TY - JOUR
T1 - Triac Treatment Prevents Neurodevelopmental and Locomotor Impairments in Thyroid Hormone Transporter Mct8/Oatp1c1 Deficient Mice
AU - Chen, Jiesi
AU - Salveridou, Eva
AU - Liebmann, Lutz
AU - Sundaram, Sivaraj M.
AU - Doycheva, Denica
AU - Markova, Boyka
AU - Hübner, Christian A.
AU - Boelen, Anita
AU - Visser, W. Edward
AU - Heuer, Heike
AU - Mayerl, Steffen
N1 - Funding Information: This work was supported by the BMBF within the E-RARE project “THYRONVERVE” (01GM1401), by grants of the Deutsche Forschungsgemeinschaft to H.H. (HE3478/7-1; 8-1 as well as CRC/TR 296; P01; P09), to S.M. (CRC/TR 296; P19) and by Sherman family funds to H.H. Publisher Copyright: © 2023 by the authors.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - Patients with inactive thyroid hormone (TH) transporter MCT8 display intellectual disability due to compromised central TH transport and action. As a therapeutic strategy, application of thyromimetic, MCT8-independent compounds Triac (3,5,3′-triiodothyroacetic acid), and Ditpa (3,5-diiodo-thyropropionic acid) was proposed. Here, we directly compared their thyromimetic potential in Mct8/Oatp1c1 double knock-out mice (Dko) modeling human MCT8 deficiency. Dko mice received either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) daily during the first three postnatal weeks. Saline-injected Wt and Dko mice served as controls. A second cohort of Dko mice received Triac (400 ng/g) daily between postnatal weeks 3 and 6. Thyromimetic effects were assessed at different postnatal stages by immunofluorescence, ISH, qPCR, electrophysiological recordings, and behavior tests. Triac treatment (400 ng/g) induced normalized myelination, cortical GABAergic interneuron differentiation, electrophysiological parameters, and locomotor performance only when administered during the first three postnatal weeks. Ditpa (4000 ng/g) application to Dko mice during the first three postnatal weeks resulted in normal myelination and cerebellar development but only mildly improved neuronal parameters and locomotor function. Together, Triac is highly-effective and more efficient than Ditpa in promoting CNS maturation and function in Dko mice yet needs to be initiated directly after birth for the most beneficial effects.
AB - Patients with inactive thyroid hormone (TH) transporter MCT8 display intellectual disability due to compromised central TH transport and action. As a therapeutic strategy, application of thyromimetic, MCT8-independent compounds Triac (3,5,3′-triiodothyroacetic acid), and Ditpa (3,5-diiodo-thyropropionic acid) was proposed. Here, we directly compared their thyromimetic potential in Mct8/Oatp1c1 double knock-out mice (Dko) modeling human MCT8 deficiency. Dko mice received either Triac (50 ng/g or 400 ng/g) or Ditpa (400 ng/g or 4000 ng/g) daily during the first three postnatal weeks. Saline-injected Wt and Dko mice served as controls. A second cohort of Dko mice received Triac (400 ng/g) daily between postnatal weeks 3 and 6. Thyromimetic effects were assessed at different postnatal stages by immunofluorescence, ISH, qPCR, electrophysiological recordings, and behavior tests. Triac treatment (400 ng/g) induced normalized myelination, cortical GABAergic interneuron differentiation, electrophysiological parameters, and locomotor performance only when administered during the first three postnatal weeks. Ditpa (4000 ng/g) application to Dko mice during the first three postnatal weeks resulted in normal myelination and cerebellar development but only mildly improved neuronal parameters and locomotor function. Together, Triac is highly-effective and more efficient than Ditpa in promoting CNS maturation and function in Dko mice yet needs to be initiated directly after birth for the most beneficial effects.
KW - Allan-Herndon-Dudley syndrome
KW - Ditpa
KW - SLC16A2
KW - SLCO1C1
KW - Triac
KW - thyroid hormone analog
KW - thyroid hormone transport
UR - http://www.scopus.com/inward/record.url?scp=85149006671&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/ijms24043452
DO - https://doi.org/10.3390/ijms24043452
M3 - Article
C2 - 36834863
SN - 1661-6596
VL - 24
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 4
M1 - 3452
ER -