in placentas associated with a NlFe compared with an AfFe, we had the unique opportunity to study placentas from 2 pregnancies of the same woman with THRB mutation G307D. One placenta supported a NlFe while the other an AfFe. METHODS: Sections of placentas were collected and frozen at -80 °C after term delivery of a NlFe and an AfFe. Two placentas from healthy women of similar gestational age were also obtained. The fetal origin of the placental tissues was established by gDNA quantitation of genes on the X and Y chromosomes and THRB gene. Expression and enzymatic activity of deiodinases 2 and 3 were measured. Expression of following genes was also quantitated: MCT10, MCT8, LAT1, LAT2, THRB, THRA. RESULTS: The placenta carrying the AfFe exhibited a significant reduction of deiodinase 2 and 3 activities as well as the expression of the TH transporters MCT10, LAT1 and LAT2, and THRA. CONCLUSION: We present the first study of the effect of the fetal THRB genotype on the placenta. Though limited by virtue of the rarity of THRB mutations and sample availability, we show that the fetal THRB genotype influences the levels of TH regulators in the placenta.

Thyroid hormone deiodinases response in brain of spontaneausly hypertensive rats after hypotensive effects induced by mandibular extension.

PURPOSE: The deiodinases activate or inactivate the thyroid hormones (TH) in virtually all tissues in both physiological and pathological conditions. The three deiodinases, DIO1, DIO2, and DIO3, have different catalytic functions and regulate TH tissue distribution. The aim of the present study was to evaluate the modulation of gene expression of the deiodinases and TH transporters and protein levels of DIO1 in parietal and frontal areas of cerebral cortex of spontaneously hypertensive rats (SHRs), after two successive mandibular extensions (ME). METHODS: ME was performed on anesthetized rats by a dilatator appropriately designed and real-time PCR and western blotting techniques were employed for gene expression and protein level study. RESULTS: Mean blood pressure (MBP) significantly decreased in 2ME-treated rats when compared to sham-operated rats (p < 0.001) and this decrease lasted for the entire observation period. In gene expression analysis, in 2ME-treated rats we did not observe any significant variation of DIO1 and DIO3 with respect to the sham-operated rats. Differently, DIO2 gene expression significantly increased in frontal area of 2ME-treated rats, with respect to sham-operated rats (p < 0.01). Furthermore, in parietal area, protein levels of DIO1 in 2ME-treated rats were significantly higher than in sham-operated rats (p < 0.01). Moreover MCT8 and OATP1C1 both resulted significantly higher (p < 0.05 and p < 0.001) in sham frontal cortex. CONCLUSION: In summary, our data on SHRs, while confirming the hypotensive effect of two MEs, show that the treatment also solicits the three deiodinases production in the cerebral cortex.

Involvement of Thyroid Hormones in Brain Development and Cancer.

The development and maturation of the mammalian brain are regulated by thyroid hormones (THs). Both hypothyroidism and hyperthyroidism cause serious anomalies in the organization and function of the nervous system. Most importantly, brain development is sensitive to TH supply well before the onset of the fetal thyroid function, and thus depends on the trans-placental transfer of maternal THs during pregnancy. Although the mechanism of action of THs mainly involves direct regulation of gene expression (genomic effects), mediated by nuclear receptors (THRs), it is now clear that THs can elicit cell responses also by binding to plasma membrane sites (non-genomic effects). Genomic and non-genomic effects of THs cooperate in modeling chromatin organization and function, thus controlling proliferation, maturation, and metabolism of the nervous system. However, the complex interplay of THs with their targets has also been suggested to impact cancer proliferation as well as metastatic processes. Herein, after discussing the general mechanisms of action of THs and their physiological effects on the nervous system, we will summarize a collection of data showing that thyroid hormone levels might influence cancer proliferation and invasion.