Celecoxib, a selective cyclooxygenase-2 inhibitor, inhibits retinal vascular endothelial growth factor expression and vascular leakage in a streptozotocin-induced diabetic rat model

• Published in: European journal of pharmacology Vol. 458; no. 3; pp. 283 - 289
• Main Authors: Ayalasomayajula, Surya P., Kompella, Uday B.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 05.01.2003; Elsevier
• Subjects: Animals; Biological and medical sciences; Blood Glucose - drug effects; Blood Glucose - metabolism; Body Weight - drug effects; Bones, joints and connective tissue. Antiinflammatory agents; Capillary Permeability - drug effects; Celecoxib; Cornea - metabolism; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacokinetics; Cyclooxygenase Inhibitors - pharmacology; Diabetes; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - physiopathology; Endothelial Growth Factors - genetics; Endothelial Growth Factors - metabolism; Eye; Gene Expression Regulation - drug effects; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Isoenzymes - genetics; Lens, Crystalline - metabolism; Lymphokines - genetics; Lymphokines - metabolism; Medical sciences; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - genetics; Pyrazoles; Rats; Rats, Sprague-Dawley; Retina - drug effects; Retina - metabolism; RNA, Messenger - drug effects; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sulfonamides - blood; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; Time Factors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; VEGF (vascular endothelial growth factor); Vitreous Body - metabolism; VEGF (vascular endothelial growth factor); Cyclooxygenase-2; Celecoxib; Diabetes; Endocrinopathy; Prostaglandin-endoperoxide synthase; Pharmacokinetic pharmacodynamic relationship; Intraperitoneal administration; Retinopathy; Rat; Retina; Absorption; Blood vessel; Neovascularization; Enzyme; Diabetes mellitus; Treatment efficiency; Rodentia; Oral administration; Enzyme inhibitor; Non steroidal antiinflammatory agent; Eye disease; Vertebrata; Chemotherapy; Mammalia; Vascular endothelium growth factor; Treatment; Animal; Distribution; Oxidoreductases; Circulatory system; Pharmacokinetics
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(02)02793-0

Overexpression of vascular endothelial growth factor (VEGF) is implicated in the development of vascular leakage and retinal neovascularization in diabetic subjects. The objective of this study was to determine whether celecoxib, a selective cyclooxygenase-2 enzyme inhibitor, reaches ocular tissues following oral administration and inhibits the retinal VEGF expression and vascular leakage in a streptozotocin-induced diabetic rat model. After administering a single intraperitoneal injection of streptozotocin (60 mg/kg) to Sprague–Dawley rats and ensuring the induction of diabetes at the end of 24 h, celecoxib was administered b.i.d. by oral gavage (50 mg/kg). On day 8, the animals were sacrificed and the retinal VEGF and cyclooxygenase-2 mRNA levels, ocular tissue celecoxib concentrations, and the vitreous/plasma protein ratio were determined. In diabetic rats, the retinal VEGF mRNA expression was 2.3-fold compared to controls, with a corresponding increase in cyclooxygenase-2 mRNA expression. Celecoxib treatment inhibited VEGF mRNA expression without any significant reduction in cyclooxygenase-2 mRNA. Furthermore, the retinal vascular leakage estimated as vitreous to plasma protein ratio increased in diabetic animals from 0.35±0.1 to 1.1±0.1 and celecoxib treatment significantly decreased this ratio to 0.4±0.1. Celecoxib levels were 24.8±6.6, 1.9±1, 1.7±0.8, and 6.9±0.9 ng/mg in the retina, vitreous, lens, and cornea, respectively. The plasma celecoxib levels were 85±24 ng/ml. Thus, celecoxib reaches the retina after oral administration and reduces diabetes-induced retinal VEGF mRNA expression and vascular leakage by inhibiting the activity of cyclooxygenase-2 enzyme.