1033 DIRECT AT2-RECEPTOR STIMULATION IMPROVES NEUROLOGICAL OUTCOME IN A MOUSE MODEL OF MULTIPLE SCLEROSIS

Abstract

Objectives: The angiotensin AT2-receptor (AT2R) acts neuroprotective in models of neuronal injury. Here we identify the impact of direct AT2R stimulation by the selective non-peptide agonist C21 in myelin oligodendrocyte glycoprotein (MOG) induced experimental autoimmune encephalomyelitis (MOG-EAE), a mouse model mimicking many aspects of multiple sclerosis. Furthermore, we examined the effects of C21 on remyelination using an in vitro model of neuroinflammation. Design and methods: C57BL/6 mice were immunized with the MOG35–55 fragment and treated from day 3 before immunization until day 28 after immunization with C21 (0.3 mg/kg bw i.p.) or vehicle. Neurological deficits were evaluated daily. Spinal cord tissue was extracted on day 28 post-immunization and stained by fluoromyelin for myelin quantification. Furthermore, to test whether AT2R-stimulation can promote remyelination, aggregating brain cell cultures consisting of neurons, astrocytes, oligodendrocytes and microglia were prepared from whole embryonic rat brain and treated for 7 days with C21 (1 μM) or vehicle after IFN-γ/LPS-induced demyelination. The degree of myelination was determined by immunofluorescence for MOG. Staining was quantified by ImageJ. <SY>Results:</SY> Preventive application of AT2R agonist C21 resulted in a significantly ameliorated course of MOG-EAE and prevented demyelination in spinal cord tissue. Additionally, AT2R stimulation led to a significant increase in MOG-positive area after IFN-γ/LPS-induced demyelination in vitro (93.02% vs 78.13%, p < 0.01) when compared to vehicle treated aggregates. In vitro effects of C21 were inhibited by the specific AT2R antagonist PD 123319. Conclusions: Direct AT2R stimulation improves neurological outcome, protects against demyelination and promotes remyelination. Our findings identify AT2R stimulation as a potential new therapeutic target for demyelinating diseases.