Ketorolac inhibits choroidal neovascularization by suppression of retinal VEGF

Abstract

We assessed the effect of topical ketorolac on laser-induced choroidal neovascularization (CNV), measured retinal PGE2 and VEGF levels after laser treatment, and determined the effect of ketorolac on PGE2 and VEGF production. Six laser burns were placed in eyes of rats which then received topical ketorolac 0.4% or artificial tears four times daily until sacrifice. Fluorescein angiography (FA) was performed at 2 and 3 weeks and retinal pigment epithelium-choroid-sclera flat mounts were prepared. The retina and vitreous were isolated at 1, 3, 5, 7, and 14 days after laser treatment and tested for VEGF and PGE2. Additional animals were lasered and treated with topical ketorolac or artificial tears and tested at 3 and 7 days for retinal and vitreous VEGF and PGE2. Ketorolac reduced CNV on FA by 27% at 2 weeks (P < 0.001) and 25% at 3 weeks (P < 0.001). Baseline retina and vitreous PGE2 levels were 29.4 μg/g and 16.5 μg/g respectively, and reached 51.2 μg/g and 26.9 μg/g respectively, 24 h after laser treatment (P < 0.05). Retinal VEGF level was 781 pg/g 24 h after laser treatment and reached 931 pg/g by 7 days (P < 0.01). Ketorolac reduced retinal PGE2 by 35% at 3 days (P < 0.05) and 29% at 7 days (P < 0.001) and retinal VEGF by 31% at 3 days (P = 0.10) and 19% at 7 days (P < 0.001). Topical ketorolac inhibited CNV and suppressed retinal PGE2 and VEGF production.

Pharmacokinetic Comparison of Ketorolac After Intracameral, Intravitreal, and Suprachoroidal Administration in Rabbits

“…11 In recent studies, the experimental efficacy of ketorolac in the inhibition of ocular neovascularization has been evaluated. 12,13 Ketorolac has obvious clinical advantages over corticosteroids in terms of cataract formation, ocular infections, and increase of intraocular pressure. [14][15][16] Nowadays, treatment of posterior segment of eyes remains a challenge because it is hard for drugs to cross the ocular barriers to the posterior chamber by topical administration of eye drops.…”

NSAIDs inhibit neovascularization of choroid through HO-1-dependent pathway

“…36 NSAIDs were reported to reduce the prostaglandin, which is a known potent inducer of inflammation, in mouse retina. 14,16 Besides, NF-kB has a central role in the expression of various pro-inflammatory mediators and leukocyte infiltration. 37 So inflammation was inhibited by NSAIDs, consequently reducing the size of CNV.…”

“…11 Several recent reports showed possible mechanisms of the inhibitory effect of NSAIDs on CNV. [11][12][13][14][15][16][17][18] VEGF is one of the most potent molecules in angiogenesis. Takahashi et al 13 reported that nepafenac inhibited neovascularization in mice with CNV due to laser-induced rupture of Bruch's membrane and Kim et al 16 showed that ketrolac reduced the size of laser-induced CNV.…”

“…10 Recently, it was reported that non-steroidal antiinflammatory drugs (NSAIDs) inhibit CNV in animals and a large retrospective study found a reduced incidence of CNV in AMD patients taking aspirin. [11][12][13][14][15][16][17] The anti-inflammatory properties of NSAIDs are believed to reside in their ability to inhibit the activity of cyclooxygenase (COX). Indeed COX2 was shown to have a pivotal role in the expression of VEGF in a CNV animal model.…”

Fluorocoxib A enables targeted detection of cyclooxygenase-2 in laser-induced choroidal neovascularization

“…In this model, an argon laser is used to induce several laser burns in the subretinal space via perforation of Bruch's membrane, which is associated with early inflammation mediated by COX-2 derived prostaglandins 1 to 3 days post laser injury, with subsequent choroidal neovascularization in later stages of the model (days 5 to 7). 9 All animal procedures were performed in accordance with the Institutional Animal Care and Use Committee (IACUC) at Vanderbilt University Medical Center. LCNV lesions were generated bilaterally in three groups of six C57BL/6J female mice using an argon laser photocoagulator (blue-green light) mounted on a slit-lamp (Nidek SL-1600).…”