Pharmacological blockade of the P2X7 receptor reverses retinal damage in a rat model of type 1 diabetes

• Published in: Acta diabetologica Vol. 56; no. 9; pp. 1031 - 1036
• Main Authors: Clapp, Carmen, Diaz-Lezama, Nundehui, Adan-Castro, Elva, Ramirez-Hernandez, Gabriela, Moreno-Carranza, Bibiana, Sarti, Alba Clara, Falzoni, Simonetta, Solini, Anna, Di Virgilio, Francesco
• Format: Journal Article
• Language: English
• Published: Milan Springer Milan 01.09.2019; Springer Nature B.V
• Subjects: Angiogenesis; Blood glucose; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetic retinopathy; Glucose; Interleukin 6; Internal Medicine; Medicine; Medicine & Public Health; Metabolic Diseases; Microvasculature; Neuronal-glial interactions; Original Article; Permeability; Retina; Retinopathy; Streptozocin; Vascular endothelial growth factor; Diabetic retinopathy; Retinal vasopermeability; Inflammation; Extracellular ATP; P2X7
• ISSN: 0940-5429; 1432-5233; 1432-5233
• DOI: 10.1007/s00592-019-01343-4

Aims Retinopathy is a leading cause of vision impairment in diabetes. Its pathogenesis involves inflammation, pathological angiogenesis, neuronal and glial dysfunction. The purinergic P2X7 receptor (P2X7R) has a leading role in inflammation and angiogenesis. Potent and selective P2X7R blockers have been synthesized and tested in Phase I/II clinical studies. We hypothesize that P2X7R blockade will ameliorate diabetes-related pathological retinal changes. Methods Streptozotocin (STZ)-treated rats were intraperitoneally inoculated with either of two small molecule P2X7R receptor inhibitors, A740003 and AZ10606120, and after blood glucose levels increased to above 400 mg/dL, retinae were analyzed for P2X7R expression, vascular permeability, VEGF, and IL-6 expression. Results STZ administration caused a near fourfold increase in blood glucose, a large increase in retinal microvasculature permeability, as well as in retinal P2X7R, VEGF, and IL-6 expression. P2X7R blockade fully reversed retinal vascular permeability increase, VEGF accumulation, and IL-6 expression, with no effect on blood glucose. Conclusion P2X7R blockade might be promising strategy for the treatment of microvascular changes observed in the early phases of diabetic retinopathy.