Anti-inflammatory action of a novel orally available peptide 317 in mouse models of inflammatory bowel diseases.

Abstract

BACKGROUND:

The endogenous opioid system constitutes an attractive target in the treatment of GI disorders, including inflammatory bowel diseases (IBD). The aim of our study was to characterize the anti-inflammatory and antinociceptive effect of P-317, a novel cyclic analog of opioid peptide morphiceptin, in animal models of IBD.

METHODS:

The anti-inflammatory effect of P-317 after intraperitoneal (ip) and oral (po) administration was assessed in two mouse models of IBD - Crohn's disease, induced by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS) and ulcerative colitis, induced by addition of dextran sodium sulfate (DSS) into drinking water. The antinociceptive action of P-317 was characterized in mice with acute colitis using mustard oil-induced pain test. Real time RT PCR was used to assess semiquantitatively the expression of IL-1β and TNF-α mRNA in mouse colonic samples. To translate our results to clinical conditions, MOP and KOP mRNA were quantified in human colonic biopsies from IBD patients.

RESULTS:

P-317 (0.1mg/kg, ip and 1mg/kg, po) alleviated colonic inflammation in TNBS- and DSS-treated mice in the opioid receptor-dependent manner. The anti-inflammatory effect of P-317 was associated with the decrease in mRNA expression of proinflammatory cytokines. The antinociceptive effect of P-317 was observed after ip and po administration in mice with acute colitis.

CONCLUSION:

Our results show a potent anti-inflammatory and antinociceptive effect of P-317 in mouse models of colitis upon activation of opioid receptors. The unique bioavailability of P-317 after oral administration suggests that it is a promising drug candidate for future treatment of IBD.

• Authors: Marta Sobczak, Piotr K Zakrzewski, Adam I Cygankiewicz, Anna Mokrowiecka, Chunqiu Chen, Maciej Sałaga, Ewa Małecka-Panas, Radzisław Kordek, Wanda M Krajewska, Jakub Fichna
• Journal: Pharmacological reports : PR (Pharmacol Rep) Vol. 66 Issue 5 Pg. 741-50 (Oct 2014) ISSN: 2299-5684 [Electronic] Switzerland
• PMID: 25149976 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Chemical References

• 2',6'-dimethyltyrosyl-cyclo(lysyl-phenylalanyl-prolyl-aspartyl)amide
• Analgesics
• Anti-Inflammatory Agents
• Cytokines
• Peptides, Cyclic
• Tumor Necrosis Factor-alpha
• Trinitrobenzenesulfonic Acid
• Dextran Sulfate

Topics

• Administration, Oral
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Analgesics (administration & dosage, pharmacokinetics, pharmacology)
• Animals
• Anti-Inflammatory Agents (administration & dosage, pharmacokinetics, pharmacology)
• Biological Availability
• Case-Control Studies
• Colitis, Ulcerative (drug therapy, physiopathology)
• Crohn Disease (drug therapy, physiopathology)
• Cytokines (metabolism)
• Dextran Sulfate (toxicity)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Middle Aged
• Peptides, Cyclic (administration & dosage, pharmacokinetics, pharmacology)
• Real-Time Polymerase Chain Reaction
• Trinitrobenzenesulfonic Acid (toxicity)
• Tumor Necrosis Factor-alpha (metabolism)
• Young Adult