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Protective effects of a coumarin derivative in diabetic rats.

AbstractPURPOSE:
Retinal microvascular cells play a crucial role in the pathogenesis of diabetic retinopathy. The endothelial effects of cloricromene, a novel coumarin derivative, on diabetic retinopathy induced by streptozotocin (STZ) in the rat were investigated.
METHODS:
Cloricromene (10 mg/kg intraperitoneally) was administered daily in diabetic rats, and 60 days later eyes were enucleated for localization of nitrotyrosine, ICAM-1, VEGF, ZO-1, occludin, claudin-5, and VE-cadherin by immunohistochemical analysis. The effect of treatment was also evaluated by TNFalpha, 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 TNFalpha, 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 BRB in diabetic rats.
AuthorsClaudio Bucolo, Keith W Ward, Emanuela Mazzon, Salvatore Cuzzocrea, Filippo Drago
JournalInvestigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 50 Issue 8 Pg. 3846-52 (Aug 2009) ISSN: 1552-5783 [Electronic] United States
PMID19279317 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, CD
  • Cadherins
  • Claudin-5
  • Cldn5 protein, rat
  • Membrane Proteins
  • Occludin
  • Ocln protein, rat
  • Phosphoproteins
  • Platelet Aggregation Inhibitors
  • Tjp1 protein, rat
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • Zonula Occludens-1 Protein
  • cadherin 5
  • vascular endothelial growth factor A, rat
  • Intercellular Adhesion Molecule-1
  • 3-nitrotyrosine
  • Tyrosine
  • cloricromen
  • Nitric Oxide Synthase Type III
  • Nos3 protein, rat
  • Chromonar
Topics
  • Animals
  • Antigens, CD (metabolism)
  • Blood-Retinal Barrier (drug effects)
  • Blotting, Western
  • Cadherins (metabolism)
  • Chromonar (analogs & derivatives, therapeutic use)
  • Claudin-5
  • Diabetes Mellitus, Experimental (drug therapy, metabolism, pathology)
  • Diabetic Retinopathy (drug therapy, metabolism, pathology)
  • Enzyme-Linked Immunosorbent Assay
  • Immunohistochemistry
  • Injections, Intraperitoneal
  • Intercellular Adhesion Molecule-1 (metabolism)
  • Male
  • Membrane Proteins (metabolism)
  • Nitric Oxide Synthase Type III (metabolism)
  • Occludin
  • Phosphoproteins (metabolism)
  • Platelet Aggregation Inhibitors (therapeutic use)
  • Rats
  • Rats, Sprague-Dawley
  • Tumor Necrosis Factor-alpha (metabolism)
  • Tyrosine (analogs & derivatives, metabolism)
  • Vascular Endothelial Growth Factor A (metabolism)
  • Zonula Occludens-1 Protein

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