Frontiers in Systems Neuroscience (May 2014)
Neurogenic effects of fingolimod in hippocampus, affecting fear memory.
Abstract
Fingolimod (FTY720; Gilenya™,Novartis Pharma AG) is a recently developed Sphingosine-1-Phosphate (S1P) analogue, orally administered as a new therapeutic agent in Multiple Sclerosis (MS) (Brinkmann V. et al. 2010). S1P receptors (S1PRs) are expressed in various sites in the CNS including the subventricular zone (Waeber C. et al. 1999; Choi J.W. et al. 2013) while endogenous S1P was shown to induce proliferation and morphological changes in embryonic hippocampal neural progenitors in culture (Harada J. et al. 2004). In this study we investigated the effects of fingolimod on adult rodent hippocampal neurogenesis and their possible functional role. To this aim, thymidine analogue BrdU was injected at the end or before a 2-week i.p. administration of a therapeutic dose of Fingolimod (0,3 mg/kg) in young and old mice. Stereological counts of BrdU+ cells revealed significant increase in both proliferation, and survival of neural stem cells (NSC) in the area of Dentate Gyrus (DG) of the hippocampus, compared to control untreated animals of young but not old ages. In the case of survival assessment, most of the BrdU + cells were also positive for NeuN, suggesting an increase of newly formed neurons. The increase in proliferation rate of NSC was also confirmed by BrdU uptake in hippocampal NSC cultures in vitro, implying that the effects of fingolimod are cell autonomous. Immunohistochemical analysis showed that S1PR was not co-localized with GFAP+ cells in the Subgranular zone (SGZ) of the DG, but was strongly co-localized with transcription factor MASH1 and weakly with DcX or PSA-NCAM positive neural progenitors. These findings suggest that expression of S1PR1 in the SGZ is restricted to transit amplifying neural progenitors and maintained also in the stage of neuroblast. In addition, the effects of Fingolimod in DG neurogenesis were positively correlated to enhanced fear memory and increased context discrimination, an established DG-dependent cognitive task (Saxa D. et al. 2006; Sahay A. et al. 2011). Conclusively, our data suggest that Fingolimod increases neurogenesis in adult hippocampus and improves memory function.
Keywords
