Glucocorticoid protection of oligodendrocytes against excitotoxin involving hypoxia-inducible factor-1alpha in a cell-type-specific manner.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
Yu-Yo SunChung Y Hsu

Abstract

Glucocorticoids are commonly used in treating diseases with white matter lesions, including demyelinating diseases and spinal cord injury (SCI). However, glucocorticoids are ineffective in gray matter injuries, such as head injury and stroke. The differential glucocorticoid effects in white and gray matter injuries are unclear. We report here a novel mechanism of methylprednisolone (MP), a synthetic glucocorticoid widely used for treating multiple sclerosis and SCI, in protecting oligodendrocytes (OLGs) against AMPA-induced excitotoxicity, which has been implicated in the white matter injuries and diseases. The cytoprotective action of MP in OLGs is causally related to its upregulation of a neuroprotective cytokine erythropoietin (Epo). MP transactivation of Epo expression involves dual transcription factors: glucocorticoid receptor (GR) and hypoxia-inducible factor-1alpha (HIF-1alpha). Coimmunoprecipitation, chromatin immunoprecipitation analysis, yeast two-hybrid analysis, and structure modeling of three-dimensional protein-protein interactions confirm that MP induces interaction between GR DNA binding domain and HIF-1alpha PAS domain, with subsequent recruitment of HIF-1beta to transactivate Epo expression in OLGs. In contra...Continue Reading

Citations

Jan 9, 2014·ASN Neuro·Kelsey J WeigelSteven M Levine
Dec 7, 2013·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Yumiko MatsusueMayumi Nishi
May 25, 2016·Revista Brasileira De Ortopedia·Renato Carlos do Vale Ramos, Nuno Alegrete
Apr 22, 2011·Journal of Neuroendocrinology·T ClarnerM Kipp
Dec 15, 2018·Journal of Neuroscience Research·Robert P Ostrowski, John H Zhang
Mar 7, 2021·Biomolecules·Jocelyn M BretonDaniela Kaufer
Mar 2, 2021·Frontiers in Neuroscience·Jorge Miguel AmayaOnno C Meijer
Mar 25, 2017·Experimental Cell Research·Gregg L Semenza
Aug 17, 2021·Frontiers in Cell and Developmental Biology·Elena V MitroshinaMaria V Vedunova

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