Fingolimod provides long‐term protection in rodent models of cerebral ischemia

Blood flow, excitotoxicity, peri-infarct depolarization, inflammation and apoptosis can affect brain ischemic stroke outcome, and have been targeted to improve stroke therapy1. Many agents modulating these processes were effective in animal models, but not in clinical trials. Sphingosine-1-phosphate (S1P) acts on five G protein-coupled receptors, regulating proliferation, apoptosis, adhesion, migration, cytoskeletal organization, differentiation/morphogenesis and inflammation2. S1P is a key player in protective mechanisms against hypoxia- or ischemia-mediated insults. S1P protects neonatal cardiac myocytes from hypoxic damage3 and reduces ischemia/reperfusion-induced cardiac injury4. Fingolimod (FTY720) was first described in 1995, following a chemical derivatization program of myriocin5. In vivo actions of FTY720 are mediated by phosphorylated FTY7206, an agonist at S1P1, S1P3, S1P4 and S1P5 receptors6. The pharmacokinetics of FTY720 have been extensively characterized7, and it has shown clinical efficacy in phase 3 clinical trials involving multiple sclerosis patients8, 9. Because FTY720 protects from ischemia-reperfusion injury in liver10, 11 and kidney12–15, we hypothesized that FTY720 would improve outcome in models of brain ischemia. Our results, previously published in an abstract16, indeed demonstrate that FTY720 treatment decreases lesion size, edema, cell death and inflammation and suggest that FTY720 might be effective in stroke.