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.
MeSH terms
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Adamantane / administration & dosage
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Adamantane / analogs & derivatives
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Adamantane / pharmacology
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Adamantane / therapeutic use
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Aminosalicylic Acids / administration & dosage
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Aminosalicylic Acids / pharmacology
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Aminosalicylic Acids / therapeutic use
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Animals
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Body Weight / drug effects
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Colon / drug effects
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Colon / enzymology
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Colon / metabolism
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Colon / pathology
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Crohn Disease / chemically induced*
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Crohn Disease / drug therapy*
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Crohn Disease / metabolism
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Crohn Disease / pathology
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Disease Models, Animal
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Drug Therapy, Combination
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use*
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Epithelial Cells / enzymology
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Epithelial Cells / metabolism
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Female
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Gastrointestinal Agents / administration & dosage
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Gastrointestinal Agents / pharmacology
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Gastrointestinal Agents / therapeutic use
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Humans
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Interleukin-1beta / metabolism
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Leukocytes / enzymology
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Leukocytes / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Neutrophils / enzymology
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Neutrophils / pathology
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Peroxidase / metabolism
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors*
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Phosphotransferases (Alcohol Group Acceptor) / metabolism
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Prednisolone / administration & dosage
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Prednisolone / pharmacology
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Prednisolone / therapeutic use
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Pyridines / administration & dosage
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Pyridines / pharmacology
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Pyridines / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Treatment Outcome
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Trinitrobenzenesulfonic Acid / administration & dosage
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Trinitrobenzenesulfonic Acid / pharmacology
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Aminosalicylic Acids
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Enzyme Inhibitors
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Gastrointestinal Agents
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Interleukin-1beta
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Pyridines
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Tumor Necrosis Factor-alpha
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Trinitrobenzenesulfonic Acid
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Prednisolone
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3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide
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Peroxidase
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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Adamantane
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olsalazine