The effects of anti-VEGF and kinin B1 receptor blockade on retinal inflammation in laser-induced choroidal neovascularization.

Abstract

Age-related macular degeneration (AMD) is a complex neurodegenerative disease treated by anti-VEGF intravitreal injections. As inflammation is potentially involved in retinal degeneration, the pro-inflammatory kallikrein-kinin system is a possible alternative pharmacological target. Here, we investigated the effects of anti-VEGF and anti-B1 receptor treatments on the inflammatory mechanisms in a rat model of choroidal neovascularization (CNV). Immediately after laser-induced CNV, Long-Evans rats were treated by eye-drop application of a B1 receptor antagonist (R-954) or by intravitreal injection of B1 receptor siRNA or anti-VEGF antibodies. Effects of treatments on gene expression of inflammatory mediators, CNV lesion regression and integrity of the blood-retinal barrier was measured 10 days later in the retina. B1 receptor and VEGF-R2 cellular localization was assessed. The three treatments significantly inhibited the CNV-induced retinal changes. Anti-VEGF and R-954 decreased CNV-induced up-regulation of B1 and B2 receptors, TNF-α, and ICAM-1. Anti-VEGF additionally reversed up-regulation of VEGF-A, VEGF-R2, HIF-1α, CCL2 and VCAM-1, whereas R-954 inhibited gene expression of IL-1β and COX-2. Enhanced retinal vascular permeability was abolished by anti-VEGF and reduced by R-954 and B1 receptor siRNA treatments. Leukocyte adhesion was impaired by anti-VEGF and B1 receptor inhibition. B1 receptors were found on astrocytes and endothelial cells. B1 receptor and VEGF pathways were both involved in retinal inflammation and damage in laser-induced CNV. The non-invasive, self-administration of B1 receptor antagonists on the surface of the cornea by eye drops might be an important asset for the treatment of AMD.