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
• Journal: JCI insight (JCI Insight) Vol. 4 Issue 8 (04 18 2019) ISSN: 2379-3708 [Electronic] United States
• PMID: 30996143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Acetates
• GC 1 compound
• Phenols
• Prodrugs
• Thyroid Hormones
• Transcription Factors
• myelin gene regulatory factor, mouse
• Gliotoxin

Topics

• Acetates (pharmacology, therapeutic use)
• Animals
• Axons (drug effects, pathology)
• Cell Differentiation (drug effects)
• Disease Models, Animal
• Female
• Gene Knockdown Techniques
• Gliotoxin (toxicity)
• Humans
• Magnetic Resonance Imaging
• Male
• Mice
• Mice, Transgenic
• Multiple Sclerosis (drug therapy, etiology, pathology)
• Myelin Sheath (drug effects, pathology)
• Oligodendroglia (drug effects, pathology)
• Phenols (pharmacology, therapeutic use)
• Prodrugs (pharmacology, therapeutic use)
• Remyelination (drug effects, genetics)
• Thyroid Hormones (administration & dosage, agonists)
• Transcription Factors (genetics)
• White Matter (cytology, diagnostic imaging, drug effects, pathology)