The protective effect of Angiotensin AT2-receptor stimulation in Neuromyelitis optica spectrum disorder is independent of astrocyte-derived BDNF
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The protective effect of Angiotensin AT2-receptor stimulation in Neuromyelitis optica spectrum disorder is independent of astrocyte-derived BDNF. / Khorooshi, Reza; Marczynska, Joanna; Dubik, Magdalena; Dieu, Ruthe Storgaard; Sørensen, Sofie Forsberg; Montanana-Rosell, Roser; Limburg, Hannah Liska; Tygesen, Camilla; Asgari, Nasrin; Steckelings, Ulrike Muscha; Owens, Trevor.
In: Multiple Sclerosis and Related Disorders, Vol. 53, 21.05.2021.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - The protective effect of Angiotensin AT2-receptor stimulation in Neuromyelitis optica spectrum disorder is independent of astrocyte-derived BDNF
AU - Khorooshi, Reza
AU - Marczynska, Joanna
AU - Dubik, Magdalena
AU - Dieu, Ruthe Storgaard
AU - Sørensen, Sofie Forsberg
AU - Montanana-Rosell, Roser
AU - Limburg, Hannah Liska
AU - Tygesen, Camilla
AU - Asgari, Nasrin
AU - Steckelings, Ulrike Muscha
AU - Owens, Trevor
PY - 2021/5/21
Y1 - 2021/5/21
N2 - 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.
AB - 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.
U2 - 10.1016/j.msard.2021.103033
DO - 10.1016/j.msard.2021.103033
M3 - Journal article
C2 - 34090131
VL - 53
JO - Multiple Sclerosis and Related Disorders
JF - Multiple Sclerosis and Related Disorders
SN - 2211-0348
ER -
ID: 270623547