Tetrac Can Replace Thyroid Hormone During Brain Development in Mouse Mutants Deficient in the Thyroid Hormone Transporter Mct8

Abstract

The monocarboxylate transporter 8 (MCT8) plays a critical role in mediating the uptake of thyroid hormones (THs) into the brain. In patients, inactivating mutations in the MCT8 gene are associated with a severe form of psychomotor retardation and abnormal serum TH levels. Here, we evaluate the therapeutic potential of the TH analog 3,5,3',5'-tetraiodothyroacetic acid (tetrac) as a replacement for T(4) in brain development. Using COS1 cells transfected with TH transporter and deiodinase constructs, we could show that tetrac, albeit not being transported by MCT8, can be metabolized to the TH receptor active compound 3,3',5-triiodothyroacetic acid (triac) by type 2 deiodinase and inactivated by type 3 deiodinase. Triac in turn is capable of replacing T(3) in primary murine cerebellar cultures where it potently stimulates Purkinje cell development. In vivo effects of tetrac were assessed in congenital hypothyroid Pax8-knockout (KO) and Mct8/Pax8 double-KO mice as well as in Mct8-KO and wild-type animals after daily injection of tetrac (400 ng/g body weight) during the first postnatal weeks. This treatment was sufficient to promote TH-dependent neuronal differentiation in the cerebellum, cerebral cortex, and striatum but was ineffective in suppressing hypothalamic TRH expression. In contrast, TSH transcript levels in the pituitary were strongly down-regulated in response to tetrac. Based on our findings we propose that tetrac administration offers the opportunity to provide neurons during the postnatal stage with a potent TH receptor agonist, thereby eventually reducing the neurological damage in patients with MCT8 mutations without deteriorating the thyrotoxic situation in peripheral tissues.

Triiodothyroacetic acid in health and disease

“…D, deiodinase; MAO, monamine oxidase; SSAO, semicarbazide-sensitive amine oxidase; ODC, ornithine decarboxylase; TK 3 , 3,3′,5-triiodothyropyruvic acid. Horn et al 2013). TA 3 is even a better substrate for D1 than T 3 , illustrated by a 16-fold higher Vmax/Km ratio (Rutgers et al 1989a).…”

MECHANISMS IN ENDOCRINOLOGY: Neurodevelopmental disorders in children born to mothers with thyroid dysfunction: evidence of fetal programming?

“…Evidence from in vitro and in vivo studies have demonstrated the important role of thyroid hormones in brain development. In cerebellar cell cultures, dendritic growth of Purkinje cells was significant in the presence of T3 or T4, but not in the absence of thyroid hormones (3,4). In rats, studies have demonstrated the structural and functional consequences of maternal thyroid dysfunction on the fetal brain including alterations in the neuronal proliferation, migration, differentiation, synaptogenesis and myelination (1,2,5).…”

MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development

“…Although some of them were shown to have beneficial effects in Mct8 KO zebrafish larvae (Zada et al 2014) and in Mct8/Oatp1c1 double KO mice (Horn et al 2013, Kersseboom et al 2014, a recent clinical trial in patients treated in the first year of infancy failed to improve mental status, probably because neurological damage was already irreversible at the onset of treatment (Verge et al 2012). A better understanding of the function of MCT8 at the neuronal level during embryonic development is therefore an important objective.…”