Intravitreal injection of adenosine A2A receptor antagonist reduces neuroinflammation, vascular leakage and cell death in the retina of diabetic mice
Intravitreal injection of adenosine A2A receptor antagonist reduces neuroinflammation, vascular leakage and cell death in the retina of diabetic mice
复制标题
DOI：
10.1038/s41598-019-53627-y
复制
发表时间：
2019-11-20
影响因子：
4.6
通讯作者：
Santiago, Ana Raquel
中科院分区：
文献类型：
--
作者：
Aires, Ines Dinis;Madeira, Maria Helena;Santiago, Ana Raquel
糖尿病视网膜病变是糖尿病的主要并发症，也是导致失明的主要原因。糖尿病视网膜病变的发病机制是伴随慢性低度炎症。有证据表明，腺苷A（2A）受体（A（2A）R）的阻断通过控制小胶质细胞介导的神经炎症来提供对视网膜的保护。在此，我们研究了A（2A）R拮抗剂在糖尿病视网膜病变模型中的治疗潜力。在4-5月龄的C57 BL/6 J小鼠中用单次腹腔注射链脲佐菌素诱导1型糖尿病。在糖尿病发作后一个月对动物进行治疗。A（2A）R拮抗剂通过玻璃体内注射递送，每周一次，持续4周。糖尿病动物视网膜中的小胶质细胞反应性和炎症介质增加。用A（2A）R拮抗剂治疗能够控制小胶质细胞反应性并停止神经炎症。此外，A（2A）R拮抗剂挽救了视网膜血管渗漏，减弱了视网膜厚度的改变，减少了糖尿病诱导的视网膜细胞死亡和视网膜神经节细胞的损失。这些结果表明，玻璃体内注射A（2A）R拮抗剂控制炎症，提供针对细胞损失的保护并减少与糖尿病相关的血管渗漏，这可以被设想为视网膜中糖尿病早期并发症的治疗方法。
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 A(2A) receptors (A(2A)R) affords protection to the retina through the control of microglia-mediated neuroinflammation. Herein, we investigated the therapeutic potential of an antagonist of A(2A)R 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 A(2A)R 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 A(2A)R antagonist was able to control microglial reactivity and halt neuroinflammation. Furthermore, the A(2A)R 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 A(2A)R 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.