title: Fingolimod impedes Schwann cell-mediated myelination: implications for the treatment of immune neuropathies?
abstract: BACKGROUND
  Fingolimod (FTY720), a first-in-class sphingosine-1-phosphate (S1P) receptor agonist, is a recently approved drug for treating relapsing multiple sclerosis. Experimental evidence suggests that FTY720 not only exhibits anti-inflammatory properties but also promotes myelination in the central nervous system by direct interaction with oligodendrocytes.
  
  
  OBJECTIVE
  To assess the effects of FTY720 on Schwann cells (SCs) and peripheral nerve myelination.
  
  
  METHODS
  Receptor expression studies and myelination were investigated in primary rat SCs and rat neuronal/SC cocultures. Cells were treated with physiologically relevant concentrations of the active phosphorylated form of FTY720 (FTY720P). In addition, S1P receptor expression was corroborated in human and rat peripheral nerve tissue sections.
  
  
  RESULTS
  Schwann cells express all known S1P receptors on the RNA level, not altered by FTY720P. In the myelination model, treatment with FTY720P resulted in a significant reduction of quantitative myelin formation. FTY720P induced reactive oxygen species in SCs associated with apoptosis of these cells, as demonstrated by the detection of cysteine aspartic acid–specific protease 3 and 7, as well as terminal deoxynucleotidyl transferase dUTP nick-end labeling. This effect was dependent of S1P signaling because the blocking of S1P receptors ameliorated reactive oxygen species production, SC apoptosis, and myelin loss.
  
  
  CONCLUSIONS
  FTY720P at greater concentrations induces apoptosis in SCs and may interfere with peripheral nerve myelination.
authors: Department of Neurology Medical Faculty, Clinical and Experimental Neuroimmunology, Heinrich-Heine-University, Düsseldorf, Germany.
authors: Angelika
authors: A
authors: Köhne
authors: Mark
authors: M
authors: Stettner
authors: Parastoo
authors: P
authors: Jangouk
authors: Thomas
authors: T
authors: Dehmel
authors: Hans-Peter
authors: HP
authors: Hartung
authors: Helmar C
authors: HC
authors: Lehmann
authors: Bernd C
authors: BC
authors: Kieseier
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D000068876:Fingolimod Hydrochloride; D005727:Ganglia, Spinal / Q000166:cytology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D009186:Myelin Sheath / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D011409:Propylene Glycols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000187:drug effects* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D049349:Receptors, Lysosphingolipid; D053148:Caspase 3; D053179:Caspase 7; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine