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

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

  • Transplantation. 2004 May 27;77(10):1494-500. doi: 10.1097/01.tp.0000123076.05313.9f.
Seiichiro Murata 1 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
Affiliations

Affiliation

  • 1 Department of Cardiothoracic Surgery, Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford, CA 94305, USA.
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.

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