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

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

  • Acta Diabetol. 2019 Sep;56(9):1031-1036. doi: 10.1007/s00592-019-01343-4.
Carmen Clapp 1,  Nundehui Diaz-Lezama 1,  Elva Adan-Castro 1,  Gabriela Ramirez-Hernandez 1,  Bibiana Moreno-Carranza 1,  Alba Clara Sarti 2,  Simonetta Falzoni 2,  Anna Solini 3,  Francesco Di Virgilio 4
Affiliations

Affiliations

  • 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. [email protected].
PMID: 30982154 DOI: 10.1007/s00592-019-01343-4
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.

Keywords

Diabetic retinopathy; Extracellular ATP; Inflammation; P2X7; Retinal vasopermeability.

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