Effects of AGI-1096, a novel antioxidant compound with anti-inflammatory and antiproliferative properties, on rodent allograft arteriosclerosis.

Abstract

BACKGROUND:

AGI-1096 is a novel phenolic intracellular antioxidant with anti-inflammatory and antiproliferative properties. In vitro, AGI-1096 inhibited the inducible expression of vascular cell adhesion molecule (VCAM)-1, E-selectin, and monocyte chemoattractant protein (MCP)-1 in endothelial cells and tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta secretion from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells. It also inhibited serum-stimulated proliferation of aortic smooth-muscle cells. In vivo, AGI-1096 demonstrated anti-inflammatory properties in a murine delayed-type hypersensitivity model. Given these antioxidant, anti-inflammatory and antiproliferative properties, we reasoned that AGI-1096 may be able to prevent chronic allograft arteriosclerosis. This hypothesis was tested in a rodent aortic transplantation model.

METHODS:

Donor descending aortas from August-Copenhagen-Irish rats were heterotopically transplanted into Lewis rat abdomens in end-to-end fashion. Animals were assigned to six groups as follows: AGI-1096 0 mg/kg per day (vehicle, n = 10), 10 mg/kg per day (n = 10), 20 mg/kg per day (n = 10), 40 mg/kg per day (n = 10), positive control (cyclosporine A 10 mg/kg per day by oral gavage, n = 10), and isograft negative control (Lewis-to-Lewis, n = 5). AGI-1096 was administrated subcutaneously to recipient animals three days before the surgery and for 90 days thereafter. On day 90, the paraffin-embedded allograft sections were stained with Elastin-van Gieson's stain, and the intima/media (I/M) ratio and luminal narrowing (1%LN) was assessed by digital morphometry.

RESULTS:

AGI-1096 demonstrated dose-dependent lowering of the I/M ratio and %LN when compared with vehicle controls.

CONCLUSION:

This is the first study to show that treatment of allograft recipients with AGI-1096 decreases the incidence of transplant arteriosclerosis. These data suggest that AGI-1096 may be a promising new therapeutic agent for use in clinical transplantation.

• Authors: Seiichiro Murata, Cynthia L Sundell, Maarten A Lijkwan, Leora B Balsam, Pekka Hammainen, Caroline Coleman, Chris York, Jayraz Luchoomun, Ki-Ling Suen, Randy Howard, Patricia K Somers, Randall E Morris, Robert C Robbins
• Journal: Transplantation (Transplantation) Vol. 77 Issue 10 Pg. 1494-500 (May 27 2004) ISSN: 0041-1337 [Print] United States
• PMID: 15239610 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Antioxidants
• Butyrates
• Cytokines
• Inflammation Mediators
• Phenols
• elsibucol

Topics

• Animals
• Anti-Inflammatory Agents (administration & dosage, chemistry)
• Antioxidants (administration & dosage, chemistry)
• Aorta (cytology, pathology, transplantation)
• Arteriosclerosis (pathology, prevention & control)
• Butyrates (administration & dosage, chemistry)
• Cell Division (drug effects)
• Cells, Cultured
• Cytokines (genetics)
• Dose-Response Relationship, Drug
• Gene Expression (drug effects)
• Humans
• Inflammation Mediators (metabolism)
• Mice
• Mice, Inbred BALB C
• Muscle, Smooth, Vascular (cytology)
• Myocytes, Smooth Muscle (cytology)
• Phenols (administration & dosage, chemistry)
• Pulmonary Artery (cytology)
• Rats
• Rats, Inbred Strains
• Transplantation, Homologous