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Here, we evaluated the potential of an agonist at this receptor, <jats:styled-content style=\"fixed-case\">FTY<\/jats:styled-content>720 (fingolimod), to activate the promyelinating pathways within the brain to encourage remyelination and neuroprotection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>In this study, we used the cuprizone model in male C57BL\/6 mice and tested the promyelinating and neuroprotective effects of <jats:styled-content style=\"fixed-case\">FTY<\/jats:styled-content>720 after acute and chronic toxin\u2010induced experimental demyelination. We used histological, immunohistochemical and gene expression methods.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone\u2010induced demyelination. Robust endogenous remyelination was evident after acute, but impaired after chronic, demyelination. <jats:styled-content style=\"fixed-case\">FTY<\/jats:styled-content>720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Markers of gliosis (astrocyte and microglia activation) were not affected by <jats:styled-content style=\"fixed-case\">FTY<\/jats:styled-content>720 treatment. Remarkably, the accumulation of amyloid precursor protein\u2010positive spheroids in axons was less distinct in <jats:styled-content style=\"fixed-case\">FTY<\/jats:styled-content>720\u2010treated animals, indicating that this compound alleviated ongoing axonal damage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>We show that even during endogenous remyelination, axonal degeneration continued at a low level, accumulating over time. This continuous neurodegenerative process was ameliorated by <jats:styled-content style=\"fixed-case\">FTY<\/jats:styled-content>720 treatment. <jats:styled-content style=\"fixed-case\">FTY<\/jats:styled-content>720 preserved <jats:styled-content style=\"fixed-case\">CNS<\/jats:styled-content> integrity by direct interaction with brain resident cells, the actions of which are still to be defined.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12938","type":"journal-article","created":{"date-parts":[[2014,9,15]],"date-time":"2014-09-15T03:39:09Z","timestamp":1410752349000},"page":"80-92","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":94,"title":["The sphingosine 1\u2010phosphate receptor agonist <scp>FTY<\/scp>720 is neuroprotective after cuprizone\u2010induced <scp>CNS<\/scp> demyelination"],"prefix":"10.1111","volume":"172","author":[{"given":"A","family":"Slowik","sequence":"first","affiliation":[{"name":"Institute of 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