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Myelin repair stimulated by CNS-selective thyroid hormone action
Meredith D. Hartley, … , Dennis Bourdette, Thomas S. Scanlan
Meredith D. Hartley, … , Dennis Bourdette, Thomas S. Scanlan
Published April 18, 2019
Citation Information: JCI Insight. 2019;4(8):e126329. https://doi.org/10.1172/jci.insight.126329.
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Research Article Endocrinology Neuroscience

Myelin repair stimulated by CNS-selective thyroid hormone action

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Abstract

Oligodendrocyte processes wrap axons to form neuroprotective myelin sheaths, and damage to myelin in disorders, such as multiple sclerosis (MS), leads to neurodegeneration and disability. There are currently no approved treatments for MS that stimulate myelin repair. During development, thyroid hormone (TH) promotes myelination through enhancing oligodendrocyte differentiation; however, TH itself is unsuitable as a remyelination therapy due to adverse systemic effects. This problem is overcome with selective TH agonists, sobetirome and a CNS-selective prodrug of sobetirome called Sob-AM2. We show here that TH and sobetirome stimulated remyelination in standard gliotoxin models of demyelination. We then utilized a genetic mouse model of demyelination and remyelination, in which we employed motor function tests, histology, and MRI to demonstrate that chronic treatment with sobetirome or Sob-AM2 leads to significant improvement in both clinical signs and remyelination. In contrast, chronic treatment with TH in this model inhibited the endogenous myelin repair and exacerbated disease. These results support the clinical investigation of selective CNS-penetrating TH agonists, but not TH, for myelin repair.

Authors

Meredith D. Hartley, Tania Banerji, Ian J. Tagge, Lisa L. Kirkemo, Priya Chaudhary, Evan Calkins, Danielle Galipeau, Mitra D. Shokat, Margaret J. DeBell, Shelby Van Leuven, Hannah Miller, Gail Marracci, Edvinas Pocius, Tapasree Banerji, Skylar J. Ferrara, J. Matthew Meinig, Ben Emery, Dennis Bourdette, Thomas S. Scanlan

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Figure 1

Sobetirome mimics thyroid hormone action in oligodendrocyte progenitor cells.

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Sobetirome mimics thyroid hormone action in oligodendrocyte progenitor c...
(A) Oligodendrocyte progenitor cells (OPCs) were incubated with vehicle (DMSO), 50 nM T3, or 50 nM sobetirome for 96 hours in the presence of PDGF. Representative images of OPCs stained with antibodies against NG2 for OPCs (green) and MBP for oligodendrocytes (red). Scale bars: 200 μm. (B) Quantification of MBP-positive oligodendrocytes demonstrated that T3 or sobetirome increased OPC differentiation. (C–E) OPCs isolated from rats were incubated with or without PDGF in the presence of DMSO (Veh), T3 (50 nM), or sobetirome (50 nM) for 24 hours. Transcript levels of Mbp, Klf9, and Hr were measured using qPCR. OPC isolation was performed in triplicate with technical qPCR duplicates. Statistical significance was determined by 1-way ANOVA across all groups (P value in figure) followed by a 2-tailed, unpaired t test for comparisons between groups denoted with asterisks (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001). All graphs show mean ± SEM.

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ISSN 2379-3708

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