Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis
Open Access
- 17 May 2012
- journal article
- review article
- Published by MDPI AG in Pharmaceuticals
- Vol. 5 (5), 514-528
- https://doi.org/10.3390/ph5050514
Abstract
Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P1) plays an essential role in lymphocyte egress from secondary lymphoid organs (SLO), as evinced by the inability of lymphocytes to exit from the SLO in mice lacking lymphocytic S1P1. Fingolimod hydrochloride (FTY720) is a first-in-class, orally active, S1P receptor modulator with a structure closely related to sphingosine. FTY720 was first synthesized by chemical modification of a natural product, myriocin. FTY720 is effectively converted to an active metabolite, FTY720 phosphate (FTY720-P) by sphingosine kinases. FTY720-P shows high affinity to 4 of the S1P receptors (S1P1, S1P3, S1P4, and S1P5). In particular, FTY720-P strongly induces internalization and degradation of S1P1, inhibits S1P responsiveness of lymphocytes in the SLO, and acts as a functional antagonist at lymphocytic S1P1. Consequently, FTY720 inhibits S1P1-dependent lymphocyte egress from the SLO to decrease circulation of lymphocytes including autoreactive Th17 cells and is highly effective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Because FTY720 shows a superior efficacy in relapsing remitting MS patients compared to intramuscular interferon-β-1a (Avonex®), S1P1 is presumed to be a useful target for the therapy of MS.Keywords
This publication has 69 references indexed in Scilit:
- Temporal sequence learning in winner-take-all networks of spiking neurons demonstrated in a brain-based deviceFrontiers in Neurorobotics, 2013
- FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P 1 ) modulationProceedings of the National Academy of Sciences of the United States of America, 2010
- FTY720 (fingolimod) in Multiple Sclerosis: therapeutic effects in the immune and the central nervous systemBritish Journal of Pharmacology, 2009
- Large-scale model of mammalian thalamocortical systemsProceedings of the National Academy of Sciences of the United States of America, 2008
- Differential regulation of central nervous system autoimmunity by TH1 and TH17 cellsNature Medicine, 2008
- S1P1 Receptor Signaling Overrides Retention Mediated by Gαi-Coupled Receptors to Promote T Cell EgressImmunity, 2008
- Natural stimuli evoke dynamic sequences of states in sensory cortical ensemblesProceedings of the National Academy of Sciences of the United States of America, 2007
- CHEMOKINES, SPHINGOSINE-1-PHOSPHATE, AND CELL MIGRATION IN SECONDARY LYMPHOID ORGANSAnnual Review of Immunology, 2005
- Simple model of spiking neuronsIEEE Transactions on Neural Networks, 2003
- Parallel processing of serial movements in prefrontal cortexProceedings of the National Academy of Sciences of the United States of America, 2002