A potent and selective inhibitor of group IIa secretory phospholipase A2 protects rats from TNBS-induced colitis

Woodruff, Trent M., Arumugam, Thiruma V., Shiels, Ian A., Newman, Michelle L., Ross, Paul A., Reid, Robert C., Fairlie, David P. and Taylor, Stephen M. (2005) A potent and selective inhibitor of group IIa secretory phospholipase A2 protects rats from TNBS-induced colitis. International Immunopharmacology, 5 5: 883-892.


Author Woodruff, Trent M.
Arumugam, Thiruma V.
Shiels, Ian A.
Newman, Michelle L.
Ross, Paul A.
Reid, Robert C.
Fairlie, David P.
Taylor, Stephen M.
Title A potent and selective inhibitor of group IIa secretory phospholipase A2 protects rats from TNBS-induced colitis
Formatted title A potent and selective inhibitor of group IIa secretory phospholipase A2 protects rats from TNBS-induced colitis
Journal name International Immunopharmacology   Check publisher's open access policy
ISSN 1567-5769
1878-1705
Publication date 2005-05
Sub-type Article (original research)
DOI 10.1016/j.intimp.2005.01.003
Volume 5
Issue 5
Start page 883
End page 892
Total pages 10
Place of publication Amsterdam, The Netherlands
Publisher Elsevier Science
Collection year 2005
Language eng
Subject C1
730399 Health and support services not elsewhere classified
279999 Biological Sciences not elsewhere classified
780103 Chemical sciences
320503 Clinical Pharmacology and Therapeutics
1115 Pharmacology and Pharmaceutical Sciences
Formatted abstract Secretory phospholipase A2 (sPLA2) enzymes have been implicated in the pathogenesis of human inflammatory bowel disease (IBD). In this study we compared the efficacy of a potent, new and highly selective inhibitor of group IIa human sPLA2 enzyme (5-(4-benzyloxyphenyl)-4S-(7-phenylheptanoylamino)-pentanoic acid; sPLA2I), with that of sulfasalazine, in a rat model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Following a single oral dose of sPLA2I (5 mg/kg), pharmacoactive levels of drug were detected in the serum within 15 min and for up to 24 h by liquid chromatography mass spectrometry analysis. Rats treated with sPLA2I (5 mg/kg/day) prior to induction of colitis were significantly healthier than TNBS-alone rats, as shown by reduced mortality, improved food intake and increased body weight, and significantly reduced colon myeloperoxidase levels, edema, tumour necrosis factor-a levels, and colon macroscopic pathology scores after 8 days. Rats pretreated with sulfasalazine (100 mg/kg/day) also had reduced disease expression markers similar to the sPLA2I, but exhibited no improvement in colon edema. This study supports a role for the group IIa sPLA2 enzyme in pathology associated with the TNBS rat model of IBD, and suggests a possible therapeutic application for selective inhibitors of group IIa sPLA2 inhibitors in the treatment of IBD.
(c) 2005 Elsevier B.V All rights reserved.
Keyword Inflammatory Bowel Disease
Phospholipase A(2)
Rat
Tumour Necrosis Factor-alpha
Inflammatory-bowel-disease
C5a Receptor Antagonist
Ulcerative-colitis
Crohns-disease
Gene-expression
Colonic-mucosa
Mediators
Serum
Neutropenia
Intestine
Immunology
Pharmacology & Pharmacy
Q-Index Code C1

 
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