title: The sphingosine-1-phosphate analogue, FTY-720, promotes the proliferation of embryonic neural stem cells, enhances hippocampal neurogenesis and learning and memory abilities in adult mice.
abstract: Fingolimod (FTY-720) is the first oral therapeutic drug approved for the relapsing-remitting forms of multiple sclerosis. Neural stem cells (NSCs) are capable of continuous self-renewal and differentiation. The dentate gyrus of the hippocampus in the adult mammalian brain contains a population of NSCs and is one of the regions where neurogenesis takes place. FTY-720 has been shown to have neuroprotective effects in several model systems, so we investigated the direct effects of FTY-720 on NSCs and adult neurogenesis.
  
  
  
  We assessed the effects of FTY-720 on the proliferation and differentiation of cultured embryonic hippocampal NSCs using the 5-bromo-2-deoxyuridine incorporation assay, the neurosphere formation assay and western blot analysis. Receptor selective agonists and antagonists were used to identify the mechanisms involved. Neurogenesis in the hippocampus of C57BL/6 mice was also assessed by immunohistochemistry. The Morris water maze and fear conditioning tests were used to detect the learning and memory abilities of mice.
  
  
  
  FTY-720 promoted the proliferation of embryonic hippocampal NSCs probably via the activation of ERK signalling, Gi/o proteins and S1P1 receptors. However, FTY-720 did not affect the differentiation of cultured hippocampal NSCs. In vivo, chronic treatment with FTY-720 promoted hippocampal neurogenesis in adult C57BL/6 mice and enhanced their learning and memory abilities.
  
  
  
  Our results suggest a new target for the activation of NSCs and provide an insight into the therapeutic effects of FTY-720 in neuropsychiatric disorders, neurodegenerative diseases and age-related cognitive decline where hippocampal neurogenesis is compromised.
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yili
authors.initials: Y
authors.lastname: Sun
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Hong
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Linyin
authors.initials: L
authors.lastname: Feng
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects*; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000068876:Fingolimod Hydrochloride