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Myelin repair stimulated by CNS-selective thyroid hormone action
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
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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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 8

Sob-AM2 treatment in iCKO-Myrf mice improves motor performance and increases myelin recovery, as observed by MRI analysis.

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Sob-AM2 treatment in iCKO-Myrf mice improves motor performance and incre...
Ablation of Myrf was induced in iCKO-Myrf mice with 5 days of once-daily tamoxifen i.p. injections, and starting 2 weeks later, mice were fed ad lib chow compounded with Sob-AM2 (84 μg/kg/d) or control chow. (A) Rotarod testing was performed weekly. (B) 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. (C) Recovery was measured by dividing the average latency during the recovery phase (weeks 18–24) by the latency before decline (weeks 0–4). (D and E) Quantification of BlackGold images was performed by threshold analysis for white matter tracts (n = 7, 2 images per animal). Data points marked with orange indicate mice imaged by MRI (n = 3, 2 images per animal). (F) Group-average magnetization transfer ratio (MTR) maps from control and Sob-AM2 mice (n = 3) at week 24. Arrows indicate the body/isthmus of the corpus callosum, and arrowheads indicate lateral corpus callosum (orange for weak remyelination and white for strong remyelination). Scale bars: 1 mm. (G) BlackGold caudal brain images from representative control and Sob-AM2 mice imaged by MRI. Scale bars: 1 mm. Statistical significance was determined by a 2-tailed, unpaired t test comparing control to Sob-AM2 (*P ≤ 0.05, **P ≤ 0.01). In A, each t test was performed independently; green asterisks indicate weeks in which Sob-AM2 mice were significantly different from control Cre-positive mice (*P ≤ 0.05), and orange asterisks indicate weeks in which the Sob-AM2–treated mice were not significantly different from unaffected Cre-negative mice (*P > 0.10). All graphs show mean ± SEM.

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