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    Direct angiotensin type 2 receptor (AT2R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice (2015)

    Art
    Zeitschriftenartikel / wissenschaftlicher Beitrag
    Autoren
    Valero-Esquitino, Verónica
    Lucht, Kristin
    Namsolleck, Pawel
    Monnet-Tschudi, Florianne
    Stubbe, Tobias
    Lucht, Franziska
    Liu, Meng
    Ebner, Friederike
    Brandt, Christine
    Danyel, Leon A
    Villela, Daniel C
    Paulis, Ludovit
    Thoene-Reineke, Christa (WE 11)
    Dahlöf, Björn
    Hallberg, Anders
    Unger, Thomas
    Sumners, Colin
    Steckelings, U Muscha
    Quelle
    Clinical science; 128(2) — S. 95–109
    ISSN: 0143-5221
    Sprache
    Englisch
    Verweise
    DOI: 10.1042/CS20130601
    Pubmed: 25052203
    Kontakt
    Institut für Tierschutz und Tierverhalten

    Königsweg 67
    Gebäude 21, 1. OG
    14163 Berlin
    +49 30 838 62901
    tierschutz@vetmed.fu-berlin.de

    Abstract / Zusammenfassung

    In the present study, we evaluated stimulation of the angiotensin type 2 receptor (AT2R) by the selective non-peptide agonist Compound 21 (C21) as a novel therapeutic concept for the treatment of multiple sclerosis using the model of experimental autoimmune encephalomyelitis (EAE) in mice. C57BL-6 mice were immunized with myelin-oligodendrocyte peptide and treated for 4 weeks with C21 (0.3 mg/kg/day i.p.). Potential effects on myelination, microglia and T-cell composition were estimated by immunostaining and FACS analyses of lumbar spinal cords. The in vivo study was complemented by experiments in aggregating brain cell cultures and microglia in vitro. In the EAE model, treatment with C21 ameliorated microglia activation and decreased the number of total T-cells and CD4+ T-cells in the spinal cord. Fluorescent myelin staining of spinal cords further revealed a significant reduction in EAE-induced demyelinated areas in lumbar spinal cord tissue after AT2R stimulation. C21-treated mice had a significantly better neurological score than vehicle-treated controls. In aggregating brain cell cultures challenged with lipopolysaccharide (LPS) plus interferon-γ (IFNγ), AT2R stimulation prevented demyelination, accelerated re-myelination and reduced the number of microglia. Cytokine synthesis and nitric oxide production by microglia in vitro were significantly reduced after C21 treatment. These results suggest that AT2R stimulation protects the myelin sheaths in autoimmune central nervous system inflammation by inhibiting the T-cell response and microglia activation. Our findings identify the AT2R as a potential new pharmacological target for demyelinating diseases such as multiple sclerosis.