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Evaluation of TRIAC as a therapeutic agent in the Allan-Herndon-Dudley síndrome

AuthorsBárez-López, Soledad; Obregón, María Jesús; Martínez de Mena, Raquel ; Moreno, Juan C.; Iglesias, Ainhoa; Bernal, Juan ; Guadaño-Ferraz, Ana ; Morte, Beatriz
Issue Date2015
CitationVII Congreso Internacional de Medicamentos Huérfanos y Enfermedades Raras (2015)
AbstractThe Allan-Herndon-Dudley syndrome (AHDS) is caused by mutations in the monocarboxylate transporter 8 (MCT8) which is a thyroid hormone (TH)-specific cell membrane transporter. Mutations in MCT8 lead to profound psychomotor retardation and abnormal serum TH levels with low T4 and high T3. In contrast to this peripheral hyperthyroidism, the brain shows signs of hypothyroidism. Currently, therapeutic options for patients are limited. The acetic acid derivative of T3, TRIAC, has potential therapeutic value. Here we have analysed the in vivo effects of TRIAC in wild type (WT) and Mct8 knockout (KO) mice after administration of 30 ng/g bw/day in the drinking water from P21 to P30. TRIAC, T4 and T3 were measured by specific RIAs. Serum TRIAC increased and reached the same concentration in WT and Mct8KO after treatment. TRIAC treatment greatly decreased serum T4 in the WT and the Mct8KO, and decreased T3 to normal levels in the Mct8KO which could ameliorate hyperthyroidism in patients. Also at a peripheral level TRIAC increased liver Dio1 activity and mRNA in both genotypes and Serca2a, a TH-dependent gene in the heart, was not affected by any of the experimental conditions. Effect of TRIAC in brain was assessed by the expression of TH-dependent genes: Hr, Cbr2, Itih3, and Flywch2 in the cerebral cortex. Expression analysis suggest that TRIAC treatment induces a state of hypothyroxinemia that at least in brain is partially compensated by its thyromimetic actions. Furthermore, Hr expression in hypothyroid WT and hypothyroid Mct8KO animals is severely decreased and increases after treatment in both conditions providing direct evidence of the regulation of gene expression by TRIAC. The amelioration of the peripheral hyperthyroidism and the potential action in brain gene expression suggest that TRIAC could be a promising treatment for the AHDS.
DescriptionResumen del póster presentado al VII Congreso Internacional de Medicamentos Huérfanos y Enfermedades Raras: "Consolidando esfuerzos: Una responsabilidad compartida”, celebrado en Sevilla (España) del 12 al 14 de febrero de 2015.
Appears in Collections:(IIBM) Comunicaciones congresos
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