A potent and selective inhibitor of group IIa secretory phospholipase A2 protects rats from TNBS-induced colitis.
Secretory phospholipase A(2) (sPLA(2)) 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 sPLA(2) enzyme (5-(4-benzyloxyphenyl)-4S-(7-phenylheptanoylamino)-pentanoic acid; sPLA(2)I), with that of sulfasalazine, in a rat model of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Following a single oral dose of sPLA(2)I (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 sPLA(2)I (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-alpha 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 sPLA(2)I, but exhibited no improvement in colon edema. This study supports a role for the group IIa sPLA(2) enzyme in pathology associated with the TNBS rat model of IBD, and suggests a possible therapeutic application for selective inhibitors of group IIa sPLA(2) inhibitors in the treatment of IBD.
Woodruff
Trent M
TM
School of Biomedical Sciences, Department of Physiology & Pharmacology, University of Queensland, Brisbane, QLD 4072, Australia.
Arumugam
Thiruma V
TV
Shiels
Ian A
IA
Newman
Michelle L
ML
Ross
Paul A
PA
Reid
Robert C
RC
Fairlie
David P
DP
Taylor
Stephen M
SM
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D054501:Group II Phospholipases A2; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000517:prevention & control; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000201:enzymology; D008070:Lipopolysaccharides / Q000633:toxicity; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D010421:Pentanoic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D051381:Rats; D017208:Rats, Wistar; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C503211:5-(4-benzyloxyphenyl)-4S-(7-phenylheptanoylamino)pentanoic acid; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D010421:Pentanoic Acids; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2