Hypothalamic-Pituitary-Thyroid Axis Perturbations in Male Mice by CNS-Penetrating Thyromimetics

Endocrinology
Skylar J FerraraThomas S Scanlan

Abstract

Thyromimetics represent a class of experimental drugs that can stimulate tissue-selective thyroid hormone action. As such, thyromimetics should have effects on the hypothalamic-pituitary-thyroid (HPT) axis, but details of this action and the subsequent effects on systemic thyroid hormone levels have not been reported to date. Here, we compare the HPT-axis effects of sobetirome, a well-studied thyromimetic, with Sob-AM2, a newly developed prodrug of sobetirome that targets sobetirome distribution to the central nervous system (CNS). Similar to endogenous thyroid hormone, administration of sobetirome and Sob-AM2 suppress HPT-axis gene transcript levels in a manner that correlates to their specific tissue distribution properties (periphery vs CNS, respectively). Dosing male C57BL/6 mice with sobetirome and Sob-AM2 at concentrations ≥10 μg/kg/d for 29 days induces a state similar to central hypothyroidism characterized by depleted circulating T4 and T3 and normal TSH levels. However, despite the systemic T4 and T3 depletion, the sobetirome- and Sob-AM2-treated mice do not show signs of hypothyroidism, which may result from the presence of the thyromimetic in the thyroid hormone-depleted background.

References

May 1, 1990·Metabolism: Clinical and Experimental·M J MüllerA G Burger
May 15, 2002·European Journal of Pharmacology·Marcin Krotkiewski
Sep 11, 2003·American Journal of Physiology. Endocrinology and Metabolism·Fatima R S FreitasCecilia H A Gouveia
Nov 10, 2004·Proceedings of the National Academy of Sciences of the United States of America·Mercedes FernandezLaura Calzà
Jun 11, 2005·Cell and Tissue Research·Elen H MiyabaraAnselmo S Moriscot
Mar 17, 2007·Critical Reviews in Toxicology·R Thomas ZoellerRochelle W Tyl
Oct 23, 2008·Nature Clinical Practice. Endocrinology & Metabolism·Masanobu Yamada, Masatomo Mori
Nov 13, 2008·Heart Failure Reviews·Thomas S Scanlan
Jan 31, 2009·Endocrinology·Maria Izabel Chiamolera, Fredric E Wondisford
Mar 27, 2009·Proceedings of the National Academy of Sciences of the United States of America·Lars P KlieverikAndries Kalsbeek
Nov 28, 2009·Best Practice & Research. Clinical Endocrinology & Metabolism·Bryan R Haugen
Aug 2, 2012·The Journal of Clinical Endocrinology and Metabolism·Luca Persani
Mar 26, 2013·The Journal of Clinical Investigation·Tatiana L FonsecaAntonio C Bianco
Oct 1, 2013·Thyroid : Official Journal of the American Thyroid Association·Joshua M EstradaOffie P Soldin
Jul 10, 2014·European Journal of Endocrinology·Eric FliersAnita Boelen
Mar 10, 2015·Endocrine Reviews·Marco MediciRobin P Peeters
May 6, 2015·Nature Reviews. Endocrinology·Juan BernalBeatriz Morte
Aug 6, 2015·Molecular Neurobiology·Mao ZhangZhongxiang Yao
Nov 14, 2015·Expert Opinion on Therapeutic Targets·Jan Lammel Lindemann, Paul Webb
Jul 2, 2016·Indian Journal of Endocrinology and Metabolism·Debmalya Sanyal, Moutusi Raychaudhuri
Oct 26, 2016·Bioorganic & Medicinal Chemistry·Andrew T PlaczekThomas S Scanlan
May 4, 2017·The Journal of Biological Chemistry·Steven HutchensSomshuvra Mukhopadhyay
Aug 2, 2017·ACS Chemical Neuroscience·J Matthew MeinigThomas S Scanlan
May 31, 2018·Thyroid : Official Journal of the American Thyroid Association·Soledad Bárez-LópezAna Guadaño-Ferraz

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Citations

Aug 8, 2019·Thyroid : Official Journal of the American Thyroid Association·Rohit A SinhaPaul M Yen
Apr 19, 2019·JCI Insight·Meredith D HartleyThomas S Scanlan
Mar 15, 2020·Cell Chemical Biology·Meredith D HartleyThomas S Scanlan
Aug 14, 2020·Journal of Medicinal Chemistry·Skylar J Ferrara, Thomas S Scanlan

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