title: FTY720 does not protect from traumatic brain injury in mice despite reducing posttraumatic inflammation.
abstract: Inflammation is a pathological hallmark of traumatic brain injury (TBI). Recent evidence suggests that immune cells such as lymphocytes are of particular relevance for lesion development after TBI. FTY720, a sphingosine-1-phosphate (S1P) receptor modulator, sequesters T lymphocytes in lymphoid organs and has been shown to improve outcome in a variety of neurological disease models. We investigated the mode of FTY720 action in models of TBI. Focal cortical cryolesion was induced in C57BL/6 mice treated with FTY720 (1mg/kg) or vehicle immediately before injury. Lesion size was assessed 24h later. Immune cells in the blood and brain were counted by flow cytometry and immunocytochemistry. The integrity of the blood-brain barrier was analyzed using Evans Blue dye. To validate the findings in a diffuse brain trauma model, FTY720-treated mice and controls were subjected to weight drop contusion injury and neurological deficits were assessed until day 7. As expected FTY720 significantly lowered the numbers of circulating lymphocytes and attenuated the invasion of immune cells into the damaged brain parenchyma. However, FTY720 was unable to improve lesion size or functional outcome in both trauma models at either stage, i.e. acute vs chronic. Accordingly, the extent of blood-brain barrier disruption and neuronal apoptosis was similar between FTY720-treated mice and controls. We conclude that pharmacological S1P receptor modulation is an unfavorable strategy to combat TBI. Moreover, our findings put into perspective the pathophysiological relevance of inflammatory cells in traumatic neurodegeneration.
authors: Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
authors: Stine
authors: S
authors: Mencl
authors: Department of Neurosurgery, University Hospital Würzburg, Würzburg, Germany.
authors: Nelli
authors: N
authors: Hennig
authors: Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
authors: Sarah
authors: S
authors: Hopp
authors: Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
authors: Michael K
authors: MK
authors: Schuhmann
authors: Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
authors: Christiane
authors: C
authors: Albert-Weissenberger
authors: Department of Neurosurgery, University Hospital Würzburg, Würzburg, Germany.
authors: Anna-Leena
authors: AL
authors: Sirén
authors: Department of Neurology, University Hospital Würzburg, Würzburg, Germany. Electronic address: christoph.kleinschnitz@uni-wuerzburg.de.
authors: Christoph
authors: C
authors: Kleinschnitz
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000276:immunology; D001929:Brain Edema / Q000188:drug therapy / Q000276:immunology; D001930:Brain Injuries / Q000188:drug therapy* / Q000276:immunology*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000188:drug therapy* / Q000276:immunology*; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000276:immunology / Q000494:pharmacology; D008231:Lymphopenia / Q000139:chemically induced / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011409:Propylene Glycols / Q000276:immunology / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: Blood–brain barrier; Edema; FTY720; Inflammation; Lymphocytes; Traumatic brain injury