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Siponimod treatment response shows partial BDNF dependency in multiple sclerosis models.
Hendek, Hasan Hüseyin; Blusch, Alina; Heitmann, Neele; Oberhagemann, Sarah; Demir, Seray; Pedreiturria, Xiomara; Gold, Ralf; Faissner, Simon.
Afiliação
  • Hendek HH; Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56, 44791, Bochum, Germany.
  • Blusch A; Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56, 44791, Bochum, Germany.
  • Heitmann N; Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56, 44791, Bochum, Germany.
  • Oberhagemann S; Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56, 44791, Bochum, Germany.
  • Demir S; Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56, 44791, Bochum, Germany.
  • Pedreiturria X; Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56, 44791, Bochum, Germany.
  • Gold R; Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56, 44791, Bochum, Germany.
  • Faissner S; Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Gudrunstr. 56, 44791, Bochum, Germany. simon.faissner@rub.de.
Sci Rep ; 14(1): 17823, 2024 08 01.
Article em En | MEDLINE | ID: mdl-39090252
ABSTRACT
So far, only a small number of medications are effective in progressive multiple sclerosis (MS). The sphingosine-1-phosphate-receptor (S1PR)-1,5 modulator siponimod, licensed for progressive MS, is acting both on peripheral immune cells and in the central nervous system (CNS). So far it remains elusive, whether those effects are related to the neurotrophin brain derived neurotrophic factor (BDNF). We hypothesized that BDNF in immune cells might be a prerequisite to reduce disease activity in experimental autoimmune encephalomyelitis (EAE) and prevent neurotoxicity. MOG35-55 immunized wild type (WT) and BDNF knock-out (BDNFko) mice were treated with siponimod or vehicle and scored daily in a blinded manner. Immune cell phenotyping was performed via flow cytometry. Immune cell infiltration and demyelination of spinal cord were assessed using immunohistochemistry. In vitro, effects on neurotoxicity and mRNA regulation were investigated using dorsal root ganglion cells incubated with EAE splenocyte supernatant. Siponimod led to a dose-dependent reduction of EAE scores in chronic WT EAE. Using a suboptimal dosage of 0.45 µg/day, siponimod reduced clinical signs of EAE independent of BDNF-expression in immune cells in accordance with reduced infiltration and demyelination. Th and Tc cells in secondary lymphoid organs were dose-dependently reduced, paralleled with an increase of regulatory T cells. In vitro, neuronal viability trended towards a deterioration after incubation with EAE supernatant; siponimod showed a slight rescue effect following treatment of WT splenocytes. Neuronal gene expression for CCL2 and CX3CL1 was elevated after incubation with EAE supernatant, which was reversed after siponimod treatment for WT, but not for BNDFko. Apoptosis markers and alternative death pathways were not affected. Siponimod exerts both anti-inflammatory and neuroprotective effects, partially related to BDNF-expression. This might in part explain effectiveness during progression in MS and could be a target for therapy.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Azetidinas / Compostos de Benzil / Fator Neurotrófico Derivado do Encéfalo / Encefalomielite Autoimune Experimental / Esclerose Múltipla Limite: Animals Idioma: En Revista: Sci Rep / Sci. rep. (Nat. Publ. Group) / Scientific reports (Nature Publishing Group) Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Azetidinas / Compostos de Benzil / Fator Neurotrófico Derivado do Encéfalo / Encefalomielite Autoimune Experimental / Esclerose Múltipla Limite: Animals Idioma: En Revista: Sci Rep / Sci. rep. (Nat. Publ. Group) / Scientific reports (Nature Publishing Group) Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha País de publicação: Reino Unido