title: Minocycline promotes remyelination in aggregating rat brain cell cultures after interferon-γ plus lipopolysaccharide-induced demyelination.
abstract: Minocycline has been shown to inhibit microglia reactivity, and to decrease the severity and progression of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. It remained to be examined whether minocycline was also able to promote remyelination. In the present study, myelinating aggregating brain cell cultures were used as a model to study the effects of minocycline on microglial reactivity, demyelination, and remyelination. Cultures were treated simultaneously with two inflammatory agents, interferon-γ (IFN-γ) and lipopolysaccharide (LPS), which caused an inflammatory response accompanied by demyelination. The inflammatory response was characterized by microglial reactivity, upregulation of inflammatory cytokines and iNOS, and increased phophorylation of P38 and P44/42 mitogen activated protein (MAP) kinases. Minocycline inhibited microglial reactivity, and attenuated the increased phophorylation of P38 and P44/42 MAP kinases. Demyelination, determined by a decrease in myelin basic protein (MBP) content and immunoreactivity 48 h after the treatment with the inflammatory agents, was not prevented by minocycline. However, 1 week after demyelination was assessed, the MBP content was restored in presence of minocycline, indicating that remyelination was promoted. Concomitantly, in cultures treated with minocycline, the markers of oligodendrocyte precursors cells (OPCs) and immature oligodendrocytes NG2 and O4, respectively, were decreased compared to cultures treated with the inflammatory agents only. These results suggest that minocycline attenuates microglial reactivity and favors remyelination by enhancing the differentiation of OPCs and immature oligodendrocytes.
authors.affiliation: Department of Physiology, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Defaux
authors.forename: M-G
authors.initials: MG
authors.lastname: Zurich
authors.forename: P
authors.initials: P
authors.lastname: Honegger
authors.forename: F
authors.initials: F
authors.lastname: Monnet-Tschudi
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D008911:Minocycline / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D007371:Interferon-gamma; D008911:Minocycline