Document Type
Journal Article
Publication Date
3-13-2015
Journal
Nature Communications
Volume
6
Inclusive Pages
6532
DOI
10.1038/ncomms7532
Keywords
Guanabenz--pharmacology; Multiple Sclerosis--drug therapy; Oligodendroglia--cytology
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.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
APA Citation
Way, S., Podojil, J., Clayton, B., Zaremba, A., Collins, T., Kunjamma, R., Robinson, A., Brugarolas, P., Miller, R. H., Miller, S., & Popko, B. (2015). Pharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic.. Nature Communications, 6 (). http://dx.doi.org/10.1038/ncomms7532
Peer Reviewed
1
Open Access
1
Included in
Anatomy Commons, Cell and Developmental Biology Commons, Nervous System Diseases Commons, Pharmaceutical Preparations Commons
Comments
Reproduced with permission of Macmillan Publishers Ltd. Nature Communications