Corticosteroids Impair Remyelination in the Corpus Callosum of Cuprizone-Treated Mice

Corticosteroids (CS) are effective in the treatment of many brain disorders, such as multiple sclerosis (MS) or traumatic brain injury. This has been scrutinised in different experimental animal models. However, neither the mechanisms, nor the site of CS action are fully understood. Short-term high-dose CS treatment improves MS symptoms and severity of clinical disability during an acute inflammatory exacerbation of disease. In the present study, we analysed the influence of CS on the expression of cellular and molecular markers of spontaneous endogenous remyelination in the toxic non-immune cuprizone animal model at early (9 days) and intermediate (21 days) remyelination, as well as steroidal effects in primary astrocytes and oligodendrocyte progenitor cultures. Dexamethasone (Dex) and methylprednisolone (MP) induced a higher expression of the differentiation markers myelin basic protein and proteolipid protein (PLP) in cultured oligodendrocyte progenitor cells (OPC). CS exposure of primary cultured astrocytes resulted in a greater expression of those genes involved in OPC proliferation [fibroblast growth factor 2 (FGF2) and platelet-derived growth factor (PDGF)-alpha alpha] and a reduced expression of the pro-maturation factor insulin-like growth factor 1. Pro-maturating effects of CS were completely blocked by FGF2 and PDGF-alpha alpha co-application in OPC cultures. MP treatment in vivo resulted in a reduced recovery of PLP-staining intensity, whereas the re-population of the demyelinated corpus callosum with adenomatous polyposis coli-expressing oligodendrocytes was not affected. The numbers of brain intrinsic inflammatory cells, microglia and astrocytes during remyelination were similar in placebo and MP-treated animals. Our findings suggest that treatment with CS might have, in addition to the well-known benefical effects on inflammatory processes, a negative influence on remyelination.Faculty of Medicine, RWTH Aachen University; Hertie-Foundatio