Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn's disease

Lynn W. Maines, Leo R. Fitzpatrick, Cecelia L. Green, Yan Zhuang, Charles D. Smith

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57 Scopus citations

Abstract

Aim: Activation of sphingosine kinase (SK) is a key response to many inflammatory processes. The present studies test the hypothesis that an orally available SK inhibitor, ABC294640, would be effective in rodent models of Crohn's disease. Methods: Trinitrobenzene sulfonic acid (TNBS) was administered rectally to mice and rats. Rats were treated with ABC294640 orally alone or in combination with olsalazine and disease progression was monitored. Results: For both rodent species, treatment with ABC294640 attenuated disease progression. Colon samples from the ABC294640-treated animals had improved histology and cytokine parameters when compared with vehicle-treated animals. The expression of SK was similarly increased in TNBS-treated animals and in human colon tissue specimens from inflammatory bowel disease patients relative to normal, control patients. Conclusions: Sphingosine kinase may be a critical mediator of colonic damage during intestinal inflammation, and pharmacologic inhibitors of this enzyme may prove useful in the treatment of Crohn's disease.

Original languageEnglish (US)
Pages (from-to)73-85
Number of pages13
JournalInflammopharmacology
Volume18
Issue number2
DOIs
StatePublished - Apr 1 2010

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All Science Journal Classification (ASJC) codes

  • Immunology
  • Pharmacology
  • Pharmacology (medical)

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