title: Fingolimod modulates microglial activation to augment markers of remyelination.
abstract: BACKGROUND
  Microglial activation in multiple sclerosis has been postulated to contribute to long-term neurodegeneration during disease. Fingolimod has been shown to impact on the relapsing remitting phase of disease by modulating autoreactive T-cell egress from lymph organs. In addition, it is brain penetrant and has been shown to exert multiple effects on nervous system cells.
  
  
  METHODS
  In this study, the impact of fingolimod and other sphingosine-1-phosphate receptor active molecules following lysophosphotidyl choline-induced demyelination was examined in the rat telencephalon reaggregate, spheroid cell culture system. The lack of immune system components allowed elucidation of the direct effects of fingolimod on CNS cell types in an organotypic situation.
  
  
  RESULTS
  Following demyelination, fingolimod significantly augmented expression of myelin basic protein in the remyelination phase. This increase was not associated with changes in neurofilament levels, indicating de novo myelin protein expression not associated with axonal branching. Myelin wrapping was confirmed morphologically using confocal and electron microscopy. Increased remyelination was associated with down-regulation of microglial ferritin, tumor necrosis factor alpha and interleukin 1 during demyelination when fingolimod was present. In addition, nitric oxide metabolites and apoptotic effectors caspase 3 and caspase 7 were reduced during demyelination in the presence of fingolimod. The sphingosine-1-phosphate receptor 1 and 5 agonist BAF312 also increased myelin basic protein levels, whereas the sphingosine-1-phosphate receptor 1 agonist AUY954 failed to replicate this effect on remyelination.
  
  
  CONCLUSIONS
  The results presented indicate that modulation of S1P receptors can ameliorate pathological effectors associated with microglial activation leading to a subsequent increase in protein and morphological markers of remyelination. In addition, sphingosine-1-phosphate receptor 5 is implicated in promoting remyelination in vitro. This knowledge may be of benefit for treatment of chronic microglial inflammation in multiple sclerosis.
authors: Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. s.j.jackson@qmul.ac.uk
authors: Samuel J
authors: SJ
authors: Jackson
authors: Gavin
authors: G
authors: Giovannoni
authors: David
authors: D
authors: Baker
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology / Q000473:pathology; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology; D011247:Pregnancy; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D018874:Spheroids, Cellular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D007166:Immunosuppressive Agents; D008244:Lysophosphatidylcholines; D004676:Myelin Basic Protein; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine