title: Pharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic.
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.
authors.affiliation: Department of Neurology, The University of Chicago Center for Peripheral Neuropathy, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Sharon W
authors.initials: SW
authors.lastname: Way
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Podojil
authors.affiliation: Department of Neurology, The University of Chicago Center for Peripheral Neuropathy, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Clayton
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Zaremba
authors.affiliation: Myelin Repair Foundation, Saratoga, California 95070, USA.
authors.forename: Tassie L
authors.initials: TL
authors.lastname: Collins
authors.affiliation: Department of Neurology, The University of Chicago Center for Peripheral Neuropathy, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Rejani B
authors.initials: RB
authors.lastname: Kunjamma
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Robinson
authors.affiliation: Department of Neurology, The University of Chicago Center for Peripheral Neuropathy, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Brugarolas
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Miller
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
authors.affiliation: Department of Neurology, The University of Chicago Center for Peripheral Neuropathy, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Popko
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D006143:Guanabenz / Q000494:pharmacology*; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology
chemical_list: D016207:Cytokines; D007371:Interferon-gamma; D006143:Guanabenz