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Tamar Leibovitch, moshe ben hemo, Myles Brookman, Orit Barinfeld, Orkun Muhsinoglu, Shalom Michowiz, Nitza Goldenberg-Cohen; Effect of a single injection of anti-VEGF agent on retinal edema in non-obese diabetic mice. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4041.
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The aims of the study were to characterize the retinal changes in a mouse model of diabetic retinopathy and to evaluate the response of the retinal edema to a single injection of anti-VEGF-A agent.
96 transgenic NOD mice were monitored. Diabetes type 1 (blood glucose levels>250mg/dl) developed spontaneously in 30 (DMT1-NOD group) and was chemically induced in 28 (STZ-NOD group); the remainder served as controls. Mice were examined after the appearance of uncontrolled high glucose levels (>500mg/dl). Retinal blood flow and leakage were evaluated with fluorescein angiography (FA); vascular perfusion, with retinal flat mounts following infusion of India ink or fluorescent gelatin; gliosis and vasculopathy, with Vimentin and GFAP immunostaining; retinal thickness with light microscopy; and expression of genes involved in ischemia (SOD-1, HO-1), angiogenesis (VEGF-A, VEGFR-1, -2), gliosis (GFAP, Vimentin), and diabetes (RAGE, IGF-1, EPO), with RT-PCR. To test the effect of anti-VEGF treatment, the right eyes of STZ-NOD mice were evaluated histologically one week after injection of bevacizumab, ranibizumab, or saline or no treatment.
In the first part of the study, the diabetic mice showed no neovascularization (NVE) on FA. Flat mount show microaneurysms and attenuated retinal vessels, and apparent tufts of NVE in a single retina. Immunostaining revealed reactive gliosis and prominent Muller cells. Mean retinal thickness was significantly higher in the DMT1-NOD mice than the nondiabetic mice. Of all genes evaluated, only GFAP decreased significantly (0.5-fold, p=0.04). Anti-VEGF treatment led to complete suppression of gliosis with retinal thinning. Bevacizumab (retinal thickness 260±53mm right eye Vs. 241±34mm left eye) appeared to be more effective than ranibizumab (267.5±47mm right eye Vs 223+39mm left eye).
In conclusion, the retinas of DMT1-NOD mice are characterized by vasculopathy and edema, reactive gliosis, and good response to a single injection of anti-VEGF agent. The short survival time of the diabetic mice may have limited the development of NVE. Accordingly, discrepancies were noted between the increase in GFAP histologically and the decrease in GFAP gene expression and between the retinal response to anti-VEGF agents and the lack of change in VEGF gene expression. The reason for the higher effect of bevacizumab than ranibizumab is unclear.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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