Fty720 (Fingolimod) Ameliorates Ischemia Reperfusion Injury In Experimental Stroke Model

Background: Fingolimod (FTY720), a widely known sphingosine-1-phosphate (S1P) receptor agonist, was approved as a treatment for multiple sclerosis due to its strong anti-inflammatory effect. Methods: In-vivo study, FTY720 was injected intraperitoneally just before reperfusion. Neurological score and infarct volume were evaluated at Day0, 1, 3, 5, and 7 after MCAO. Evans Blue analysis and immunohistochemistry were conducted at day1 and day7. [18F]DPA-714 PET was performed 2 and 9 days after MCAO. In vitro study, in order to perform OGD, Bovine Brain Microvascular Endothelial Cells (BBMVECs) were incubated in a glucose-free medium under 1% oxygen condition, and then reperfused for 4 hours. In vitro models of ischemia/reperfusion injury were exposed to FTY720, FTY720-P, S1P and SEW (100 nM) immediately after reperfusion. The effects of FTY720 on the blood brain barrier were examined by real-time PCR analysis and immunofluorescence staining. Results: In this study, we observed that FTY720 reduced infarction size and improved neurological score after MCAO. [18F]DPA-714 PET showed a high standardized uptake value (SUV) around the ischemic area 2 days after MCAO. Although SUV was increased further 9 days after MCAO in both treatment groups, the increase was significantly inhibited in 1.5mg/kg group. In addition, FTY720 recovered the integrity of blood brain barrier which has been disrupted by ischemia/reperfusion injury. However, we observed that FTY720 can improve the integrity of blood brain barrier by inducing the translocation of tight junction and adherins junction, but FTY720 cannot ameliorate the expression of tight junction and adherins junction. Conclusions: The present results suggest that FTY720 improves neurological score, reduces infarction size, inflammatory activation and neuronal apoptosis. Especially ameliorates the integrity of Blood-Brain Barrier by inducing the translocation of tight junction and adherins junction after transient MCAO.