Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage

William B. Rolland, Tim Lekic, Paul R. Krafft, Yu Hasegawa, Orhan Altay, Richard Hartman, Robert Ostrowski, Anatol Manaenko, Jiping Tang, John H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

T-lymphocytes promote cerebral inflammation, thus aggravating neuronal injury after stroke. Fingolimod, a sphingosine 1-phosphate receptor analog, prevents the egress of lymphocytes from primary and secondary lymphoid organs. Based on these findings, we hypothesized fingolimod treatment would reduce the number of T-lymphocytes migrating into the brain, thereby ameliorating cerebral inflammation following experimental intracerebral hemorrhage (ICH). We investigated the effects of fingolimod in two well-established murine models of ICH, implementing intrastriatal infusions of either bacterial collagenase (cICH) or autologous blood (bICH). Furthermore, we tested the long term neurological improvements by Fingolimod in a collagenase-induced rat model of ICH. Fingolimod, in contrast to vehicle administration alone, improved neurological functions and reduced brain edema at 24 and 72. h following experimental ICH in CD-1 mice (n = 103; p. <0.05). Significantly fewer lymphocytes were found in blood and brain samples of treated animals when compared to the vehicle group (p. <0.05). Moreover, fingolimod treatment significantly reduced the expression of intercellular adhesion molecule-1 (ICAM-1), interferon-γ (INF-γ), and interleukin-17 (IL-17) in the mouse brain at 72. h post-cICH (p. <0.05 compared to vehicle). Long-term neurocognitive performance and histopathological analysis were evaluated in Sprague-Dawley rats between 8 and 10. weeks post-cICH (n = 28). Treated rats showed reduced spatial and motor learning deficits, along with significantly reduced brain atrophy and neuronal cell loss within the basal ganglia (p. <0.05 compared to vehicle). We conclude that fingolimod treatment ameliorated cerebral inflammation, at least to some extent, by reducing the availability and subsequent brain infiltration of T-lymphocytes, which improved the short and long-term sequelae after experimental ICH in rodents.

Original languageEnglish
Pages (from-to)45-55
Number of pages11
JournalExperimental Neurology
Volume241
Issue number1
DOIs
StatePublished - Mar 2013

ASJC Scopus Subject Areas

  • Neurology
  • Developmental Neuroscience

Keywords

  • Behavior
  • Brain edema
  • Fingolimod
  • Inflammation
  • Intracerebral hemorrhage
  • Lymphocyte
  • Neuroprotection
  • Lymphocytes/drug effects
  • Intercellular Adhesion Molecule-1/metabolism
  • CD3 Complex/metabolism
  • Cell Count
  • Space Perception/drug effects
  • Functional Laterality/drug effects
  • Leukocytes/drug effects
  • Interleukin-17/metabolism
  • Male
  • Nervous System Diseases/etiology
  • Sphingosine/analogs & derivatives
  • Blood Transfusion, Autologous/adverse effects
  • Time Factors
  • Behavior, Animal/drug effects
  • Disease Models, Animal
  • Cerebral Hemorrhage/chemically induced
  • Basal Ganglia/pathology
  • Cerebral Cortex/pathology
  • Fingolimod Hydrochloride
  • Interferon-gamma/metabolism
  • Rats
  • Psychomotor Disorders/drug therapy
  • Rats, Sprague-Dawley
  • Brain Edema/etiology
  • Animals
  • Analysis of Variance
  • Collagenases/toxicity
  • Forelimb/physiopathology
  • Immunosuppressive Agents/therapeutic use
  • Mice
  • Maze Learning/drug effects
  • Propylene Glycols/pharmacology

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