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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 4

Treatment with sobetirome improves motor performance in iCKO-Myrf mice.

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Treatment with sobetirome improves motor performance in iCKO-Myrf mice.
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iCKO-Myrf mice were induced with 5 days of once-daily tamoxifen i.p. injections, and starting 2 weeks later, a cohort was fed ad lib chow compounded with sobetirome (80 μg/kg/d nominal dose). The control cohort was provided normal chow. (A) Clinical scores were assigned weekly (0, no disability; 1, wide gait or limp tail; 2, hindlimb weakness; 3, hindlimb paralysis). (B) Rotarod testing was performed weekly. (C) Summary analysis of rotarod data was performed by determining the week at which the mice crossed above a 60-second threshold for the remainder of the experiment. (D) Individual recovery was measured by dividing the average latency during the recovery phase (weeks 18–24) by the latency before decline (weeks 0–4). Statistical significance was determined by a 2-tailed, unpaired t test comparing control to sobetirome (*P ≤ 0.05, **P ≤ 0.01). In A and B, each t test was performed independently. All graphs show mean ± SEM.

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ISSN 2379-3708

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