Carmen Clapp1, Nundehui Diaz-Lezama1, Elva Adan-Castro1, Gabriela Ramirez-Hernandez1, Bibiana Moreno-Carranza1, Alba Clara Sarti2, Simonetta Falzoni2, Anna Solini3, Francesco Di Virgilio4. 1. Institute of Neurobiology, National University of Mexico [UNAM], Querétaro, Mexico. 2. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Via Borsari 46, 44121, Ferrara, Italy. 3. Department of Surgical, Medical, Molecular, and Critical Area Pathology, University of Pisa, Pisa, Italy. 4. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Via Borsari 46, 44121, Ferrara, Italy. fdv@unife.it.
Abstract
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.
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.
Authors: Areez Shafqat; Saleha Abdul Rab; Osama Ammar; Sulaiman Al Salameh; Anas Alkhudairi; Junaid Kashir; Khaled Alkattan; Ahmed Yaqinuddin Journal: Front Med (Lausanne) Date: 2022-08-23