Abstract
Purpose: :
Study the inhibitory effects of an angiostatic corticosteroid (Dexamethasone) and a LMW VEGFR2 tyrosine kinase inhibitor (PTK787) on angiogenesis in mouse and rat laser-induced CNV models by oral and intravitreal administration of compound.
Methods: :
Choroidal angiogenesis in murine or rat laser-induced CNV models was induced in 8-week old C57/bl6 female mice or 200g male Brown Norway rats by laser injury. The laser (Iridex Oculight® GLx 532nm green laser) was applied at three locations for mice and four locations for the rats. Eyes were studied at 7 days and 12 days post laser for mouse and rat, respectively. Dexamethasone or PTK787 were administrated orally 1-hour prior to the laser injury and then once daily. In separate experiments, IVT injections were administered immediately after laser, with rats receiving a second IVT injection on Day 6. On the day of euthanasia, mice or rats were injected IV with FITC concanavalin A or FITC dextran, respectively. To mask the data in efficacy studies, the microscope slides were labeled with randomized numbers. The RPE-choroid-scleral complexes were isolated and then mounted on a microscope slide with a cover slip and mounting medium. Fluorescent images of each CNV induced by the laser were captured using an Axiocam MR3 camera on an Axio.Image M1 microscope and CNV lesion size was quantified with Axiovision software (Version 4.5 Zeiss). Inter-group differences were analyzed by one-way analysis of variance (ANOVA) with a Neuman-keuls post hoc analysis.PTK787 was dosed orally at 10, 30, 50, 100 and 150 mg/kg and IVT at a concentration of 0.12mg/ml in PEG 300. Dexamethasone was orally dosed at 0.03, 0.3 and 3.0 mg/kg and IVT at a concentration of 3 and 10mg/ml in CMC. 10 rodents were used for each vehicle or efficacy group.
Results: :
In efficacy studies oral PTK787 had an ED50 of 63.7 mg/kg in mice and 69.3 mg/kg in rats while IVT PTK787 was not efficacious. Oral dexamethasone achieved an ED30 at 3.0mg/kg in mice. IVT injected dexamethasone at 10mg/ml-inhibited CNV 54% in mice and 59% in rats.
Conclusions: :
The effects of compound administration on CNV can be determined by using PTK787 and Dexamethasone as positive controls for systemic administration in both mouse and rat laser-induced CNV model. Dexamethasone can be used positive control for IVT administration in rodent CNV models.
Keywords: choroid: neovascularization • laser