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Poly(ADP-Ribose)Polymerase Inhibition Counteracts Cataract Formation and Early Retinal Changes in Streptozotocin-Diabetic Rats

¹From the Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana; ²MGI Pharma, Baltimore, Maryland; ³Department of Pharmaceutical Sciences, College of Pharmacy, and ⁴Department of Ophthalmology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska; ⁵Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia, Augusta, Georgia; and ⁶Medical Clinic III, University Hospital, Dresden, Germany.

PURPOSE. This study evaluated the role for poly(ADP-ribose) polymerase (PARP) in diabetes-induced cataractogenesis and early retinal changes.

METHODS. Control and streptozotocin (STZ)-diabetic rats were treated with or without the PARP inhibitors 1,5-isoquinolinediol (ISO; 3 mg kg^–1 d^–1 intraperitoneally) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3–1 (GPI-15427, 30 mg kg^–1 d^–1 orally) for 10 weeks after the first 2 weeks without treatment. Lens clarity was evaluated by indirect ophthalmoscopy and slit lamp examination, and retinal changes were evaluated by immunohistochemistry and Western blot analysis. In in vitro studies, cultured human lens epithelial cells and bovine retinal pericytes and endothelial cells were exposed to high glucose or palmitate.

RESULTS. PARP is expressed in lens, and poly(ADP-ribosyl)ated proteins are primarily localized in the 38- to 87-kDa range of the protein spectrum, with several minor bands at 17 to 38 kDa. The 38- to 87-kDa and the 17- to 38-kDa poly(ADP-ribosyl)ated protein expression increased by 74% and 275%, respectively, after 4 weeks of diabetes and by approximately 65% early after exposure of lens epithelial cells to 30 mM glucose. Both PARP inhibitors delayed, but did not prevent, the formation of diabetic cataract. The number of TUNEL-positive nuclei in flatmounted retinas increased approximately 4-fold in STZ diabetic rats, and this increase was prevented by ISO and GPI-15427. Both PARP inhibitors reduced diabetes-induced retinal oxidative-nitrosative and endoplasmic reticulum stress and glial activation. GPI-15427 (20 µM) prevented oxidative-nitrosative stress and cell death in palmitate-exposed pericytes and endothelial cells.

CONCLUSIONS. PARP activation is implicated in the formation of diabetic cataract and in early retinal changes. These findings provide a rationale for the development of PARP inhibitors for the prevention of diabetic ocular complications.

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