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

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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.

Original languageEnglish (US)
Pages (from-to)2733-2740
Number of pages8
JournalEndocrinology
Volume159
Issue number7
DOIs
StatePublished - Jul 1 2018

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Thyroid Gland
Central Nervous System
Thyroid Hormones
Hypothyroidism
Prodrugs
Tissue Distribution
Inbred C57BL Mouse
GC 1 compound
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Endocrinology

Cite this

Hypothalamic-Pituitary-Thyroid Axis Perturbations in Male Mice by CNS-Penetrating Thyromimetics. / Ferrara, Skylar J.; Bourdette, Dennis; Scanlan, Thomas (Tom).

In: Endocrinology, Vol. 159, No. 7, 01.07.2018, p. 2733-2740.

Research output: Contribution to journalArticle

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