Title:Blockage of Central Sphingosine-1-phosphate Receptor does not Abolish the Protective Effect of FTY720 in Early Brain Injury after Experimental Subarachnoid Hemorrhage
Volume: 14
Issue: 6
Author(s): Yu Hasegawa*, Ken Uekawa, Takayuki Kawano, Hidenori Suzuki and Shokei Kim-Mitsuyama
Affiliation:
- Department of Pharmacology and Molecular Therapeutics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Chuo-ku, Kumamoto-shi, Kumamoto-ken, 8608556,Japan
Keywords:
Brain edema, central sphingosine 1-phosphate receptor, early brain injury, FTY720, subarachnoid hemorrhage,
VPC23019.
Abstract: Background: Although sphingosine 1-phosphate (S1P) receptor activation by FTY720 (fingolimod)
has been suggested to improve the prognosis of experimental stroke, the effect of the drug in
early brain injury (EBI) after subarachnoid hemorrhage (SAH) and the precise mechanism of the effect
are undetermined. In this study, we investigated the protective effect of systemic administration of
FTY720 in EBI after SAH and assessed the mechanism using intracerebroventricular infusion of
VPC23019 which is the S1P receptor antagonist.
Method: SAH rats were produced by the endovascular perforation model and injected saline or 1mg/kg
FTY720 intraperitoneally at 30 minutes after SAH induction. Neurological function, cerebral blood
flow, amount of subarachnoid blood, and brain edema were evaluated to confirm the protective effect
of systemic administration of FTY720. SAH rats also received VPC23019 intraventricularly before
SAH induction to abolish the central S1P receptor activation.
Results: Systemic administration of FTY720 significantly ameliorated SAH-induced neurological
deficits and brain edema without modulation of CBF and the amount of subarachnoid blood. Blockage
of central S1P receptor with VPC23019 did not abolish the protective effects of FTY720.
Conclusion: The present study suggests that systemic administration of FTY720 reduces EBI after
SAH and that the effect might not come from central S1P activation but be associated with pleiotropic
actions of the drug.