Efficacy and immunomodulatory actions of ONO-4641, a novel selective agonist for sphingosine 1-phosphate receptors 1 and 5, in preclinical models of multiple sclerosis
| Autor: | H Hagiya, H Shioya, R Kozaki, M Imai, M Kurono, T Komiya, H Habashita, R Suzuki, Y Inagaki, S Nakade, Kazuhisa Sato, Y Takada, H Kurata, K Otsuki, T Maeda |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Agonist
Encephalomyelitis Autoimmune Experimental Multiple Sclerosis medicine.drug_class Encephalomyelitis Sphingosine-1-phosphate receptor Immunology Down-Regulation Biology chemistry.chemical_compound Mice Mice Inbred NOD medicine Immunology and Allergy Animals Immunologic Factors Sphingosine-1-phosphate Lymphocyte Count Lymphocytes Receptor Sphingosine Multiple sclerosis Experimental autoimmune encephalomyelitis Original Articles medicine.disease Rats Disease Models Animal Receptors Lysosphingolipid chemistry Spinal Cord Rats Inbred Lew Female |
| Popis: | Summary ONO-4641 is a next-generation sphingosine 1-phosphate (S1P) receptor agonist selective for S1P receptors 1 and 5. The objective of the study was to characterize the immunomodulatory effects of ONO-4641 using preclinical data. ONO-4641 was tested in both in-vitro pharmacological studies as well as in-vivo models of transient or relapsing–remitting experimental autoimmune encephalomyelitis (EAE). In vitro, ONO-4641 showed highly potent agonistic activities versus S1P receptors 1 and 5 [half maximal effective concentration (EC50) values of 0·0273 and 0·334 nM, respectively], and had profound S1P receptor 1 down-regulating effects on the cell membrane. ONO-4641 decreased peripheral blood lymphocyte counts in rats by inhibiting lymphocyte egress from secondary lymphoid tissues. In a rat experimental autoimmune encephalomyelitis (EAE) model, ONO-4641 suppressed the onset of disease and inhibited lymphocyte infiltration into the spinal cord in a dose-dependent manner at doses of 0·03 and 0·1 mg/kg. Furthermore, ONO-4641 prevented relapse of disease in a non-obese diabetic mouse model of relapsing-remitting EAE. These observations suggest that ONO-4641 may provide therapeutic benefits in the treatment of multiple sclerosis. |
| Databáze: | OpenAIRE |
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