Abstract
Purpose: :
In diabetes, advanced glycation end-products and oxidative stress progressively damage retinal vasculature leading to vascular leakage, leukostasis, development of avascular hypoxic areas, and at a later stage, pre-retinal neovascularization. The kallikrein-kinin system has been proposed to play a role in the development of DR. In this study, we investigated the effect of FOV2304, a nonpeptide selective and potent kinin B1 receptor antagonist, on retinopathy of diabetic rats.
Methods: :
Type-1 diabetes was induced in Brown-Norway (BN) or Wistar (W) rats by streptozotocin (STZ). The distribution of B1 receptors in the retina was evaluated using a specific fluorescent ligand. Eye drops of FOV2304 (0.1 to 1%) were given twice a day, from day 7 to day 14, after STZ. At day 14, retinal vascular leakage, expression of components of inflammatory pathways, and leukocyte adhesion to the retinal vasculature were measured. Concentration of FOV2304 was determined in ocular tissues of the rabbit at different time-points following a single 30 µl eye drop of 2% FOV2304.
Results: :
B1 receptors were expressed in the retina of diabetic but not control rats. FOV2304 inhibited in a dose-dependent manner (0.1 to 1%) retinal vascular leakage with a maximal inhibitory effect of 60% and 100% in BN and W rats, respectively. Vascular leukostasis and expression of mRNA for iNOS, COX-2, B1R, ICAM-1, HIF-1alpha, IL-1beta, VEGF-A and VEGF-R2 were increased in the retina of diabetic rats and were normalized by FOV2304. Maximal concentration of FOV2304 into the rabbit retina was about 1 µM which is highly compatible with a pharmacological effect.
Conclusions: :
FOV2304, given as eye drops efficiently reduced the retinal inflammatory response associated with diabetes in rats. These data support the hypothesis that the kallikrein-kinin system is activated and detrimental in DR. In addition, we believe that FOV2304, which is currently in Phase 1 clinical trial, deserves further investigation as a treatment of DR.
Keywords: diabetic retinopathy • receptors • inflammation