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Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis
Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P(1)) plays an essential role in lymphocyte egress from secondary lymphoid organs (SLO), as evinced by the inability of lymp...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2012
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763654/ https://www.ncbi.nlm.nih.gov/pubmed/24281561 http://dx.doi.org/10.3390/ph5050514 |
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author | Chiba, Kenji Adachi, Kunitomo |
author_facet | Chiba, Kenji Adachi, Kunitomo |
author_sort | Chiba, Kenji |
collection | PubMed |
description | Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P(1)) 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 S1P(1). 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 (S1P(1), S1P(3), S1P(4), and S1P(5)). In particular, FTY720-P strongly induces internalization and degradation of S1P(1), inhibits S1P responsiveness of lymphocytes in the SLO, and acts as a functional antagonist at lymphocytic S1P(1). Consequently, FTY720 inhibits S1P(1)-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(®)), S1P(1) is presumed to be a useful target for the therapy of MS. |
format | Online Article Text |
id | pubmed-3763654 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-37636542013-11-14 Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis Chiba, Kenji Adachi, Kunitomo Pharmaceuticals (Basel) Review Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P(1)) 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 S1P(1). 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 (S1P(1), S1P(3), S1P(4), and S1P(5)). In particular, FTY720-P strongly induces internalization and degradation of S1P(1), inhibits S1P responsiveness of lymphocytes in the SLO, and acts as a functional antagonist at lymphocytic S1P(1). Consequently, FTY720 inhibits S1P(1)-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(®)), S1P(1) is presumed to be a useful target for the therapy of MS. MDPI 2012-05-18 /pmc/articles/PMC3763654/ /pubmed/24281561 http://dx.doi.org/10.3390/ph5050514 Text en © 2012 by the authors; licensee MDPI, Basel, Switzerland. http://creativecommons.org/licenses/by/3.0/ This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/). |
spellingShingle | Review Chiba, Kenji Adachi, Kunitomo Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis |
title | Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis |
title_full | Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis |
title_fullStr | Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis |
title_full_unstemmed | Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis |
title_short | Sphingosine 1-Phosphate Receptor 1 as a Useful Target for Treatment of Multiple Sclerosis |
title_sort | sphingosine 1-phosphate receptor 1 as a useful target for treatment of multiple sclerosis |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3763654/ https://www.ncbi.nlm.nih.gov/pubmed/24281561 http://dx.doi.org/10.3390/ph5050514 |
work_keys_str_mv | AT chibakenji sphingosine1phosphatereceptor1asausefultargetfortreatmentofmultiplesclerosis AT adachikunitomo sphingosine1phosphatereceptor1asausefultargetfortreatmentofmultiplesclerosis |