Pharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic

Nat Commun. 2015 Mar 13;6:6532. doi: 10.1038/ncomms7532.

Abstract

Oligodendrocyte death contributes to the pathogenesis of the inflammatory demyelinating disease multiple sclerosis (MS). Nevertheless, current MS therapies are mainly immunomodulatory and have demonstrated limited ability to inhibit MS progression. Protection of oligodendrocytes is therefore a desirable strategy for alleviating disease. Here we demonstrate that enhancement of the integrated stress response using the FDA-approved drug guanabenz increases oligodendrocyte survival in culture and prevents hypomyelination in cerebellar explants in the presence of interferon-γ, a pro-inflammatory cytokine implicated in MS pathogenesis. In vivo, guanabenz treatment protects against oligodendrocyte loss caused by CNS-specific expression of interferon-γ. In a mouse model of MS, experimental autoimmune encephalomyelitis, guanabenz alleviates clinical symptoms, which correlates with increased oligodendrocyte survival and diminished CNS CD4+ T cell accumulation. Moreover, guanabenz ameliorates relapse in relapsing-remitting experimental autoimmune encephalomyelitis. Our results provide support for a MS therapy that enhances the integrated stress response to protect oligodendrocytes against the inflammatory CNS environment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • Cell Differentiation
  • Cell Survival
  • Cells, Cultured
  • Central Nervous System / metabolism
  • Cerebellum / metabolism
  • Cytokines / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Female
  • Guanabenz / pharmacology*
  • Inflammation
  • Interferon-gamma / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Multiple Sclerosis / drug therapy*
  • Myelin Sheath / metabolism
  • Oligodendroglia / cytology*
  • Rats
  • Rats, Sprague-Dawley
  • Stem Cells / cytology

Substances

  • Cytokines
  • Interferon-gamma
  • Guanabenz