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.
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Acknowledgments
We thank Dr. Walter Koltun (Department of Surgery) of the Penn State College of Medicine for providing the human tissue samples.
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Maines, L.W., Fitzpatrick, L.R., Green, C.L. et al. Efficacy of a novel sphingosine kinase inhibitor in experimental Crohn’s disease. Inflammopharmacol 18, 73–85 (2010). https://doi.org/10.1007/s10787-010-0032-x
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DOI: https://doi.org/10.1007/s10787-010-0032-x