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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 2

T3 and sobetirome treatment promotes myelin repair in lysolecithin and cuprizone models.

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T3 and sobetirome treatment promotes myelin repair in lysolecithin and c...
(A) BlackGold staining of demyelinated lesion after PBS or lysolecithin injection (lesion outlined in yellow). Scale bars: 200 μm. (B and C) Mice were injected with lysolecithin on day 0, and daily i.p. injections with vehicle, T3 (1 mg/kg), or sobetirome (1 or 5 mg/kg) began on day 5. (D–H) Mice were treated with cuprizone for 12 weeks followed by 3 weeks of normal chow and daily i.p. injections with vehicle, T3 (1 mg/kg), or sobetirome (1 mg/kg). (D) Representative immunofluorescence images in the hippocampus. Brain sections were stained with antibodies for ASPA (red) and MBP (green). Scale bars: 200 μm. (E and F) ASPA-positive cells were quantified, and MBP intensity was quantified by threshold analysis. Data represent the following groups (for ASPA, Veh [n = 6], T3 [n = 5], and Sob [n = 6]; for MBP, Veh [n = 6], T3 [n = 4], and Sob [n = 5]). Two images were quantified for each animal. (G) Quantification of myelinated axons in the corpus callosum. Data represent n = 3, and 3 images were quantified for each animal. Naive mice that did not receive cuprizone (No cup) were not included in the statistical analysis. (H) Representative electron microscopy images from the medial caudal corpus callosum. Scale bars: 1 μm. 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 vehicle and treatment denoted with asterisks (*P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001). All graphs show mean ± SEM.

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