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SP Ayalasomayajula, UB Kompella; Celecoxib, a Selective COX-2 Inhibitor, Reduces Diabetes-induced Retinal VEGF Expression Both in vitro and in vivo . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1314.
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Purpose:To determine whether celecoxib, a selective COX-2 inhibitor, reduces VEGF expression in human retinal pigment epithelial cells (ARPE-19) and in diabetic rat retinas. Methods:ARPE-19 cells were treated with celecoxib (100 pM to 10 µM) for 12 hours and secreted VEGF and intracellular VEGF mRNA expression were determined using ELISA and RTPCR, respectively. The effect of celecoxib was tested in vivo in diabetic Sprague Dawly rats. In rats fasted for 24 hours, diabetes was induced with a single intraperitoneal injection of streptozotocin (60 mg/kg). After ensuring the induction of diabetes, celecoxib was administered b.i.d. orally (50 mg/kg) as a suspension in 0.5% carboxy methyl cellulose (CMC) beginning 1 day after administering streptozotocin. The blood glucose and body weights were measured periodically until day 8. Untreated diabetic rats served as controls. Animals were sacrificed on day 8, and the eyes were enucleated. The drug levels in the plasma, cornea, lens and vitreous were determined using a HPLC. The retinal VEGF mRNA levels were normalized to 18S rRNA. The retinal vascular leakage was estimated as the ratio of vitreous to plasma protein determined using a BCA protein assay kit (Pierce, Rockford, IL). Results:Celecoxib treatment reduced the secretion and mRNA levels of VEGF in ARPE-19 cells in a dose-dependent manner. The body weight of diabetic rats was significantly decreased and celecoxib (50 mg/kg) treatment had no effect on induced-blood glucose levels and body weights. In diabetic rat retinas, the VEGF mRNA levels were elevated by 50% at the end of 8 days and celecoxib (50 mg/Kg) treatment reduced this effect significantly. On day 8, the drug levels in the cornea, lens, and vitreous were 6.9 ± 0.9, 1.7 ± 0.8, and 1.9 ± 1 ng/mg, respectively. The plasma drug levels were 0.22 ± 0.06 µM (85 ± 25 ng/ml). The vitreous/plasma protein ratio increased in diabetic animals from 0.33 ± 0.08 to 0.99 ± 0.3. Celecoxib treatment decreased this ratio to 0.22 ± 0.08 . Conclusion:VEGF mRNA expression and vascular leakage are increased in streptozotocin-induced diabetic rat retinas by day 8 and daily celecoxib treatment reduced this effect, suggesting a role for COX-2 inhibitors in the treatment of diabetic retinopathy.
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