Article

Evidence for a role of the type III-iodothyronine deiodinase in the regulation of 3,5,3'-triiodothyronine content in the human central nervous system.

Department of Endocrinology and Metabolism, University of Pisa, Italy.
European Journal of Endocrinology (Impact Factor: 3.14). 07/2001; 144(6):577-83. DOI: 10.1530/eje.0.1440577
Source: PubMed

ABSTRACT Thyroid hormone is essential for maintaining normal neurological functions both during development and in adult life. Type III-iodothyronine deiodinase (D3) degrades thyroid hormones by converting thyroxine and 3,5,3'-triiodothyroinine (T3) to inactive metabolites. A regional expression of D3 activity has been observed in the human central nervous system (CNS), and a critical role for D3 has been suggested in the regulation of local T3 content in concert with other enzymes.
This study was undertaken to further characterize D3 activity in human CNS and to understand its role in the local regulation of T3 content.
Autoptic specimens from various areas of human CNS were obtained 6--27 h postmortem from 14 donors who died from cardiovascular accident, neoplastic disease or infectious disease. D3 was determined by measuring the conversion of T3 to 3,3'-diiodothyronine. The T3 content was measured by radioimmunoassay in ethanol extracts, using a specific antiserum.
High levels of D3 activity were observed in hippocampus and temporal cortex, lower levels being found in the thalamus, hypothalamus, midbrain cerebellum, parietal and frontal cortex, and brain stem. An inverse relationship between D3 activity and T3 content in these areas was demonstrated.
We have concluded that D3 contributes to the local regulation of T3 content in the human CNS.

0 Bookmarks
 · 
52 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: N-TERA-2 cl/D1 (NT2) cells, a human embryonal cell line with characteristics of central nervous system precursor cells, were utilised to study thyroid hormone action during early neuronal growth and differentiation. Undifferentiated NT2 cells expressed mRNAs encoding thyroid hormone receptors (TRs) alpha1, alpha2 and beta1, iodothyronine deiodinases types 2 (D2) and 3 (D3) (which act as the pre-receptor regulators), and the thyroid hormone-responsive genes myelin basic protein (MBP) and neuroendocrine specific protein A (NSP-A). When terminally differentiated into post-mitotic neurons (hNT), TRalpha1 and TRbeta1 mRNA expression was decreased by 74% (P=0.05) and 95% (P<0.0001) respectively, while NSP-A mRNA increased 7-fold (P<0.05). However, mRNAs encoding TRalpha2, D2, D3 and MBP did not alter significantly upon neuronal differentiation and neither did activities of D2 and D3. With increasing 3,5,3'-triiodothyronine (T(3)) concentrations, TRbeta1 mRNA expression in cultured NT2 cells increased 2-fold at 10 nM T(3) and 1.3-fold at 100 nM T(3) (P<0.05) compared with that in T(3)-free media but no change was seen with T(3) treatment of hNT cells. D3 mRNA expression in NT2 cells also increased 3-fold at 10 nM T(3) (P=0.01) and 2.4-fold at 100 nM T(3) (P<0.05) compared with control, but there was no change in D3 enzyme activity. In contrast there was a 20% reduction in D3 mRNA expression in hNT cells at 10 nM T(3) (P<0.05) compared with control, with accompanying reductions in D3 activity with increasing T(3) concentrations (P<0.05). There was no significant change in the expression of the TRalpha isoforms, D2, MBP and NSP-A with increasing T(3) concentrations in either NT2 or hNT cells. Undifferentiated NT2 and differentiated hNT cells show differing patterns of T(3)-responsiveness, suggesting that there are different regulatory factors operating within these cell types.
    Journal of Endocrinology 08/2003; 178(1):159-67. · 4.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: 1. In addition to its role in cellular metabolic activity, thyroid hormone (TH) is critically involved in growth, development, and function of the central nervous system. In the brain, as in other structures, TH is described to exert its major action by the binding of L-3,5,3'-triiodothyronine (T3), considered as the bioactive form of the hormone, to nuclear thyroid hormone receptors (TR) that function as ligand-dependent transcription factors. 2. The transcription of numerous brain genes was indeed shown to be positively or negatively regulated by TH, turning these TR-mediated effects one explanation for the physiological effects of TH. In this context, the knowledge from TR-knockout studies provides some surprising results, since neonatal hypothyroidism is associated to more significant abnormalities than is TR deficiency. Some (nonexclusive) hypotheses include a permissive effect of TH, allowing derepression of unliganded-TR effects and non-TR-mediated effects of the hormone, further emphasizing the importance of a controlled accessibility of neural cells to TH. 3. On the other hand, T3 was demonstrated to directly act not only on neuronal but also on glial cells proliferation and differentiation, contributing to the harmonious development of the brain. Interestingly, in addition to these direct actions on neuronal and glial cells, several lines of evidence, notably developped in our laboratory, point out the role of thyroid hormone in neuronal-glial interactions.
    Cellular and Molecular Neurobiology 01/2003; 22(5-6):517-44. · 2.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Thyrotropin (TSH) changes in extreme primary hypothyroidism include increased secretion, slowed degradation, and diminished or absent TSH circadian rhythms. Diminished rhythms are also observed in central hypothyroid patients and have been speculated to be a cause of central hypothyroidism. We examined whether TSH secretion saturation, previously suggested in extreme primary hypothyroidism, might explain diminished circadian rhythms in both disorders. We augmented and extended the range of our published feedback control system model to reflect nonlinear changes in extreme primary hypothyroidism, including putative TSH secretion saturation, and quantified and validated it using multiple clinical datasets ranging from euthyroid to extreme hypothyroid (postthyroidectomy). We simulated central hypothyroidism by reducing overall TSH secretion and also simulated normal TSH secretion without circadian oscillation, maintaining plasma TSH at constant normal levels. We also utilized the validated model to explore thyroid hormone withdrawal protocols used to prepare remnant ablation in thyroid cancer patients postthyroidectomy. Both central and extreme primary hypothyroidism simulations yielded low thyroid hormone levels and reduced circadian rhythms, with simulated daytime TSH levels low-to-normal for central hypothyroidism and increased in primary hypothyroidism. Simulated plasma TSH showed a rapid rise immediately following triiodothyronine (T(3)) withdrawal postthyroidectomy, compared with a slower rise after thyroxine withdrawal or postthyroidectomy without replacement. Diminished circadian rhythms in central and extreme primary hypothyroidism can both be explained by pituitary TSH secretion reaching maximum capacity. In simulated remnant ablation protocols using the extended model, TSH shows a more rapid rise after T(3) withdrawal than after thyroxine withdrawal postthyroidectomy, supporting the use of replacement with T(3) prior to (131)I treatment.
    Thyroid: official journal of the American Thyroid Association 11/2010; 20(11):1215-28. · 2.60 Impact Factor

Full-text

View
0 Downloads
Available from