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 language | English |
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Pages (from-to) | 45-55 |
Number of pages | 11 |
Journal | Experimental Neurology |
Volume | 241 |
Issue number | 1 |
DOIs | |
State | Published - 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