Prominence of central sphingosine-1-phosphate receptor-1 in attenuating aß-induced injury by fingolimod.

ABSTRACT

FTY720 (fingolimod), the sphingosine-1-phosphate (S1P) analogue, has been experimentally indicated to exert substantial ameliorating effects in animal models of Alzheimer's disease (AD). The present work aims to answer whether central S1P receptor 1 (S1P1) plays significant role in the impact of fingolimod in AD. To verify the prominence of central FTY720 phosphorylation, DMS (sphingosine kinase inhibitor) was infused intracerebrally in parallel with systemic FTY720 administration to prevent central formation of FTY720-P as the recognized active ligand for S1PRs. The corresponding S1P1 modulation was also investigated using the pharmacological blockage of central S1P1 by W123. Both DMS and W123 were efficiently capable of suppressing FTY720-ameliorating effects in AD animals, either on memory deficit or on COX-II and TNF-α expression. Our data conclude that experimental benefits of FTY720 in the context of AD depend on central S1P1 modulation, as well as on S1P kinase activity in the brain.