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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 5

Sobetirome hastens myelin recovery and oligodendrocyte maturation in iCKO-Myrf mice.

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Sobetirome hastens myelin recovery and oligodendrocyte maturation in iCK...
(A and B) Representative BlackGold images from Cre-positive mice treated with control or sobetirome chow. Scale bars: 1 mm (full-brain images); 0.25 mm (magnified inset, blue box). (C and D) Quantification of BlackGold images was performed by threshold analysis for white matter tracts (n = 4 for control and n = 6 for Sob, 2 images per animal). (E) Representative spinal cord EM images from control- and sobetirome-treated Cre-positive mice and Cre-negative mice at 24 weeks. Scale bars: 2 μm. (F) Myelinated axons were quantified in the ventrolateral spinal cord (n = 4 for control, n = 5 for Sob, 2 images per animal). (G) G-ratio analysis of spinal cord axons representing 100–200 axons per group. (H) Representative images from the caudal corpus callosum at week 10 stained for PDGFRα (white), ASPA (red), and EdU (green) from mice treated with control or sobetirome chow from weeks 2–10 and coadministered EdU from weeks 4–10. Scale bars: 20 μm. (I and J) Quantification of the PDGFRα/EdU colabeled oligodendrocyte precursor cells (OPCs) and ASPA/EdU-colabeled oligodendrocytes (n = 4 for all groups, 2 images per animal). Statistical significance was determined by a 2-tailed, unpaired t test comparing control to sobetirome (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001). All graphs show mean ± SEM.

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