Novel oxazolo-oxazole derivatives of FTY720 reduce endothelial cell permeability, immune cell chemotaxis and symptoms of experimental autoimmune encephalomyelitis in mice

Imeri, Faik; Fallegger, Daniel; Zivkovic, Aleksandra; Schwalm, Stephanie; Enzmann, Gaby; Blankenbach, Kira; Meyer zu Heringdorf, Dagmar; Homann, Thomas; Kleuser, Burkhard; Pfeilschifter, Josef; Engelhardt, Britta; Stark, Holger; Huwiler, Andrea (2014). Novel oxazolo-oxazole derivatives of FTY720 reduce endothelial cell permeability, immune cell chemotaxis and symptoms of experimental autoimmune encephalomyelitis in mice. Neuropharmacology, 85, pp. 314-327. Elsevier 10.1016/j.neuropharm.2014.05.012

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The immunomodulatory FTY720 (fingolimod) is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that acts by modulating sphingosine 1-phosphate (S1P) receptor signaling. In this study, we have developed and characterized two novel oxazolo-oxazole derivatives of FTY720, ST-968 and the oxy analog ST-1071, which require no preceding activating phosphorylation, and proved to be active in intact cells and triggered S1P1 and S1P3, but not S1P2, receptor internalization as a result of receptor activation. Functionally, ST-968 and ST-1071 acted similar to FTY720 to abrogate S1P-triggered chemotaxis of mouse splenocytes, mouse T cells and human U937 cells, and reduced TNFa- and LPS-stimulated endothelial cell permeability. The compounds also reduced TNFα-induced ICAM-1 and VCAM-1 mRNA expression, but restored TNFα-mediated downregulation of PECAM-1 mRNA expression. In an in vivo setting, the application of ST-968 or ST-1071 to mice resulted in a reduction of blood lymphocytes and significantly reduced the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice comparable to FTY720 either by prophylactic or therapeutic treatment. In parallel to the reduced clinical symptoms, infiltration of immune cells in the brain was strongly reduced, and in isolated tissues of brain and spinal cord, the mRNA and protein expressions of ICAM-1 and VCAM-1, as well as of matrix metalloproteinase-9 were reduced by all compounds, whereas PECAM-1 and tissue inhibitor of metalloproteinase TIMP-1 were upregulated. In summary, the data suggest that these novel butterfly derivatives of FTY720 could have considerable implication for future therapies of multiple sclerosis and other autoimmune diseases.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Theodor Kocher Institute
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Imeri, Faik; Fallegger, Daniel; Enzmann, Gaby; Engelhardt, Britta and Huwiler, Andrea

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0028-3908

Publisher:

Elsevier

Language:

German

Submitter:

Anita Dähler

Date Deposited:

19 Jan 2015 14:33

Last Modified:

11 Nov 2015 10:09

Publisher DOI:

10.1016/j.neuropharm.2014.05.012

PubMed ID:

24863045

BORIS DOI:

10.7892/boris.61977

URI:

https://boris.unibe.ch/id/eprint/61977

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