Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

• Published in: International journal of molecular medicine Vol. 21; no. 6; pp. 667 - 676
• Main Authors: Drel, Viktor, Pacher, Pal, Ali, Tayyeba, Shin, Jeho, Julius, Ulrich, El-Remessy, Azza, Obrosova, Irina
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.06.2008
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Animals; Apoptosis - drug effects; Apoptosis Regulatory Proteins - analysis; bcl-2-Associated X Protein - analysis; Blood Glucose - analysis; Blotting, Western; Cataract - drug therapy; Cataract - etiology; Cataract - prevention & control; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - metabolism; Diabetic Retinopathy - drug therapy; Diabetic Retinopathy - etiology; Diabetic Retinopathy - prevention & control; Glial Fibrillary Acidic Protein - analysis; Imidazolidines - therapeutic use; Immunohistochemistry; In Situ Nick-End Labeling; Neuroglia - drug effects; Neuroglia - metabolism; Ophthalmoscopy; Oxidative Stress - drug effects; Poly(ADP-ribose) Polymerases - analysis; Rats; Retina - drug effects; Retina - metabolism; Retina - pathology; Streptozocin; Tyrosine - analogs & derivatives; Tyrosine - analysis
• ISSN: 1107-3756; 1791-244X
• DOI: 10.3892/ijmm.21.6.667

This study was aimed at evaluating the potent and specific aldose reductase inhibitor fidarestat, on diabetes-associated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis. Control and streptozotocin-diabetic rats were treated with or without fidarestat (16 mg kg-1d-1) for 10 weeks after an initial 2-week period without treatment. Lens changes were evaluated by indirect ophthalmoscopy and portable slit lamp. Nitrotyrosine, poly(ADP-ribose), and glial fibrillary acidic protein expression were assessed by immunohistochemistry. The rate of apoptosis was quantified in flat-mounted retinas by TUNEL assay with immunoperoxidase staining. To dissect the effects of high glucose exposure in retinal microvascular cells, primary bovine retinal pericytes and endothelial cells were cultured in 5 or 30 mM glucose, with or without fidarestat (10 μM) for 3-14 days. Apoptosis was assessed by TUNEL assay, nitrotyrosine and poly(ADP-ribose) by immunocytochemistry, and Bax and Bcl-2 expression by Western blot analyses. Fidarestat treatment prevented diabetic cataract formation and counteracted retinal nitrosative stress, and poly(ADP-ribose) polymerase activation, as well as glial activation. The number of TUNEL-positive nuclei (mean ± SEM) was increased approximately 4-fold in diabetic rats vs. controls (207±33 vs. 49±4, p<0.01), and this increase was partially prevented by fidarestat (106±34, p<0.05 vs. untreated diabetic group). The apoptotic cell number increased with the prolongation of exposure of both pericytes and endothelial cells to high glucose levels. Fidarestat counteracted nitrotyrosine and poly(ADP-ribose) accumulation and apoptosis in both cell types. Antiapoptotic effect of fidarestat in high glucose-exposed retinal pericytes was not associated with the inhibition of Bax or increase in Bcl-2 expression. In conclusion, the findings, i) support an important role for aldose reductase in diabetes-associated cataract formation, and retinal oxidative-nitrosative stress, glial activation, and apoptosis, and ii) provide a rationale for the development of aldose reductase inhibitors, and, in particular, fidarestat, for the prevention and treatment of diabetic ocular complications.