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.

Exosomes derived from microglia exposed to elevated pressure amplify the neuroinflammatory response in retinal cells

“…In the same animal, one eye was injected with 3 μl BV‐Exo‐Control and the contralateral eye with 3 μl BV‐Exo‐EHP. Retinal sections were prepared as previously described (Aires, Madeira, et al, 2019) and labeled with antibodies for Iba‐1 (green) and major histocompatibility class II positive (MHC‐II; red), and nuclei were stained with DAPI (blue) (a). The number of microglial cells (Iba‐1 + ) per mm was counted, n = 6 (b).…”

“…Retinal sections were immunolabeled to identify responsive microglia (major histocompatibility class II positive (MHC‐II + ) and ionized calcium‐binding adapter molecule 1 positive (Iba‐1 + ) cells) and RGCs (brain‐specific homeobox/POU domain protein 3A positive [Brn3a + ] cells), using the antibodies identified in Table 1, as previously described (Aires, Madeira, et al, 2019). Retinal cryosections were imaged using an inverted fluorescence microscope (Zeiss Axio Observer.Z1 microscope equipped with an AxioCam HRm and Zen Blue 2012 software, Carl Zeiss) with a 20x objective (Plan Achromat ×20/0.8 M27).…”

Adenosine Receptors as Neuroinflammation Modulators: Role of A1 Agonists and A2A Antagonists

“…It is worth noting that A 2A AR expression in microglia increases as a result of brain insults leading to signal transductions that do not occur in cells with the receptors expressed at a normal level such as facilitating the release of cytokines [ 17 ]. On the other hand, A 2A AR antagonists suppress microglia activation in in vitro and in vivo studies [ 18 , 19 , 20 , 21 ].…”

Blockade of Adenosine A2A Receptor Protects Photoreceptors after Retinal Detachment by Inhibiting Inflammation and Oxidative Stress

“…Increased A 2A R expression has been reported in several retinal disease models, including oxygen-induced retinopathy [ 22 ], diabetic retinopathy [ 46 ], glaucoma [ 41 ], and light-induced retinal degeneration [ 47 ]. Therefore, A 2A R may be a critical factor for the inflammatory response during various acute and chronic retinal diseases.…”