Differential Effects of the Glucocorticoid Dexamethasone and the COX–2 Inhibitor NS–398 in a Mouse Model of Laser–Induced Choroidal Neovascularization.

Abstract

Abstract: : Purpose: The current study examined the effects of the cyclooxygenase (COX)–2–selective non–steroidal anti–inflammatory drug (NSAID), NS–398, and the glucocorticoid, dexamethasone (DEX), in a mouse model of laser–induced choroidal neovascularization (CNV). In addition, the role of two inflammatory proteins was evaluated in the same model using mice homozygous for either the targeted disruption of intracellular adhesion molecule–1 (ICAM–1) or the type 1 interleukin–1 receptor (IL1R1). Methods: Choroidal neovascular lesions were induced in mice by laser photoablation of two distinct areas, one temporal and one nasal to the optic nerve head. Optimal results were obtained with a Zeiss diode laser and settings of 80mW power, for 100 ms, with a spot diameter of 100 µm. Fourteen days after laser injury, mice were euthanized and perfused via the left ventricle with 10 mg/ml high molecular weight FITC–dextran. RPE–choroid–sclera was flat–mounted and the lesions were imaged with fluorescence microscopy. During pharmacology studies, C57BL/6 mice received either subcutaneous (s.c.) DEX at 5 and 20 mg/kg/day, or NS–398 at 10 and 20 mg/kg/day. Control mice received vehicle alone (s.c.). In transgenic studies, wild–type mice of the same gender were used as controls. Results: Compared to vehicle, DEX at 5 and 20 mg/kg/day, dose–dependently inhibited laser–induced CNV by 60% (p=0.001) and 91% (p<0.00001), respectively. The estimated ED₅₀ for subcutaneous DEX is 3.4 mg/kg/day. In contrast, the selective COX–2 inhibitor, NS–398, failed to inhibit CNV at either dose. In an independent study, partial inhibition was observed in mice lacking pro–inflammatory proteins. A null mutation in the type 1 IL–1 receptor resulted in 30% less CNV (p=0.059), whereas a targeted mutation of cell surface ICAM–1 expression resulted in 49% less CNV (p=0.001). Conclusions: Dexamethasone treatment resulted in a dose–dependent and near complete inhibition of experimental CNV in mice. However, the COX–2–selective NSAID, NS–398, was ineffective. The mechanisms underlying dexamethasone’s anti–angiogenic effect are unclear, but they may involve modulation of inflammatory mediators such as IL–1 and ICAM–1.

Keywords: choroid: neovascularization • corticosteroids • pharmacology