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

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 6

Hyper- and hypothyroidism produce different outcomes in the iCKO-Myrf model.

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Hyper- and hypothyroidism produce different outcomes in the iCKO-Myrf mo...
(A) Mice were administered T3/T4 chow starting 2 weeks after tamoxifen. The mice experienced a more severe disease course with no recovery and were euthanized at 14 weeks. (B) Mice were administered hypothyroid-inducing water starting 2 weeks after tamoxifen and were followed weekly by rotarod analysis. (C) Individual 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 F) Representative BlackGold brain images from control and hypothyroid groups. Scale bars: 1 mm (full-brain images); 0.25 mm (magnified insets, blue box). (E and G) Quantification of BlackGold images was performed by threshold analysis for white matter tracts (n = 4, 2 images per animal). Statistical significance was determined by a 2-tailed, unpaired t test comparing control to treatment (*P ≤ 0.05). In A and B, each t test was performed independently (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001). No differences were significant for C (*P = 0.42), E (*P = 0.56), or G (*P = 0.31). All graphs show mean ± SEM.