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FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation.
Proc Natl Acad Sci U S A. 2011 Jan 11; 108(2):751-6.PN

Abstract

Sphingosine 1-phosphate (S1P), a lysophospholipid, has gained relevance to multiple sclerosis through the discovery of FTY720 (fingolimod), recently approved as an oral treatment for relapsing forms of multiple sclerosis. Its mechanism of action is thought to be immunological through an active phosphorylated metabolite, FTY720-P, that resembles S1P and alters lymphocyte trafficking through receptor subtype S1P(1). However, previously reported expression and in vitro studies of S1P receptors suggested that direct CNS effects of FTY720 might theoretically occur through receptor modulation on neurons and glia. To identify CNS cells functionally contributing to FTY720 activity, genetic approaches were combined with cellular and molecular analyses. These studies relied on the functional assessment, based on clinical score, of conditional null mouse mutants lacking S1P(1) in CNS cell lineages and challenged by experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. All conditional null mutants displayed WT lymphocyte trafficking that responded normally to FTY720. In marked contrast, EAE was attenuated and FTY720 efficacy was lost in CNS mutants lacking S1P(1) on GFAP-expressing astrocytes but not on neurons. In situ hybridization studies confirmed that astrocyte loss of S1P(1) was the key alteration in functionally affected mutants. Reductions in EAE clinical scores were paralleled by reductions in demyelination, axonal loss, and astrogliosis. Receptor rescue and pharmacological experiments supported the loss of S1P(1) on astrocytes through functional antagonism by FTY720-P as a primary FTY720 mechanism. These data identify nonimmunological CNS mechanisms of FTY720 efficacy and implicate S1P signaling pathways within the CNS as targets for multiple sclerosis therapies.

Authors+Show Affiliations

Department of Molecular Biology, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21177428

Citation

Choi, Ji Woong, et al. "FTY720 (fingolimod) Efficacy in an Animal Model of Multiple Sclerosis Requires Astrocyte Sphingosine 1-phosphate Receptor 1 (S1P1) Modulation." Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 2, 2011, pp. 751-6.
Choi JW, Gardell SE, Herr DR, et al. FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci USA. 2011;108(2):751-6.
Choi, J. W., Gardell, S. E., Herr, D. R., Rivera, R., Lee, C. W., Noguchi, K., Teo, S. T., Yung, Y. C., Lu, M., Kennedy, G., & Chun, J. (2011). FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proceedings of the National Academy of Sciences of the United States of America, 108(2), 751-6. https://doi.org/10.1073/pnas.1014154108
Choi JW, et al. FTY720 (fingolimod) Efficacy in an Animal Model of Multiple Sclerosis Requires Astrocyte Sphingosine 1-phosphate Receptor 1 (S1P1) Modulation. Proc Natl Acad Sci USA. 2011 Jan 11;108(2):751-6. PubMed PMID: 21177428.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. AU - Choi,Ji Woong, AU - Gardell,Shannon E, AU - Herr,Deron R, AU - Rivera,Richard, AU - Lee,Chang-Wook, AU - Noguchi,Kyoko, AU - Teo,Siew Teng, AU - Yung,Yun C, AU - Lu,Melissa, AU - Kennedy,Grace, AU - Chun,Jerold, Y1 - 2010/12/21/ PY - 2010/12/24/entrez PY - 2010/12/24/pubmed PY - 2011/2/25/medline SP - 751 EP - 6 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 108 IS - 2 N2 - Sphingosine 1-phosphate (S1P), a lysophospholipid, has gained relevance to multiple sclerosis through the discovery of FTY720 (fingolimod), recently approved as an oral treatment for relapsing forms of multiple sclerosis. Its mechanism of action is thought to be immunological through an active phosphorylated metabolite, FTY720-P, that resembles S1P and alters lymphocyte trafficking through receptor subtype S1P(1). However, previously reported expression and in vitro studies of S1P receptors suggested that direct CNS effects of FTY720 might theoretically occur through receptor modulation on neurons and glia. To identify CNS cells functionally contributing to FTY720 activity, genetic approaches were combined with cellular and molecular analyses. These studies relied on the functional assessment, based on clinical score, of conditional null mouse mutants lacking S1P(1) in CNS cell lineages and challenged by experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. All conditional null mutants displayed WT lymphocyte trafficking that responded normally to FTY720. In marked contrast, EAE was attenuated and FTY720 efficacy was lost in CNS mutants lacking S1P(1) on GFAP-expressing astrocytes but not on neurons. In situ hybridization studies confirmed that astrocyte loss of S1P(1) was the key alteration in functionally affected mutants. Reductions in EAE clinical scores were paralleled by reductions in demyelination, axonal loss, and astrogliosis. Receptor rescue and pharmacological experiments supported the loss of S1P(1) on astrocytes through functional antagonism by FTY720-P as a primary FTY720 mechanism. These data identify nonimmunological CNS mechanisms of FTY720 efficacy and implicate S1P signaling pathways within the CNS as targets for multiple sclerosis therapies. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/21177428/FTY720__fingolimod__efficacy_in_an_animal_model_of_multiple_sclerosis_requires_astrocyte_sphingosine_1_phosphate_receptor_1__S1P1__modulation_ DB - PRIME DP - Unbound Medicine ER -