Experimental anterior ischemic optic neuropathy in diabetic mice exhibited severe retinal swelling associated with VEGF elevation

Abstract

PURPOSE. Diabetes mellitus (DM) is one of the most important risk factors for nonarteritic anterior ischemic optic neuropathy (AION). In this study, we investigated for the first time the impact of experimental AION in a DM model. METHODS. We induced a photochemical thrombosis model of AION after streptozotocininduced DM and performed serial optical coherence tomography (OCT), morphometric analyses, and VEGF levels in the retina and sera. RESULTS. Compared with non-DM animals, experimental AION in DM mice led to significantly greater retinal swelling on day 1 and worse thinning at week 3 on OCT measurements. Greater retinal swelling on OCT in DM-AION eyes was associated with significantly increased loss of brain-specific homeobox/POU domain protein 3A (Brn3A+) retinal ganglion cells at week 3. In acute AION, there was greater inflammation as seen by an increase in ionized calcium-binding adapter molecule 1 (Iba1þ)-activated microglia. On day 1, there was increase in vascular endothelial growth factor (VEGF) level in nondiabetic AION retinae and sera, but the VEGF level was the highest in the diabetic AION group, which decreased to nondiabetic levels after insulin treatment. The decrease in retinal and serum VEGF levels after insulin treatment correlated with a reduction in retinal swelling. CONCLUSIONS. In the setting of hyperglycemia, AION led to greater acute, postischemic microglial activation and elevation of VEGF levels, which likely contributed to greater retinal swelling acutely and worse retinal thinning and loss of retinal ganglion cells chronically. Treatment of hyperglycemia with insulin reduced VEGF levels and retinal swelling, consistent with the idea that VEGF is an important factor in postischemic swelling and that good glycemic control following AION may lead to better visual outcome.