Intracerebroventricular High Doses of 3,3′,5-Triiodothyroacetic Acid at Juvenile Stages Improve Peripheral Hyperthyroidism and Mediate Thyromimetic Effects in Limited Brain Regions in a Mouse Model of Monocarboxylate Transporter 8 Deficiency

Abstract

Introduction: Patients lacking functional Monocarboxylate transporter 8 (MCT8), a highly specific thyroid hormone (TH) transporter, present severe psychomotor disabilities. MCT8 deficiency leads to peripheral hyperthyroidism and brain hypothyroidism, the latter due to impaired transport of TH across brain barriers. Available Ttreatments options for patients are limited and focused onaim to overcomeing the limited TH transport across brain barriers. The use of TH analogues such as 3,3′,5-triiodothyroacetic acid (TRIAC) that do not require MCT8 to cross the cellular membranes is considered a potential therapy for MCT8 deficiency. Previous studies have shown that When TRIAC is administered systemically administration of TRIAC at therapeutic doses , there is nodoes not increase in TRIAC content in the brain, while . iIntracerebroventricular (ICV) administration of therapeutic doses of TRIAC increases TRIAC content in the brain but does not mediate thyromimetic effects. In view of this, Wwe hypothesise that ICV administration of high doses of TRIAC can mediate thyromimetic effects in the brain without worsening the brain hypothyroidism or peripheral hyperthyroidism of patients. Methods: 400 ng/g of body weight per day of TRIAC were administered ICV to a mouse model of MCT8 deficiency: Mct8 −/y and deiodinase 2 (Dio2) −/ − double knockout mice. The effects of this treatment on TH and TRIAC levels/content in blood and tissues were determined by radioimmunoassay and effects on TH-regulated genes were assessed by RT-qPCR in peripheral and central tissues. Results: ICV administration of high doses of TRIAC ameliorated the peripheral hyperthyroidism. In the brain, this treatment did not further aggravate brain hypothyroidism and increased TRIAC content in several brain regions; however, only moderate thyromimetic activity was observed in restricted brain areas.

In a zebrafish biomedical model of human Allan-Herndon-Dudley syndrome impaired MTH signaling leads to decreased neural cell diversity

“…Until recently, postnatal treatment of these patients with TH supplementation, with the TH analogs, TRIAC ( 24 ) or DITPA that do not require transport by MCT8 results in better thyroid function tests, improving hypermetabolism. However, no motor or cognitive skills improvement was observed ( 25 ). Very recently, prenatal treatment using levothyroxine (LT4) ameliorated the neuromotor and neurocognitive function of an AHDS patient ( 26 )…”