Fingolimod provides remarkable protection in Aβ-induced injury through central sphingosine-1-phosphate receptor-1
Sanaz Nasoohi1, Masoumeh Asle-Rousta1, Zeynab Kolahdooz1, Leila Dargahi1, Abolhassan Ahmadiani1; 1Neuroscience Research Center, Shahid Beheshti University of Medical Sciences
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 type 1 (S1P1) plays significant role in the impact of fingolimod in AD. Aβ (2 μg/2 μl) bilateral intra-hippocampal injection was used to produce AD-like neurodegeneration in male adult wistar rats, as established by weak memory performance in morris water maze (MWM) test post Aβ infusion. After a recovery period of 24 h, animals were subjected to intraperitoneal FTY720 (1 mg/kg) treatment which led to remarkable improvement in animals’ memory deficits. To verify the prominence of central FTY720 phosphorylation, the sphingosine kinase inhibitor N,N-Dimethylsphingosine (DMS; 2 μΜ) was administered freely moving through intracerebroventricular (i.c.v) infusion concurrent with systemic FTY720 dosing to prevent central formation of phospho-FTY720, as the established active ligand for S1PRs. The corresponding S1P1 modulation was then investigated using the pharmacological blockage of central S1P1 by daily i.c.v injections of W123 (25 μΜ) in a separate group of FTY720 receiving animals. Following the MWM probe trial, cerebral hippocampi were harvested immediately after animals’ euthanization to prepare for COX-II and TNF-α immunoblotting. Based on our data, 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 S1P1 modulation as well as on S1P kinase activity in the brain.
Topic Area: EXECUTIVE PROCESSES: Working memory