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EFFECTS OF AGI-1096, A NOVEL ANTIOXIDANT COMPOUND WITH ANTI-INFLAMMATORY AND ANTIPROLIFERATIVE PROPERTIES, ON RODENT ALLOGRAFT ARTERIOSCLEROSIS

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)-&agr; and interleukin (IL)-1β 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 (%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.