Early Diabetes–induced Retinal Vascular Abnormalities Are Ameliorated By The Antioxidant Agix–4207 In Diabetic Rats

Abstract

Abstract: : Purpose: Hyperglycemia is associated with oxidant stress and upregulation of adhesion molecules and inflammatory cytokines that may contribute to the progression of diabetic retinopathy. AGIX–4207 is a novel phenolic antioxidant with anti–inflammatory properties. This study investigates whether AGIX–4207 can reduce redox–sensitive inflammatory gene expression and prevent retinal microvascular abnormalities in short–duration diabetic rats. Methods: Diabetes was induced by STZ (65 mg/kg) in Long Evans rats. At onset, non–diabetic (NDM) and diabetic (DM) rats received either vehicle or AGIX–4207 at 30mg/kg/d by oral gavage. After 16 days, retinal blood flow (RBF) was measured by video fluorescein angiography, leukostasis was assessed by acridine orange, and retinal vascular leakage (RVP) was measured using Evan’s blue albumin permeation. In a subset, retinal VCAM–1 mRNA expression was measured by quantitative real–time PCR. Results: In vitro, treatment of bovine retinal endothelial cells with AGIX–4207 resulted in a concentration–dependent reduction of intracellular reactive oxygen species and TNF–a–induced VCAM–1 mRNA. In vivo, DM+vehicle rats had decreased RBF (282±72 vs 397±40 au, p<0.001), increased leukostasis (5.1±2.8 vs 2.4±1.4 cells/pixel² x 10^–5, p<0.05), and increased RVP (27.0±10.2 vs 10.0±3.8 µl/g/h, p<0.05) as compared to NDM+vehicle. AGIX–4207 treatment inhibited the diabetes–induced abnormalities in RBF by 57±63% (347±73 au), leukostasis by 87±90% (3.1±2.4 cells/pixel² x 10^–5, p <0.05) and RVP by 69±28% (15.2±4.7 µl/g/h, p<0.05) as compared to vehicle controls. VCAM–1 mRNA expression increased 2.2 fold in DM vehicle rats as compared to control, an effect inhibited 76±95% by AGIX–4207 treatment. Conclusions: AGIX–4207 reduced intracellular ROS and VCAM–1 mRNA expression and partially normalized early diabetes–induced microvascular abnormalities. Treatment with antioxidants exhibiting these characteristics may delay or prevent the development of diabetic retinopathy.

Keywords: antioxidants • diabetic retinopathy • drug toxicity/drug effects