Effects of PKF242-484 and PKF241-466, novel dual inhibitors of TNF-alpha converting enzyme and matrix metalloproteinases, in a model of intestinal reperfusion injury in mice.

Abstract

Tumor necrosis factor (TNF)-alpha plays an important role in the mediation of reperfusion-induced tissue injury and lethality. Here, we assessed the effects of PKF242-484 and PKF241-466, two dual inhibitors of TNF-alpha converting enzyme (TACE) and matrix metalloproteinases (MMPs), in a model of ischemia and reperfusion injury in mice. Reperfused animals that received PKF242-484 or PKF241-466 treatment had a dose-dependent reduction of TNF-alpha concentrations in serum. Both drugs delayed and partially inhibited the reperfusion-associated lethality. Maximal inhibition occurred at 10 mg/kg. At this dose, both inhibitors reduced reperfusion-associated local and remote tissue injury, as assessed by changes in vascular permeability, neutrophil recruitment and hemorrhage. In addition, the compounds markedly reduced production of TNF-alpha, CXCL1 (keratinocyte-derived chemokine, KC) and CCL2 (monocyte chemoattractant protein-1, MCP-1) in intestine and lungs of animals which underwent reperfusion. FN-439, an inhibitor of MMPs which possesses no effect on TACE, decreased MMP-2 and MMP-3 activity, but failed to affect tissue injury, TNF-alpha production or lethality. Thus, combined TACE and MMP inhibitors might be effective co-adjuvants in treatments of injuries that follow reperfusion of an ischemic vascular territory. The effects of these drugs on TNF-alpha production appear to be more relevant than their effects on MMP inhibition.

• Authors: Danielle G Souza, Flávio Lopes Ferreira, Caio T Fagundes, Flávio A Amaral, Angélica T Vieira, Rodolfo Assis Lisboa, Marcus Vinícius Melo Andrade, Alexandre Trifilieff, Mauro M Teixeira
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 571 Issue 1 Pg. 72-80 (Sep 24 2007) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17619015 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-aminobenzoyl-glycyl-prolyl-leucyl-alanine hydroxamic acid
• Chemokines
• Cytokines
• Hydroxamic Acids
• Matrix Metalloproteinase Inhibitors
• N(4)-(2,2-dimethyl-1-methylcarbamoylpropyl)-N(1)-hydroxy-2-hydroxymethyl-3-(4-methoxyphenyl)succinamide
• N(4)-(2,2-dimethyl-1-methylcarbamoylpropyl)-N(1)-hydroxy-2-hydroxymethyl-3-phenylsuccinamide
• Oligopeptides
• Tumor Necrosis Factor-alpha
• Interleukin-10
• ADAM Proteins
• Matrix Metalloproteinases
• ADAM17 Protein
• Adam17 protein, mouse

Topics

• ADAM Proteins (antagonists & inhibitors, metabolism)
• ADAM17 Protein
• Animals
• Capillary Permeability (drug effects)
• Chemokines (blood, metabolism)
• Cytokines (blood, metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme-Linked Immunosorbent Assay
• Hydroxamic Acids (administration & dosage, pharmacology)
• Interleukin-10 (blood, metabolism)
• Intestinal Mucosa (metabolism)
• Intestines (blood supply, drug effects)
• Lung (drug effects, metabolism, pathology)
• Male
• Matrix Metalloproteinase Inhibitors
• Matrix Metalloproteinases (metabolism)
• Mice
• Mice, Inbred C57BL
• Oligopeptides (administration & dosage, pharmacology)
• Reperfusion Injury (metabolism, mortality, prevention & control)
• Survival Rate
• Tumor Necrosis Factor-alpha (blood, metabolism)