Sobetirome and its Amide Prodrug Sob-AM2 Exert Thyromimetic Actions in Mct8-Deficient Brain

Thyroid : Official Journal of the American Thyroid Association
Soledad Bárez-LópezAna Guadaño-Ferraz

Abstract

Loss of function mutations in the thyroid hormone (TH)-specific cell membrane transporter, the monocarboxylate transporter 8 (MCT8), lead to profound psychomotor retardation and abnormal TH serum levels, with low thyroxine (T4) and high triiodothyronine (T3). Several studies point to impaired TH transport across brain barriers as a crucial pathophysiological mechanism resulting in cerebral hypothyroidism. Treatment options for MCT8-deficient patients are limited and are focused on overcoming the brain barriers. The aim of this study was to evaluate the ability of the TH analog sobetirome and its prodrug Sob-AM2 to access the brain and exert thyromimetic actions in the absence of Mct8. Juvenile wild-type (Wt) mice and mice lacking Mct8 and deiodinase type 2 (Mct8/Dio2KO) were treated systemically with daily injections of vehicle, 1 mg of sobetirome/kg body weight/day, or 0.3 mg of Sob-AM2/kg body weight/day for seven days. Sobetirome content was measured using liquid chromatography-tandem mass spectrometry, and T4 and T3 levels by specific radioimmunoassays. The effect of sobetirome treatment in the expression of T3-dependent genes was measured in the heart, liver, and cerebral cortex by real-time polymerase chain reaction. Sob-...Continue Reading

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Citations

Jul 31, 2019·Thyroid : Official Journal of the American Thyroid Association·Soledad Bárez-LópezAna Guadaño-Ferraz
Nov 23, 2019·Endocrine Reviews·Stefan GroenewegW Edward Visser
May 16, 2020·Frontiers in Neuroscience·Carmen Grijota-MartínezAna Guadaño-Ferraz
Apr 19, 2019·JCI Insight·Meredith D HartleyThomas S Scanlan
Jun 2, 2020·Frontiers in Endocrinology·Pieter VancampSylvie Remaud
Oct 23, 2020·European Thyroid Journal·Doreen Braun, Ulrich Schweizer

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Methods Mentioned

BETA
PCR

Clinical Trials Mentioned

NCT02060474
NCT03196765

Software Mentioned

GraphPad

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