title: Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage.
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.
authors.affiliation: Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA 92354, USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Rolland
authors.forename: Tim
authors.initials: T
authors.lastname: Lekic
authors.forename: Paul R
authors.initials: PR
authors.lastname: Krafft
authors.forename: Yu
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Orhan
authors.initials: O
authors.lastname: Altay
authors.forename: Richard
authors.initials: R
authors.lastname: Hartman
authors.forename: Robert
authors.initials: R
authors.lastname: Ostrowski
authors.forename: Anatol
authors.initials: A
authors.lastname: Manaenko
authors.forename: Jiping
authors.initials: J
authors.lastname: Tang
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001479:Basal Ganglia / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001804:Blood Transfusion, Autologous / Q000009:adverse effects; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D017252:CD3 Complex / Q000378:metabolism; D002452:Cell Count; D002540:Cerebral Cortex / Q000473:pathology*; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D017364:Collagenases / Q000633:toxicity; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D005552:Forelimb / Q000503:physiopathology; D007839:Functional Laterality / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009422:Nervous System Diseases / Q000209:etiology / Q000517:prevention & control; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D011596:Psychomotor Disorders / Q000188:drug therapy / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013028:Space Perception / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D017252:CD3 Complex; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D011409:Propylene Glycols; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D017364:Collagenases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine