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

AbstractAIM:
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.
AuthorsLynn W Maines, Leo R Fitzpatrick, Cecelia L Green, Yan Zhuang, Charles D Smith
JournalInflammopharmacology (Inflammopharmacology) Vol. 18 Issue 2 Pg. 73-85 (Apr 2010) ISSN: 1568-5608 [Electronic] Switzerland
PMID20151210 (Publication Type: Journal Article)
Chemical References
  • Aminosalicylic Acids
  • Enzyme Inhibitors
  • Gastrointestinal Agents
  • Interleukin-1beta
  • Pyridines
  • Tumor Necrosis Factor-alpha
  • Trinitrobenzenesulfonic Acid
  • Prednisolone
  • 3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
  • Peroxidase
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Adamantane
  • olsalazine
Topics
  • Adamantane (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
  • Aminosalicylic Acids (administration & dosage, pharmacology, therapeutic use)
  • Animals
  • Body Weight (drug effects)
  • Colon (drug effects, enzymology, metabolism, pathology)
  • Crohn Disease (chemically induced, drug therapy, metabolism, pathology)
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Enzyme Inhibitors (pharmacology, therapeutic use)
  • Epithelial Cells (enzymology, metabolism)
  • Female
  • Gastrointestinal Agents (administration & dosage, pharmacology, therapeutic use)
  • Humans
  • Interleukin-1beta (metabolism)
  • Leukocytes (enzymology, metabolism)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neutrophils (enzymology, pathology)
  • Peroxidase (metabolism)
  • Phosphotransferases (Alcohol Group Acceptor) (antagonists & inhibitors, metabolism)
  • Prednisolone (administration & dosage, pharmacology, therapeutic use)
  • Pyridines (administration & dosage, pharmacology, therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Treatment Outcome
  • Trinitrobenzenesulfonic Acid (administration & dosage, pharmacology)
  • Tumor Necrosis Factor-alpha (metabolism)

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