title: Fingolimod provides long-term protection in rodent models of cerebral ischemia.
abstract: OBJECTIVE
  The sphingosine-1-phosphate (S1P) receptor agonist fingolimod (FTY720), that has shown efficacy in advanced multiple sclerosis clinical trials, decreases reperfusion injury in heart, liver, and kidney. We therefore tested the therapeutic effects of fingolimod in several rodent models of focal cerebral ischemia. To assess the translational significance of these findings, we asked whether fingolimod improved long-term behavioral outcomes, whether delayed treatment was still effective, and whether neuroprotection can be obtained in a second species.
  
  
  METHODS
  We used rodent models of middle cerebral artery occlusion and cell-culture models of neurotoxicity and inflammation to examine the therapeutic potential and mechanisms of neuroprotection by fingolimod.
  
  
  RESULTS
  In a transient mouse model, fingolimod reduced infarct size, neurological deficit, edema, and the number of dying cells in the core and periinfarct area. Neuroprotection was accompanied by decreased inflammation, as fingolimod-treated mice had fewer activated neutrophils, microglia/macrophages, and intercellular adhesion molecule-1 (ICAM-1)-positive blood vessels. Fingolimod-treated mice showed a smaller infarct and performed better in behavioral tests up to 15 days after ischemia. Reduced infarct was observed in a permanent model even when mice were treated 4 hours after ischemic onset. Fingolimod also decreased infarct size in a rat model of focal ischemia. Fingolimod did not protect primary neurons against glutamate excitotoxicity or hydrogen peroxide, but decreased ICAM-1 expression in brain endothelial cells stimulated by tumor necrosis factor alpha.
  
  
  CONCLUSIONS
  These findings suggest that anti-inflammatory mechanisms, and possibly vasculoprotection, rather than direct effects on neurons, underlie the beneficial effects of fingolimod after stroke. S1P receptors are a highly promising target in stroke treatment.
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wei
authors.forename: Muge
authors.initials: M
authors.lastname: Yemisci
authors.forename: Hyung-Hwan
authors.initials: HH
authors.lastname: Kim
authors.forename: Lai Ming
authors.initials: LM
authors.lastname: Yung
authors.forename: Hwa Kyoung
authors.initials: HK
authors.lastname: Shin
authors.forename: Seo-Kyoung
authors.initials: SK
authors.lastname: Hwang
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Guo
authors.forename: Tao
authors.initials: T
authors.lastname: Qin
authors.forename: Nafiseh
authors.initials: N
authors.lastname: Alsharif
authors.forename: Volker
authors.initials: V
authors.lastname: Brinkmann
authors.forename: James K
authors.initials: JK
authors.lastname: Liao
authors.forename: Eng H
authors.initials: EH
authors.lastname: Lo
authors.forename: Christian
authors.initials: C
authors.lastname: Waeber
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000517:prevention & control*; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000276:immunology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D020258:Neurotoxicity Syndromes / Q000517:prevention & control; D011409:Propylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D049349:Receptors, Lysosphingolipid / Q000819:agonists; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy* / Q000517:prevention & control
chemical_list: D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine