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

Abstract

Background and Purpose: 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 kallikreinkinin system is a possible alternative pharmacological target. Here, we investigated the effects of anti-VEGF and anti-B 1 receptor treatments on the inflammatory mechanisms in a rat model of choroidal neovascularization (CNV). Experimental Approach: Immediately after laser-induced CNV, Long-Evans rats were treated by eye-drop application of a B 1 receptor antagonist (R-954) or by intravitreal injection of B 1 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. B 1 receptor and VEGF-R2 cellular localization was assessed. Key Results: The three treatments significantly inhibited the CNV-induced retinal changes. Anti-VEGF and R-954 decreased CNV-induced up-regulation of B 1 and B 2 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 B 1 receptor siRNA treatments. Leukocyte adhesion was impaired by anti-VEGF and B 1 receptor inhibition. B 1 receptors were found on astrocytes and endothelial cells.Conclusion and Implications: B 1 receptor and VEGF pathways were both involved in retinal inflammation and damage in laser-induced CNV. The non-invasive, selfadministration of B 1 receptor antagonists on the surface of the cornea by eye drops might be an important asset for the treatment of AMD.

Kinins and Their Receptors as Potential Therapeutic Targets in Retinal Pathologies

“…B1R antagonism or deletion plays a protective role in inflammation, organ damage, and lethal thrombosis in septic shock in diabetes [53]; lipopolysaccharide (LPS) mediated acute renal inflammation [54]; renal ischemia-reperfusion injury [55]; and in cardiovascular [56] and retinal [57][58][59][60] inflammatory diseases. B1R inhibition reversed vascular [61] and retinal [58,60] inflammation induced by diabetes mellitus.…”

“…Similarly to other organs, the KKS in the eye is a double-edged sword, as it contributes to many physiological processes including blood-flow regulation and vascular tone control, but also partakes in the complex processes of inflammation [4,57,89]. It was reported that the KKS underlies a number of ocular pathologies (DR, AMD, choroidal neovascularization, macular edema) associated with inflammation and pathological neovascularization, particularly in the human and rat retina [57][58][59][60]69,[90][91][92][93]. For instance, PK and HK, by binding to the vascular endothelium, release BK and subsequently activate B2R, which plays a key role in the control of vascular tone [4].…”

Stem/progenitor cell-based transplantation for retinal degeneration: a review of clinical trials

“…Among them, ophthalmologic antioxidant cocktails (e.g., vitamins 21 , lutein and zeaxanthin 22 ) have been applied to protect retinal cells from oxidative damage, yet the therapeutic outcomes are unsatisfactory due to the unfriendly schedule and underlying biosafety concerns (such as potential risks of skin rashes 23 , haemorrhagic stroke 24 and lung cancer in cigarette smokers 25 ). Injection of anti-VEGF agents, including ranibizumab 26 , aflibercept 27 and bevacizumab 28 , which bind to the VEGF receptors to block VEGF, is mainly used to treat wet AMD 29 via inhibition of choroidal neovascularisation 30 . However, adverse reactions of the eyes (such as endophthalmitis, uveitis, retina split holes and vitreous haemorrhage) and systemic adverse reactions (such as hypertension, myocardial infarction and stroke) caused by frequent intravitreal injections and the high cost of treatment lead to poor patient compliance and compromised effectiveness 31 .…”

High Density Display of an Anti-Angiogenic Peptide on Micelle Surfaces Enhances Their Inhibition of αvβ3 Integrin-Mediated Neovascularization In Vitro

“…Anti-VEGF therapy is considered to be one of the most effective treatment options for DR and wet-AMD and is frequently used off label to treat ROP [11][12][13][14][15]. Current FDA approved anti-VEGF agents include bevacizumab, ranibizumab, and aflibercept, which are administered via monthly or bi-weekly intravitreal injections [14,[16][17][18].…”