Neurological S1P signaling as an emerging mechanism of action of oral FTY720 (fingolimod) in multiple sclerosis.
FTY720 (fingolimod, Novartis) is a promising investigational drug for relapsing forms of multiple sclerosis (MS), an autoimmune and neurodegenerative disorder of the central nervous system. It is currently under FDA review in the United States, and could represent the first approved oral treatment for MS. Extensive, ongoing clinical trials in Phase II/III have supported both the efficacy and safety of FTY720. FTY720 itself is not bioactive, but when phosphorylated (FTY720-P) by sphingosine kinase 2, it becomes active through modulation of 4 of the 5 known G protein-coupled sphingosine 1-phosphate (S1P) receptors. The mechanism of action (MOA) is thought to be immunological, where FTY720 alters lymphocyte trafficking via S1P1. However, MOA for FTY720 in MS may also involve a direct, neurological action within the central nervous system in view of documented S1P receptor-mediated signaling influences in the brain, and this review considers observations that support an emerging neurological MOA.
Department of Molecular Biology, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Chang Wook
CW
Lee
Ji Woong
JW
Choi
Jerold
J
Chun
D000818:Animals; D015507:Drugs, Investigational / Q000494:pharmacology / Q000627:therapeutic use; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D008246:Lysophospholipids / Q000378:metabolism*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use*; D020033:Protein Isoforms / Q000819:agonists / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
D015507:Drugs, Investigational; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D011355:Prodrugs; D011409:Propylene Glycols; D020033:Protein Isoforms; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine