Maya Golan1, Karin Mausner-Fainberg1, Bassima Ibrahim2, Moshe Benhamou1,3, Adi Wilf-Yarkoni4, Hadar Kolb4, Keren Regev4, Arnon Karni5,6,7,8. 1. Neuroimmunology Laboratory, Neurology Division, Tel Aviv Sourasky Medical Center, 6 Weizman Street, 6423906, Tel Aviv, Israel. 2. Segol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. 3. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. 4. Neuroimmunology Clinic, Neurology Division, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 5. Neuroimmunology Laboratory, Neurology Division, Tel Aviv Sourasky Medical Center, 6 Weizman Street, 6423906, Tel Aviv, Israel. arnonk@tlmc.gov.il. 6. Neuroimmunology Clinic, Neurology Division, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. arnonk@tlmc.gov.il. 7. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. arnonk@tlmc.gov.il. 8. Segol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel. arnonk@tlmc.gov.il.
Abstract
BACKGROUND: The pathophysiology of multiple sclerosis involves an autoimmune and a neurodegenerative mechanism. Central nervous system-infiltrating immune cells in multiple sclerosis also possess a neuroprotective activity through secretion of neurotrophins, such as brain-derived neurotrophic factor. Fingolimod was shown to slow the progression of disability and loss of brain volume. OBJECTIVE: The objective of this study was to explore whether fingolimod induces secretion of neurotrophins by immune cells. METHODS: Blood was drawn from 21 patients before the initiation of treatment with fingolimod and at 6 and 12 months of follow-up. The levels of the neurotrophic factors brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, β-nerve growth factor, neurotrophin-3, neurotrophin-4, basic fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor were screened in the supernatants of separated T cells and monocyte cultures using a customized, multiplex enzyme-linked immunosorbent assay. Brain-derived neurotrophic factor levels were further validated by a specific enzyme-linked immunosorbent assay. RESULTS: Treatment with fingolimod significantly increased brain-derived neurotrophic factor secretion from T cells. A specific enzyme-linked immunosorbent assay confirmed these results in the supernatant of T cells after 6 and 12 months of therapy. CONCLUSIONS: T cells that reach the bloodstream of fingolimod-treated patients with multiple sclerosis may contribute to the neuroprotective effect of this therapy by increased secretion of brain-derived neurotrophic factor. This mechanism of action of fingolimod in patients with multiple sclerosis has not been previously reported.
BACKGROUND: The pathophysiology of multiple sclerosis involves an autoimmune and a neurodegenerative mechanism. Central nervous system-infiltrating immune cells in multiple sclerosis also possess a neuroprotective activity through secretion of neurotrophins, such as brain-derived neurotrophic factor. Fingolimod was shown to slow the progression of disability and loss of brain volume. OBJECTIVE: The objective of this study was to explore whether fingolimod induces secretion of neurotrophins by immune cells. METHODS: Blood was drawn from 21 patients before the initiation of treatment with fingolimod and at 6 and 12 months of follow-up. The levels of the neurotrophic factors brain-derived neurotrophic factor, glial cell-derived neurotrophic factor, β-nerve growth factor, neurotrophin-3, neurotrophin-4, basic fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor were screened in the supernatants of separated T cells and monocyte cultures using a customized, multiplex enzyme-linked immunosorbent assay. Brain-derived neurotrophic factor levels were further validated by a specific enzyme-linked immunosorbent assay. RESULTS: Treatment with fingolimod significantly increased brain-derived neurotrophic factor secretion from T cells. A specific enzyme-linked immunosorbent assay confirmed these results in the supernatant of T cells after 6 and 12 months of therapy. CONCLUSIONS: T cells that reach the bloodstream of fingolimod-treated patients with multiple sclerosis may contribute to the neuroprotective effect of this therapy by increased secretion of brain-derived neurotrophic factor. This mechanism of action of fingolimod in patients with multiple sclerosis has not been previously reported.
Authors: Anders B Klein; Rebecca Williamson; Martin A Santini; Christoffer Clemmensen; Anders Ettrup; Maribel Rios; Gitte M Knudsen; Susana Aznar Journal: Int J Neuropsychopharmacol Date: 2010-07-07 Impact factor: 5.176
Authors: G Sferruzza; F Clarelli; E Mascia; L Ferrè; L Ottoboni; M Sorosina; S Santoro; L Moiola; V Martinelli; G Comi; F Martinelli Boneschi; M Filippi; P Provero; Federica Esposito Journal: Mol Neurobiol Date: 2021-06-28 Impact factor: 5.590