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• W3095800997 abstract "Patients with inactivating mutations in the thyroid hormone (TH) transporter MCT8 manifest a severe form of psychomotor retardation in combination with abnormal TH concentrations in the circulation (Allan-Herndon-Dudley Syndrome, AHDS). The neurological symptoms are most likely due to an impaired transport of TH into the central nervous system (CNS) and, consequently, a disturbed differentiation and maturation of neural cells. Passage of TH across the blood-brain barrier (BBB) and/or blood-cerebrospinal fluid barrier (BCSFB) is also impeded in mice lacking the TH transporters Mct8 and Oatp1c1. These Mct8/Oatp1c1 double knockout (M/O dko) mice display a delayed cerebellar development, diminished myelination and a disturbed maturation of GABAergic interneurons thereby replicating the abnormalities found in AHDS patients. Treatment of AHDS patients with TH analogs that are not dependent on MCT8 but can activate TH receptors inside the brain has been suggested as a promising therapeutic approach. Candidates for such thyromimetic agents are the synthetic compound sobetirome (Sob1) and the recently developed four Sob derivatives (Sob2-5). The aim of this thesis was therefore to assess and to compare the thyromimetic potential of these novel compounds in neural development in vitro as well as in vivo. In vitro studies were conducted using murine cerebellar cultures that were treated for two weeks with the TH receptor-active T3, Triac or with different concentrations of synthetic sobetirome compounds. Purkinje cell dendritic outgrowth was monitored and the number of PV+ interneurons was quantified, as both parameters are highly dependent on TH. While 10 nM Triac and 10 nM sobetirome were as effective as 1 nM T3 in promoting neuronal differentiation, significant lower doses (0.1 nM) of two sobetirome compounds (Sob2 and Sob5) were sufficient to achieve similar thyromimetic effects. Interestingly, both two prodrugs have to be first hydrolyzed into their active compound, a reaction that can be carried out by Fatty Acid Amide Hydrolase (FAAH). Indeed, application of FAAH specific inhibitors to primary cerebellar cultures abolished the Sob2- and Sob5- induced Purkinje cell development confirming a critical role of FAAH in prodrug-activation. Further, the capacity of sobetirome compounds to promote neuronal differentiation and myelination were also studied in M/O dko mice and revealed the strongest TH-like effects for Sob2 and Sob5. Thus, Sob2 and Sob5 may be considered as therapeutic options for patients with AHDS." @default.
• W3095800997 created "2020-11-09" @default.
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• W3095800997 date "2020-01-01" @default.
• W3095800997 modified "2023-09-27" @default.
• W3095800997 title "Allan-Herndon-Dudley Syndrome: Pathogenic Mechanisms and Therapeutic Approaches" @default.
• W3095800997 hasPublicationYear "2020" @default.
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