Abstract
Purpose: :
Vascular endothelial growth factor (VEGF) has emerged as a key mediator of blood retinal barrier (BRB) breakdown and choroidal neovascularization (CNV) formation. The α2 adrenergic receptor agonist, Brimonidine (BRI) has been shown to significantly attenuate retinal VEGF protein level (1). The objective of this study was to investigate whether BRI could inhibit hyperglycemia-induced BRB breakdown and laser-induced CNV formation in the rats.
Methods: :
Rats were treated with a single IV injection of vehicle (VEH) or streptozotocin, STZ (65 mg/kg) to induce diabetes. One or six wks following treatment, animals were further treated with VEH or BRI (1 mg/kg/day) for another 4 wks using mini-osmotic pumps. At the end, vitreoretinal VEGF protein & glutamate levels and retinal BRB breakdown were measured in different groups of rats. CNV formation in rats was induced using laser energy to disrupt Bruch's membrane. Rats were treated with VEH, BRI (1 mg/kg/day, systemic using mini-osmotic pumps or one drop of 0.15% BRI, BID, topical) or Memantine, MEM (NMDA receptor antagonist, 10 mg/kg/day, systemic using mini-pumps) at different times before (1h-3d) or after (1h) laser injury. The treatment was continued till CNV assay at 11 days after laser.
Results: :
The diabetic rats demonstrated significantly elevated vitreoretinal VEGF & glutamate levels and retinal BRB leakage compared to VEH treated non-diabetic control rats. Without affecting vitreal glutamate, chronic BRI treatment brought elevated retinal VEGF and BRB breakdown of diabetic animals similar to levels observed in controls. BRI also significantly reduced BRB breakdown and VEGF in aged diabetic rats. Both topical and systemic treatment with BRI markedly inhibited CNV in rats. Lesions from BRI treated animals showed significantly less area compared to non-treated rats. MEM also significantly inhibited laser induced CNV formation in rats.
Conclusions: :
BRI mediated marked inhibition of retinal BRB breakdown in diabetic rats and CNV formation in laser treated rats could be through attenuation of retinal NMDA receptor activity since BRI did not affect vitreal glutamate and MEM significantly decreased ocular VEGF and BRB leakage (2) and CNV formation. Decreased retinal NMDA receptor activity might decrease VEGF through attenuation of Ca++ and PKC. These results indicate that BRI could be useful for treatment of ocular diseases including diabetic retinopathy and age-related macular degeneration with elevated BRB leakage and CNV, respectively.1. Kusari, et. al. Program # 5893, ARVO, 20062. Kusari, et. al. IOVS 48, 5152, 2007
Keywords: choroid: neovascularization • diabetic retinopathy • drug toxicity/drug effects