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Novel oxazolo-oxazole derivatives of FTY720 reduce endothelial cell permeability, immune cell chemotaxis and symptoms of experimental autoimmune encephalomyelitis in mice
- Source :
- Neuropharmacology. 85:314-327
- Publication Year :
- 2014
- Publisher :
- Elsevier BV, 2014.
-
Abstract
- 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 S1P(1) and S1P(3), but not S1P(2), 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 TNF alpha-induced ICAM-1 and VCAM-1 mRNA expression, but restored TNF alpha-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. (C) 2014 Elsevier Ltd. All rights reserved.
- Subjects :
- Cell Membrane Permeability
Encephalomyelitis, Autoimmune, Experimental
T-Lymphocytes
CHO Cells
Biology
Cell Line
Mice
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Cricetulus
Immune system
Sphingosine
medicine
Animals
Humans
Lymphocytes
Sphingosine-1-phosphate
Oxazoles
Cells, Cultured
Pharmacology
ICAM-1
Fingolimod Hydrochloride
Chemotaxis
Experimental autoimmune encephalomyelitis
Endothelial Cells
U937 Cells
medicine.disease
Fingolimod
3. Good health
Mice, Inbred C57BL
Endothelial stem cell
Receptors, Lysosphingolipid
chemistry
Propylene Glycols
Immunology
Cancer research
Female
Institut für Ernährungswissenschaft
Tumor necrosis factor alpha
Immunosuppressive Agents
medicine.drug
Subjects
Details
- ISSN :
- 00283908
- Volume :
- 85
- Database :
- OpenAIRE
- Journal :
- Neuropharmacology
- Accession number :
- edsair.doi.dedup.....fdcecb56a5f5db445d9609c87f8e612c