Thyroid hormone, the thyromimetic sobetirome and its CNS penetrating prodrug Sob-AM2 reduce disease severity in EAE.
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Thyroid hormone, sobetirome and Sob-AM2 reduce myelin and axonal degeneration and protect oligodendrocytes in EAE.
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Sobetirome and Sob-AM2 may protect oligodendrocytes directly and by reducing inflammatory effects of macrophages/microglia.
Abstract
We have previously demonstrated that thyromimetics stimulate oligodendrocyte precursor cell differentiation and promote remyelination in murine demyelination models. We investigated whether a thyroid receptor-beta selective thyromimetic, sobetirome (Sob), and its CNS-targeted prodrug, Sob-AM2, could prevent myelin and axonal degeneration in experimental autoimmune encephalomyelitis (EAE). Compared to controls, EAE mice receiving triiodothyronine (T3, 0.4 mg/kg), Sob (5 mg/kg) or Sob-AM2 (5 mg/kg) had reduced clinical disease and, within the spinal cord, less tissue damage, more normally myelinated axons, fewer degenerating axons and more oligodendrocytes. T3 and Sob also protected cultured oligodendrocytes against cell death. Thyromimetics thus might protect against oligodendrocyte death, demyelination and axonal degeneration as well as stimulate remyelination in multiple sclerosis.