scholarly journals A Thyroid Hormone Analog with Reduced Dependence on the Monocarboxylate Transporter 8 for Tissue Transport

Endocrinology ◽  
2009 ◽  
Vol 150 (9) ◽  
pp. 4450-4458 ◽  
Author(s):  
Caterina Di Cosmo ◽  
Xiao-Hui Liao ◽  
Alexandra M. Dumitrescu ◽  
Roy E. Weiss ◽  
Samuel Refetoff
Keyword(s):  
Thyroid Hormone ◽  
Neurological Impairment ◽  
Monocarboxylate Transporter ◽  
Human Thyroid ◽  
Th Cell ◽  
Hormone Analog ◽  
Potential Clinical Utility ◽  
The Brain ◽  
Serum Tsh ◽  
Different Doses

Abstract Mutations of the thyroid hormone (TH) cell membrane transporter MCT8, on chromosome-X, produce severe mental and neurological impairment in men. We generated a Mct8-deficient mouse (Mct8KO) manifesting the human thyroid phenotype. Although these mice have no neurological manifestations, they have decreased brain T3 content and high deiodinase 2 (D2) activity, reflecting TH deprivation. In contrast and as in serum, liver T3 content is high, resulting in increased deiodinase 1 (D1), suggesting that in this tissue TH entry is Mct8 independent. We tested the effect of 3,5-diiodothyropropionic acid (DITPA), a TH receptor agonist, for its dependence on Mct8 in Mct8KO and wild-type (Wt) mice tissues. After depletion of endogenous TH, mice were given three different doses of DITPA. Effects were compared with treatment with two doses of l-T4. As expected, physiological doses of l-T4 normalized serum TSH, brain D2, and liver D1 in Wt mice but not the Mct8KO mice. The higher dose of T4 suppressed TSH in the Wt mice, normalized TSH and brain D2 in Mct8KO mice, but produced a thyrotoxic effect on liver D1 in both genotypes. In contrast DITPA produced similar effects on TSH, D2, and D1 in both Wt and Mct8KO mice. The higher dose fully normalized all measurements and other parameters of TH action. Thus, DITPA is relatively MCT8 independent for entry into the brain and corrects the TH deficit in Mct8KO mice without causing thyrotoxic effect in liver. The potential clinical utility of this analog to patients with MCT8 mutations requires further studies.

scholarly journals The Thyroid Hormone Analog DITPA Ameliorates Metabolic Parameters of Male Mice With Mct8 Deficiency

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 3889-3894 ◽  
Author(s):  
Alfonso Massimiliano Ferrara ◽  
Xiao-Hui Liao ◽  
Honggang Ye ◽  
Roy E. Weiss ◽  
Alexandra M. Dumitrescu ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Energy Expenditure ◽  
Target Genes ◽  
High Serum ◽  
Metabolic Parameters ◽  
Monocarboxylate Transporter ◽  
Hormone Analog ◽  
Serum T3 ◽  
Mct8 Deficiency ◽  
The Brain

Mutations in the gene encoding the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), cause mental retardation in humans associated with a specific thyroid hormone phenotype manifesting high serum T3 and low T4 and rT3 levels. Moreover, these patients have failure to thrive, and physiological changes compatible with thyrotoxicosis. Recent studies in Mct8-deficient (Mct8KO) mice revealed that the high serum T3 causes increased energy expenditure. The TH analog, diiodothyropropionic acid (DITPA), enters cells independently of Mct8 transport and shows thyromimetic action but with a lower metabolic activity than TH. In this study DITPA was given daily ip to adult Mct8KO mice to determine its effect on thyroid tests in serum and metabolism (total energy expenditure, respiratory exchange rate, and food and water intake). In addition, we measured the expression of TH-responsive genes in the brain, liver, and muscles to assess the thyromimetic effects of DITPA. Administration of 0.3 mg DITPA per 100 g body weight to Mct8KO mice brought serum T3 levels and the metabolic parameters studied to levels observed in untreated Wt animals. Analysis of TH target genes revealed amelioration of the thyrotoxic state in liver, somewhat in the soleus, but there was no amelioration of the brain hypothyroidism. In conclusion, at the dose used, DITPA mainly ameliorated the hypermetabolism of Mct8KO mice. This thyroid hormone analog is suitable for the treatment of the hypermetabolism in patients with MCT8 deficiency, as suggested in limited preliminary human trials.

scholarly journals Placenta Passage of the Thyroid Hormone Analog DITPA to Male Wild-Type and Mct8-Deficient Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (10) ◽  
pp. 4088-4093 ◽  
Author(s):  
Alfonso Massimiliano Ferrara ◽  
Xiao-Hui Liao ◽  
Pilar Gil-Ibáñez ◽  
Juan Bernal ◽  
Roy E. Weiss ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Monocarboxylate Transporter ◽  
Thyroid Function Tests ◽  
Wild Type ◽  
Peripheral Tissues ◽  
Hormone Analog ◽  
Neurological Phenotype ◽  
Serum T4 ◽  
Mct8 Deficiency ◽  
Serum Tsh

Abstract Monocarboxylate transporter 8 (MCT8) deficiency causes severe X-linked intellectual and neuropsychological impairment associated with abnormal thyroid function tests (TFTs) producing thyroid hormone (TH) deprivation in brain and excess in peripheral tissues. The TH analog diiodothyropropionic acid (DITPA) corrected the TFTs abnormalities and hypermetabolism of MCT8-deficient children but did not improve the neurological phenotype. The latter result was attributed to the late initiation of treatment. Therefore, we gave DITPA to pregnant mice carrying Mct8-deficient embryos to determine whether DITPA, when given prenatally, crosses the placenta and affects the serum TFTs and cerebral cortex of embryos. After depletion of the endogenous TH, Mct8-heterozygous pregnant dams carrying both wild-type (Wt) and Mct8-deficient (Mct8KO) male embryos were given DITPA. Effects were compared with those treated with levothyroxine (L-T4). With DITPA treatment, serum DITPA concentration was not different in the two genotypes, which produced equal effect on serum TSH levels in both groups of pups. In contrast, with L-T4 treatment, TSH did not normalize in Mct8KO pups whereas it did in the Wt littermates and dams despite higher concentration of serum T4. Finally, both treatments similarly modulated the expression of the TH-dependent genes Shh, Klf9, and Aldh1a3 in brain. Thus, the ability of DITPA to cross the placenta, its thyromimetic action on the expression of TH-dependent genes in brain, and its better accessibility to the pituitary than L-T4, as assessed by serum TSH, make DITPA a candidate for the prenatal treatment of MCT8 deficiency.

scholarly journals Adeno Associated Virus 9–Based Gene Therapy Delivers a Functional Monocarboxylate Transporter 8, Improving Thyroid Hormone Availability to the Brain of Mct8-Deficient Mice

Thyroid ◽  
2016 ◽  
Vol 26 (9) ◽  
pp. 1311-1319 ◽  
Author(s):  
Hideyuki Iwayama ◽  
Xiao-Hui Liao ◽  
Lyndsey Braun ◽  
Soledad Bárez-López ◽  
Brian Kaspar ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Thyroid Hormone ◽  
Monocarboxylate Transporter ◽  
Adeno Associated Virus ◽  
The Brain ◽  
Deficient Mice

scholarly journals Diagnostic and Therapeutic Challenges in the Allan—Herndon—Dudley Syndrome

2016 ◽  
Vol 12 (02) ◽  
pp. 90 ◽  
Author(s):  
Stefan Groeneweg ◽  
Robin P Peeters ◽  
Theo J Visser ◽  
W Edward Visser ◽  
◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Serum Levels ◽  
Monocarboxylate Transporter ◽  
Normal Brain ◽  
Thyroid Function Tests ◽  
Neurocognitive Development ◽  
Transporter Protein ◽  
Male Patients ◽  
The Brain ◽  
Normal Brain Development

Thyroid hormone (TH) is important for normal brain development. The TH transporter protein monocarboxylate transporter 8 (MCT8) is crucial to maintain adequate TH levels in the brain during development and throughout life. Mutations in MCT8 result in the Allan–Herndon–Dudley syndrome (AHDS), which is characterized by a severe delay in neurocognitive development, combined with abnormal serum thyroid function tests (TFTs). The combination of an increased (F)T3 and decreased (F)T4 and rT3 serum levels are characteristic for the presence of AHDS in male patients with moderate to severe delay in neurocognitive development. Here, we provide an overview of current insights, challenges and pitfalls in the diagnosis and management of patients with AHDS.

scholarly journals Importance of His192 in the Human Thyroid Hormone Transporter MCT8 for Substrate Recognition

Endocrinology ◽  
2013 ◽  
Vol 154 (7) ◽  
pp. 2525-2532 ◽  
Author(s):  
Stefan Groeneweg ◽  
Elaine C. Lima de Souza ◽  
W. Edward Visser ◽  
Robin P. Peeters ◽  
Theo J. Visser
Keyword(s):  
Thyroid Hormone ◽  
Transmembrane Domain ◽  
Substrate Recognition ◽  
Inhibitory Effect ◽  
Psychomotor Retardation ◽  
Site Directed Mutagenesis ◽  
Monocarboxylate Transporter ◽  
Human Thyroid ◽  
Extracellular Loop

Abstract Monocarboxylate transporter 8 (MCT8) facilitates cellular uptake and efflux of thyroid hormone (TH). So far, functional domains within MCT8 are not well defined. Mutations in MCT8 result in severe psychomotor retardation due to impaired neuronal differentiation. One such mutation concerns His192 (H192R), located at the border of transmembrane domain (TMD) 1 and extracellular loop (ECL) 1, suggesting that this His residue is important for efficient TH transport. Here, we studied the role of different His residues, predicted within TMDs or ECLs of MCT8, in substrate recognition and translocation. Therefore, we analyzed the effects of the His-modifying reagent diethylpyrocarbonate (DEPC) and of site-directed mutagenesis of several His residues on TH transport by MCT8. Reaction of MCT8 with DEPC inhibited subsequent uptake of T3 and T4, whereas T3 and T4 efflux were not inhibited. The inhibitory effect of DEPC on TH uptake was prevented in the presence of T3 or T4, suggesting that TH blocks access to DEPC-sensitive residues. Three putative DEPC target His residues were replaced by Ala: H192A, H260A, and H450A. The H260A and H450A mutants showed similar TH transport and DEPC sensitivity as wild-type MCT8. However, the H192A mutant showed a significant reduction in TH uptake and was insensitive to DEPC. Taken together, these results indicate that His192 is sensitive to modification by DEPC and may be located close to a putative substrate recognition site within the MCT8 protein, important for efficient TH uptake.

scholarly journals The Role of Hypothalamic Tri-Iodothyronine Availability in Seasonal Regulation of Energy Balance and Body Weight

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Michelle Murphy ◽  
Francis J. P. Ebling
Keyword(s):  
Body Weight ◽  
Thyroid Hormone ◽  
Energy Balance ◽  
Third Ventricle ◽  
Peripheral Circulation ◽  
Brain Cell ◽  
Monocarboxylate Transporter ◽  
Type Iii ◽  
Seasonal Regulation ◽  
The Brain

Seasonal cycles of body weight provide a natural model system to understand the central control of energy balance. Studies of such cycles in Siberian hamsters suggest that a change in the hypothalamic availability of thyroid hormone is the key determinant of annual weight regulation. Uptake of thyroid hormone into the hypothalamus from the peripheral circulation occurs largely through a specific monocarboxylate transporter expressed by tanycyte cells lining the third ventricle. Tanycytes are the principal brain cell type expressing type II and type III deiodinases, so they control the local concentrations of T4, T3, and inactive metabolites. Type III deiodinase mRNA in tanycytes is photoperiodically upregulated in short photoperiod. This would be expected to reduce the availability of T3 in the hypothalamus by promoting the production of inactive metabolites such as rT3. Experimental microimplantation of T3 directly into the hypothalamus during short-days promotes a long-day phenotype by increasing food intake and body weight without affecting the peripheral thyroid axis. Thus, thyroid hormone exerts anabolic actions within the brain that play a key role in the seasonal regulation of body weight. Understanding the precise actions of thyroid hormone in the brain may identify novel targets for long-term pharmacological manipulation of body weight.

Allan-Herndon-Dudley-Syndrome: Considerations about the Brain Phenotype with Implications for Treatment Strategies

2020 ◽  
Vol 128 (06/07) ◽  
pp. 414-422
Author(s):  
Heiko Krude ◽  
Heike Biebermann ◽  
Markus Schuelke ◽  
Timo D. Müller ◽  
Matthias Tschöp
Keyword(s):  
Thyroid Hormone ◽  
Treatment Strategies ◽  
Fetal Brain ◽  
Monocarboxylate Transporter ◽  
Target Cells ◽  
Neurodevelopmental Delay ◽  
Pyramidal Tracts ◽  
Fetal Brain Development ◽  
The Brain ◽  
Cerebellar Symptoms

AbstractDespite its first description more than 75 years ago, effective treatment for “Allan-Herndon-Dudley-Syndrome (AHDS)”, an X-linked thyroid hormone transporter defect, is unavailable. Mutations in the SLC16A2 gene have been discovered to be causative for AHDS in 2004, but a comprehensive understanding of the function of the encoded protein, monocarboxylate transporter 8 (MCT8), is incomplete. Patients with AHDS suffer from neurodevelopmental delay, as well as extrapyramidal (dystonia, chorea, athetosis), pyramidal (spasticity), and cerebellar symptoms (ataxia). This suggests an affection of the pyramidal tracts, basal ganglia, and cerebellum, most likely already during fetal brain development. The function of other brain areas relevant for mood, behavior, and vigilance seems to be intact. An optimal treatment strategy should thus aim to deliver T3 to these relevant structures at the correct time points during development. A potential therapeutic strategy meeting these needs might be the delivery of T3 via a “Trojan horse mechanism” by which T3 is delivered into target cells by a thyroid hormone transporter independent T3 internalization.

Central Nerve System Impairment, AMA Guides, Sixth Edition: An Overview

2018 ◽  
Vol 23 (1) ◽  
pp. 10-13
Author(s):  
James B. Talmage ◽  
Jay Blaisdell
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Neurological Impairment ◽  
Sixth Edition ◽  
Central Nerve System ◽  
The Central Nervous System ◽  
The One ◽  
Nerve System ◽  
The Brain

Abstract Injuries that affect the central nervous system (CNS) can be catastrophic because they involve the brain or spinal cord, and determining the underlying clinical cause of impairment is essential in using the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), in part because the AMA Guides addresses neurological impairment in several chapters. Unlike the musculoskeletal chapters, Chapter 13, The Central and Peripheral Nervous System, does not use grades, grade modifiers, and a net adjustment formula; rather the chapter uses an approach that is similar to that in prior editions of the AMA Guides. The following steps can be used to perform a CNS rating: 1) evaluate all four major categories of cerebral impairment, and choose the one that is most severe; 2) rate the single most severe cerebral impairment of the four major categories; 3) rate all other impairments that are due to neurogenic problems; and 4) combine the rating of the single most severe category of cerebral impairment with the ratings of all other impairments. Because some neurological dysfunctions are rated elsewhere in the AMA Guides, Sixth Edition, the evaluator may consult Table 13-1 to verify the appropriate chapter to use.

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