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

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.

• Authors: Lynn W Maines, Leo R Fitzpatrick, Cecelia L Green, Yan Zhuang, Charles D Smith
• Journal: Inflammopharmacology (Inflammopharmacology) Vol. 18 Issue 2 Pg. 73-85 (Apr 2010) ISSN: 1568-5608 [Electronic] Switzerland
• PMID: 20151210 (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)