Intravitreal injection of adenosine A2A receptor antagonist reduces neuroinflammation, vascular leakage and cell death in the retina of diabetic mice

Abstract

Diabetic retinopathy is a major complication of diabetes mellitus and a leading cause of blindness. The pathogenesis of diabetic retinopathy is accompanied by chronic low-grade inflammation. Evidence shows that the blockade of adenosine A2A receptors (A2AR) affords protection to the retina through the control of microglia-mediated neuroinflammation. Herein, we investigated the therapeutic potential of an antagonist of A2AR in a model of diabetic retinopathy. Type 1 diabetes was induced in 4-5 months old C57BL/6 J mice with a single intraperitoneal injection streptozotocin. Animals were treated one month after the onset of diabetes. The A2AR antagonist was delivered by intravitreal injection once a week for 4 weeks. Microglia reactivity and inflammatory mediators were increased in the retinas of diabetic animals. The treatment with the A2AR antagonist was able to control microglial reactivity and halt neuroinflammation. Furthermore, the A2AR antagonist rescued retinal vascular leakage, attenuated alterations in retinal thickness, decreased retinal cell death and the loss of retinal ganglion cells induced by diabetes. These results demonstrate that intravitreal injection of the A2AR antagonist controls inflammation, affords protection against cell loss and reduces vascular leakage associated with diabetes, which could be envisaged as a therapeutic approach for the early complications of diabetes in the retina.