title: Protective role of fingolimod (FTY720) in rats subjected to subarachnoid hemorrhage.
abstract: BACKGROUND
  Subarachnoid hemorrhage (SAH) is a neurological emergency with limited pharmacological treatment options. Inflammation is increasingly recognized as a key pathogenic contributor to brain injury in this condition. In the present study, we examined the neuroprotective effects of the immunomodulatory agent, fingolimod, in rats subjected to SAH.
  
  
  METHODS
  We utilized an endovascular rat perforation model of SAH. Animals were divided into four groups: (1) sham-vehicle; (2) sham-fingolimod; (3) SAH-vehicle; and (4) SAH-fingolimod. Rats received either vehicle solution or fingolimod (0.5 mg/kg) intraperitoneally 3 hours after sham surgery or SAH. A closed cranial window and intravital microscope system was used at 48 hours to assess neuroinflammation, which was represented by rhodamine-6G-labeled leukocyte trafficking in pial venules, and pial arteriolar dilating responses to a variety of vasodilators, including hypercapnia, and topically-applied acetylcholine, adenosine, and S-nitroso-N-acetyl penicillamine. In addition, motor-sensory function was evaluated.
  
  
  RESULTS
  Compared to sham-vehicle rats, SAH-vehicle animals displayed a four-times greater increase in pial venular intraluminal leukocyte adhesion. Treatment with fingolimod largely reduced the intravascular leukocyte adhesion. Vehicle-treated SAH animals displayed a significant decrease in pial arteriolar responses to all the vasodilators tested and vascular reactivity was preserved, to a significant degree, in the presence of fingolimod. In addition, neurological scores obtained at 48 hours post-SAH indicated significant neurological deficits in the vehicle-treated group (versus sham-vehicle surgical control). Those deficiencies were partially reduced by fingolimod (P < 0.0001 compared to the vehicle-treated SAH group).
  
  
  CONCLUSIONS
  Treatment of rats with fingolimod was associated with a marked limitation in the intravascular adhesion of leukocytes to pial venules, preserved pial arteriolar dilating function, and improved neurological outcome in rats subjected to SAH.
authors.affiliation: Neuroanesthesia Research Laboratory, University of Illinois College of Medicine, Chicago, IL, USA. hlxu@uic.edu.
authors.forename: Hao-Liang
authors.initials: HL
authors.lastname: Xu
authors.affiliation: Neuroanesthesia Research Laboratory, University of Illinois College of Medicine, Chicago, IL, USA. dpell@uic.edu.
authors.forename: Dale A
authors.initials: DA
authors.lastname: Pelligrino
authors.affiliation: Department of Anesthesiology of the University of Illinois College of Medicine, Chicago, IL, USA. oon@uic.edu.
authors.forename: Chanannait
authors.initials: C
authors.lastname: Paisansathan
authors.affiliation: Department of Neurology and Rehabilitation of the University of Illinois College of Medicine, 912 S Wood Street, Rm 855 N NPI (MC 796), Chicago, IL, 60612-7330, USA. testai@uic.edu.
authors.forename: Fernando D
authors.initials: FD
authors.lastname: Testai
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002452:Cell Count; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D000068876:Fingolimod Hydrochloride