title: Fingolimod phosphate promotes the neuroprotective effects of microglia.
abstract: Fingolimod phosphate (FTY720) is a sphingosine 1-phosphate (S1P) receptor agonist that is being used as a new oral drug for multiple sclerosis. FTY720 prevents lymphocytes from moving out of the lymphoid organs and inhibits autoreactive lymphocytes from infiltrating the central nervous system. Whether FTY720 directly affects microglia-the innate immune cells of the central nervous system-is unclear. Here we show that FTY720 binds S1P1 receptors to downregulate activated microglial production of such pro-inflammatory cytokines as tumor necrosis factor-α, interleukin-1β, and interleukin-6. FTY720 also upregulates microglial production of brain-derived neurotrophic factor and glial cell-derived neurotrophic factor. These results suggested that FTY720 directly promotes the neuroprotective effects of microglia. Therefore, FTY720 may be a potent therapeutic agent for not only multiple sclerosis but also other neurologic diseases associated with microglial activation.
authors.affiliation: Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Noda
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mizuno
authors.forename: Akio
authors.initials: A
authors.lastname: Suzumura
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011409:Propylene Glycols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D004791:Enzyme Inhibitors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D011409:Propylene Glycols; D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine