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

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Evaluating Therapeutic Interventions in the SHIP-deficient Mouse Model of Crohn Disease-like Ileitis and Fibrosis
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Evaluating Therapeutic Interventions in the SHIP-deficient Mouse Model of Crohn Disease-like Ileitis and Fibrosis

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Lynn W Maines1, Leo R Fitzpatrick, Cecelia L Green

  • 1Apogee Biotechnology Corporation, Hershey Center for Applied Research, 1214 Research Blvd, Suite 1016, Hummelstown, PA 17036, USA. LWMaines@apogee-biotech.com

Inflammopharmacology
|February 13, 2010
PubMed
Abstract

Insights

An orally available sphingosine kinase (SK) inhibitor, ABC294640, effectively reduced inflammation and improved colon health in rodent models of Crohn's disease, suggesting therapeutic potential.

Area of Science:

  • Gastroenterology
  • Pharmacology
  • Inflammation Research

Background:

  • Sphingosine kinase (SK) activation is a critical inflammatory response.
  • SK plays a role in inflammatory processes relevant to Crohn's disease.

Purpose of the Study:

  • To evaluate the efficacy of ABC294640, an orally available SK inhibitor, in rodent models of Crohn's disease.
  • To test the hypothesis that inhibiting SK can ameliorate intestinal inflammation.

Main Methods:

  • Rodent models of Crohn's disease were induced using trinitrobenzene sulfonic acid (TNBS).
  • Animals were treated orally with ABC294640, alone or with olsalazine, and disease progression was monitored.
  • Histological and cytokine parameters in colon tissues were analyzed.

Main Results:

  • ABC294640 treatment significantly attenuated disease progression in both mice and rats.
  • Improved colon histology and cytokine profiles were observed in treated animals compared to controls.
  • Increased SK expression was noted in TNBS-treated animals and human inflammatory bowel disease tissues.

Conclusions:

  • Sphingosine kinase is implicated as a key mediator of colonic damage in intestinal inflammation.
  • Pharmacologic inhibition of SK, using agents like ABC294640, shows promise for treating Crohn's disease.

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