title: Prominence of central sphingosine-1-phosphate receptor-1 in attenuating aβ-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.
authors.affiliation: Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Masoumeh
authors.initials: M
authors.lastname: Asle-Rousta
authors.forename: Zeynab
authors.initials: Z
authors.lastname: Kolahdooz
authors.forename: Leila
authors.initials: L
authors.lastname: Dargahi
authors.forename: Abolhassan
authors.initials: A
authors.lastname: Ahmadiani
authors.forename: Sanaz
authors.initials: S
authors.lastname: Nasoohi
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068876:Fingolimod Hydrochloride; D008297:Male; D018782:Maze Learning; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D011409:Propylene Glycols / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors; D000068876:Fingolimod Hydrochloride; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase; C489691:Ptgs2 protein, rat; C061800:N,N-dimethylsphingosine