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The sphingosine 1‐phosphate receptor agonist FTY 720 is neuroprotective after cuprizone‐induced CNS demyelination
Author(s) -
Slowik A,
Schmidt T,
Beyer C,
Amor S,
Clarner T,
Kipp M
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12938
Subject(s) - remyelination , neuroprotection , astrogliosis , microglia , multiple sclerosis , agonist , fingolimod , gliosis , medicine , astrocyte , sphingosine 1 phosphate receptor , experimental autoimmune encephalomyelitis , receptor , myelin , pharmacology , neuroscience , immunology , endocrinology , sphingosine , biology , central nervous system , pathology , sphingosine 1 phosphate , inflammation
Background and Purpose Modulation of the sphingosine 1‐phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti‐inflammatory effect of retaining lymphocytes within the lymph nodes. Here, we evaluated the potential of an agonist at this receptor, FTY 720 (fingolimod), to activate the promyelinating pathways within the brain to encourage remyelination and neuroprotection. Experimental Approach In this study, we used the cuprizone model in male C57BL/6 mice and tested the promyelinating and neuroprotective effects of FTY 720 after acute and chronic toxin‐induced experimental demyelination. We used histological, immunohistochemical and gene expression methods. Key Results The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone‐induced demyelination. Robust endogenous remyelination was evident after acute, but impaired after chronic, demyelination. FTY 720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Markers of gliosis (astrocyte and microglia activation) were not affected by FTY 720 treatment. Remarkably, the accumulation of amyloid precursor protein‐positive spheroids in axons was less distinct in FTY 720‐treated animals, indicating that this compound alleviated ongoing axonal damage. Conclusions and Implications We show that even during endogenous remyelination, axonal degeneration continued at a low level, accumulating over time. This continuous neurodegenerative process was ameliorated by FTY 720 treatment. FTY 720 preserved CNS integrity by direct interaction with brain resident cells, the actions of which are still to be defined.