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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.
AuthorsStine Mencl, Nelli Hennig, Sarah Hopp, Michael K Schuhmann, Christiane Albert-Weissenberger, Anna-Leena Sirén, Christoph Kleinschnitz
JournalJournal of neuroimmunology (J Neuroimmunol) Vol. 274 Issue 1-2 Pg. 125-31 (Sep 15 2014) ISSN: 1872-8421 [Electronic] Netherlands
PMID25081505 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
Chemical References
  • Immunosuppressive Agents
  • Propylene Glycols
  • Fingolimod Hydrochloride
  • Sphingosine
Topics
  • Animals
  • Blood-Brain Barrier (drug effects, immunology)
  • Brain Edema (drug therapy, immunology)
  • Brain Injuries (drug therapy, immunology)
  • Disease Models, Animal
  • Encephalitis (drug therapy, immunology)
  • Fingolimod Hydrochloride
  • Flow Cytometry
  • Immunosuppressive Agents (immunology, pharmacology)
  • Lymphopenia (chemically induced, immunology)
  • Mice
  • Mice, Inbred C57BL
  • Propylene Glycols (immunology, pharmacology)
  • Signal Transduction (drug effects, immunology)
  • Sphingosine (analogs & derivatives, immunology, pharmacology)
  • T-Lymphocytes (drug effects, immunology)
  • Treatment Outcome

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