title: FTY720 improves functional recovery after spinal cord injury by primarily nonimmunomodulatory mechanisms.
abstract: Spinal cord injury (SCI) is an incapacitating injury that can result in limited functional recovery. We have previously shown increases in the lysophospholipid mediator, sphingosine-1-phosphate (S1P), in the spinal cord after contusion injury. To apply S1P receptor modulation to the treatment of SCI, we examined the therapeutic effects of FTY720, an S1P receptor agonist, on locomotor recovery after SCI in mice. Oral administration of FTY720 shortly after contusion SCI significantly improved motor function recovery, as assessed by both Basso Mouse Scale scores and Rotarod Performance test results. FTY720 induced lymphopenia and reduced T-cell infiltration in the spinal cord after SCI but did not affect the early infiltration of neutrophils and the activation of microglia. In addition, plasma levels and mRNA expression of inflammatory cytokines in the spinal cord after SCI were not attenuated by FTY720. Vascular permeability and astrocyte accumulation were both decreased by FTY720 in the injured spinal cord. The therapeutic effects of FTY720 were not solely dependent on immune modulation, as confirmed by the demonstration that FTY720 also ameliorated motor function after SCI in mice with severe combined immunodeficiency. Finally, the S1P(1) receptor agonist, SEW2871, partly mimicked the therapeutic effect of FTY720. Our data highlight the importance of immune-independent functions of FTY720 in decreasing vascular permeability and astrogliosis in the injured spinal cord and promoting locomotor function recovery after SCI.
authors.affiliation: Department of Orthopedics, Jichi Medical University School of Medicine, Tochigi, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Norimatsu
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ohmori
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kimura
authors.forename: Seiji
authors.initials: S
authors.lastname: Madoiwa
authors.forename: Jun
authors.initials: J
authors.lastname: Mimuro
authors.forename: Atsushi
authors.initials: A
authors.lastname: Seichi
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yatomi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hoshino
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Sakata
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D018836:Inflammation Mediators / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D017628:Microglia / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D011409:Propylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D049349:Receptors, Lysosphingolipid / Q000819:agonists; D020127:Recovery of Function / Q000187:drug effects; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine