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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.

journal_name

Transplantation

journal_title

Transplantation

authors

Murata S,Sundell CL,Lijkwan MA,Balsam LB,Hammainen P,Coleman C,York C,Luchoomun J,Suen KL,Howard R,Somers PK,Morris RE,Robbins RC

doi

10.1097/01.tp.0000123076.05313.9f

subject

Has Abstract

pub_date

2004-05-27 00:00:00

pages

1494-500

issue

eissn

0041-1337

issn

1534-6080

journal_volume

pub_type

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