The protective effect of Angiotensin AT2-receptor stimulation in Neuromyelitis optica spectrum disorder is independent of astrocyte-derived BDNF

Abstract

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated autoimmune inflammatory disease of the central nervous system (CNS), resulting in primary astrocytopathy. We have previously shown that Angiotensin AT2-receptor (AT2R) stimulation with the specific agonist Compound 21 (C21) attenuated NMOSD-like pathology. Recent studies have proposed that the mechanism behind protective effects of AT2R includes induction of brain derived neurotrophic factor (BDNF). Astrocytes are a major cellular source of BDNF. In this study we used mice with conditional BDNF deficiency in astrocytes (GfapF) to examine the involvement of astrocyte-derived BDNF in NMOSD-like pathology and in mediating the protective effect of AT2R stimulation. MethodsAnti-aquaporin-4 IgG (AQP4-IgG) from an NMOSD patient and human complement (C) were co-injected intrastriatally to GfapF and wildtype littermate BDNFfl/fl mice (WT), together with either C21 or vehicle at day 0, followed by intrathecal injection of C21 or vehicle at day 2 and tissue collection at day 4. ResultsIntracerebral/intrathecal injection of C21, alone or in combination with AQP4-IgG + C, induced BDNF expression in WT mice. Injection of AQP4-IgG + C induced NMOSD-like pathology, including loss of AQP4 and GFAP. There was no difference in the severity of pathological changes between GfapF and WT mice. C21 treatment significantly and equally ameliorated NMOSD-like pathology in both WT and GfapF mice. ConclusionOur findings indicate that astrocyte-derived BDNF neither reduces the severity of NMOSD-like pathology nor is it necessary for the protective effect of AT2R stimulation in NMOSD-like pathology.