title: FTY720 reduces inflammation and promotes functional recovery after spinal cord injury.
abstract: A robust and complex inflammatory cascade is known to be a prominent component of secondary injury following spinal cord injury (SCI). Specifically, the concept of trauma-induced autoimmunity has linked the lymphocyte population with neural tissue injury and neurologic deficit. FTY720, a sphingosine receptor modulator that sequesters lymphocytes in secondary lymphoid organs, has been shown to be effective in the treatment of a variety of experimental autoimmune disorders. Accordingly, by reducing lymphocyte infiltration into the spinal cord following SCI, this novel immunomodulator may enhance tissue preservation and functional recovery. In the present study, a moderate to severe contusion SCI was simulated in adult Long-Evans hooded rats. Using flow cytometry we showed that daily FTY720 treatment dramatically reduced T-cell infiltration into the SCI lesion site at 4 and 7 days post-injury, while other inflammatory cell populations were relatively unaltered. To assess functional recovery, three groups of injured animals (treated, vehicle, and injury only) were evaluated weekly for hindlimb recovery. Animals in the treated group consistently exhibited higher functional scores than animals in the control groups after 2 weeks post-injury. This finding was associated with a greater degree of white matter sparing at the lesion epicenter when cords were later sectioned and stained. Furthermore, treated animals were found to exhibit improved bladder function and a reduced incidence of hemorrhagic cystitis compared to control counterparts. Collectively these results demonstrate the neuroprotective potential of FTY720 treatment after experimental SCI.
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Kangmin D
authors.initials: KD
authors.lastname: Lee
authors.forename: Woon N
authors.initials: WN
authors.lastname: Chow
authors.forename: Carmen
authors.initials: C
authors.lastname: Sato-Bigbee
authors.forename: Martin R
authors.initials: MR
authors.lastname: Graf
authors.forename: Robert S
authors.initials: RS
authors.lastname: Graham
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Colello
authors.forename: Harold F
authors.initials: HF
authors.lastname: Young
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Mathern
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D020278:Demyelinating Autoimmune Diseases, CNS / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D009187:Myelitis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009416:Nerve Regeneration / Q000187:drug effects* / Q000276:immunology; D010243:Paralysis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans; D020127:Recovery of Function / Q000187:drug effects* / Q000276:immunology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D001750:Urinary Bladder, Neurogenic / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D014855:Wallerian Degeneration / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine