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.
Highlights
Neuromyelitis optica spectrum disorder (NMOSD) is an inflamma tory disease of the central nervous system (CNS), that involves anti bodies directed against the water channel aquaporin-4 (AQP4-IgG) on astrocytes, resulting in astrocytopathy with secondary demyelination (Bennett and Owens, 2017; Weinshenker and Wingerchuk, 2017)
We have previously demonstrated that Angio tensin AT2-receptor (AT2R) stimulation with the specific AT2R agonist Compound 21 (C21) attenuates NMOSD-like pathology in an interleukin-10 (IL-10) dependent manner (Khorooshi et al, 2019)
Treatment with the AT2R agonist C21 (Vicore Pharma, Goth enburg, Sweden) consisted of intrastriatal co-injection of 0.015 μg C21 / mouse at day 0 followed by an intrathecal injection of 0.125 μg C21 / mouse to cerebrospinal fluid (CSF) via cisterna magna at day 2
Summary
Neuromyelitis optica spectrum disorder (NMOSD) is an inflamma tory disease of the central nervous system (CNS), that involves anti bodies directed against the water channel aquaporin-4 (AQP4-IgG) on astrocytes, resulting in astrocytopathy with secondary demyelination (Bennett and Owens, 2017; Weinshenker and Wingerchuk, 2017). The involvement of BDNF in the AT2R protective effect in NMOSD has not been studied. 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. Conclusion: Our findings indicate that astrocyte-derived BDNF neither reduces the severity of NMOSD-like pa thology nor is it necessary for the protective effect of AT2R stimulation in NMOSD-like pathology
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