Document Detail


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.
MedLine Citation:
PMID:  23199323     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 (EC(50) ) 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.
Authors:
T Komiya; K Sato; H Shioya; Y Inagaki; H Hagiya; R Kozaki; M Imai; Y Takada; T Maeda; H Kurata; M Kurono; R Suzuki; K Otsuki; H Habashita; S Nakade
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Clinical and experimental immunology     Volume:  171     ISSN:  1365-2249     ISO Abbreviation:  Clin. Exp. Immunol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-03     Completed Date:  2013-02-19     Revised Date:  2014-01-10    
Medline Journal Info:
Nlm Unique ID:  0057202     Medline TA:  Clin Exp Immunol     Country:  England    
Other Details:
Languages:  eng     Pagination:  54-62     Citation Subset:  IM    
Copyright Information:
© 2012 ONO Pharmaceutical Co., Ltd Clinical and Experimental Immunology © 2012 British Society for Immunology.
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MeSH Terms
Descriptor/Qualifier:
Animals
Disease Models, Animal
Down-Regulation / drug effects
Encephalomyelitis, Autoimmune, Experimental / drug therapy*
Female
Immunologic Factors / therapeutic use*
Lymphocyte Count
Lymphocytes / drug effects
Mice
Mice, Inbred NOD
Multiple Sclerosis / drug therapy*
Rats
Rats, Inbred Lew
Receptors, Lysosphingolipid / agonists*
Spinal Cord / drug effects
Chemical
Reg. No./Substance:
0/Immunologic Factors; 0/Receptors, Lysosphingolipid
Comments/Corrections

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