Anticataract effect as a predictor of drug efficacy against early diabetes‐induced retinal changes

Abstract

Abstract Purpose To evaluate if anticataract effect predicts drug efficacy against early diabetes‐induced retinal changes, using STZ‐diabetic rat model and cultured retinal microvascular cells. Methods Mature control and STZ‐diabetic rats received one of the following treatments (a prevention approach): 1) the aldose reductase inhibitor (ARI) fidarestat, 2) the PARP inhibitors, 1,5‐isoquinolinediol or GPI‐15427; 3) the Na+/H+‐exchanger‐1 (NHE‐1) inhibitor cariporide; and 4) two agents, counteracting endoplasmic reticulum stress,trimethylamine N‐oxide dehydrate or 4‐phenylbutyric acid. The duration of diabetes was 12 wks. Cataract formation was monitored by indirects ophthalmoscopy and slit lamp examination.Oxidative stress and apoptosis were assessed as early diabetes‐induced retinal changes in rat retinae and cultured bovine retinal pericytes and endothelial cells. Results An ARI treatment completely prevented cataract formation in STZ‐diabetic rats, whereas three other treatments delayed, but did not prevent, diabetes‐induced cataractogenesis. All four classes of agents counteracted diabetes‐induced apoptosis in rat retinae, and the ARI, PARP inhibitor, and NHE‐1 inhibitor treatments prevented high glucose and NEFA‐induced apoptosis in pericytes and endothelial cells. Fidarestat, PARP inhibitors, and cariporide treatments also counteracted diabetes‐related oxidative stress in the retinae and cultured retinal microvascular cells. The effect of agents counteracting endoplasmic reticulum stress on retinal oxidative stress has not been explored. Conclusion Anticataract effect ia a likely predictor of the efficacy of experimental pharmacological agents against, at least, early diabetes‐associated retinal changes which may facilitate diabetes drug discovery. Commercial interest