Abstract
Abstract: :
Purpose: VEGF is a potent vasopermeable and angiogenic factor that has been implicated in ischemic retinopathies. The breakdown of the blood-retinal barrier in early diabetic retinopathy may be due to increased levels of VEGF. In this study, we examine whether VEGF-induced retinal vascular leakage can be prevented in vivo by the oral VEGF receptor kinase inhibitor CEP-7055. Methods: Retinal vascular leakage in non-diabetic (ndm) and STZ-induced 2 week diabetic (dm) Sprague-Dawley rats was measured using the Evans Blue albumin permeation technique. Animals were treated with CEP-7055 acutely at 20 mg/kg or chronically for 5 days (10 mg/kg BID) by oral gavage. Controls were treated with vehicle alone (1% acetic acid/PBS). In the acute study, 10 uL of VEGF (25 ng/ml) or 0.1% BSA was injected into the vitreous of each eye after a 1 hour pretreatment gavage. Results: In the acute study, VEGF increased permeability in ndm (300±157%, n=5, p=0.048) and dm (225±144%, n=6, p=0.048) vehicle–treated rats as compared to the opposite eye. CEP-7055 treatment reduced VEGF induced leakage in ndm rats to 157±50% (n=7, p=0.031), representing a 68±29% inhibition. VEGF-induced leakage in CEP-7055 treated dm rats remained elevated (212±114%, n=8, p=0.01). No effect was observed on basal leakage of CEP-7055 treated dm and ndm rats as compared to vehicle-treated rats. In the chronic study, basal retinal leakage in dm vehicle-treated rats was increased 2-fold (4.4±2.1 vs 2.2±0.3 µL/g/hr, n=10, p=0.007) as compared to ndm rats. CEP-7055 treatment decreased basal leakage in dm rats by 87±36% (2.5±0.8, n=7, p=0.038). Conclusion: Chronic but not acute treatment with VEGF/R kinase inhibitor normalizes retinal vascular leakage in diabetic rats. Oral inhibition of VEGF action may be a useful therapeutic agent for the suppression of vascular permeability in many ocular disorders.
Keywords: 423 growth factors/growth factor receptors • 388 diabetic retinopathy • 316 animal model