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A more recent version of this article appeared on August 1, 2009
 (Investigative Ophthalmology and Visual Science. )
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.08-3328
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Article

Protective Effects of a Coumarin Derivative in Diabetic Rats

Claudio Bucolo 1*, Keith W Ward 2, Emanuela Mazzon 3, Salvatore Cuzzocrea 4, and Filippo Drago 5

1 Experimental and Clinical Pharmacology, University of Catania, Viale A. Doria 6, Catania, 95125, Italy
2 R&D, Bausch & Lomb, Rochester, New York, United States
3 Centro Neurolesi Bonino-Pulejo, IRCCS, Messina, Italy
4 Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy
5 Experimental and Clinical Pharmacology, University of Catania, Catania, Italy

* To whom correspondence should be addressed. E-mail: bucocla{at}unict.it.


  Abstract

Purpose: Retinal microvascular cells play a crucial role in the pathogenesis of diabetic retinopathy. We investigate the endothelial effects of cloricromene, a novel coumarin derivative, on diabetic retinopathy induced by streptozotocin (STZ) in the rat. Methods: Cloricromene (10 mg/kg i.p.) was administered daily in diabetes rats, and 60 days later eyes were enucleated for localisation of nitrotyrosine, ICAM-1, VEGF, ZO-1, occludin, claudin-5 and VE-cadherin by immunohistochemical analysis. The effect of treatment was also evaluated by TNF{alpha}, ICAM-1, VEGF and eNOS protein levels measurement in the retina with the respective ELISA kits. Blood-retinal barrier (BRB) integrity was also evaluated by Evans blue. Results: Increased amounts of cytokines, adhesion molecule and nitric oxide synthase were observed in retina. Cloricromene treatment significantly lowered retinal TNF{alpha}, ICAM-1, VEGF and eNOS. Furthermore, immunohistochemical analysis for VEGF, ICAM-1, nitrotyrosine (a marker of peroxynitrite), and tight junctions revealed positive staining in the retina from STZ-treated rats. The degree of staining for VEGF, ICAM-1, nitrotyrosine, and tight junctions was markedly reduced in tissue sections obtained from diabetic rats treated with cloricromene. Treatment with cloricromene suppressed diabetes-related BRB breakdown by 45%. Conclusions: This study provides the first evidence that the new coumarin derivative cloricromene attenuates the degree of inflammation preserving the blood-retinal barrier in diabetic rats.

Key Words: diabetic retinopathy, cytokine, tight junction, blood-retinal barrier






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