The effect of angiostatic steroids and β-cyclodextrin tetradecasulfate on corneal neovascularization in the rat

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Experimental Eye Research

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Folkman and coworkers have described angiostatic steroids that markedly inhibit neovascularization of the rabbit cornea when given topically with β-cyclodextrin tetradecasulfate (β-CD), yet have minimal or no glucocorticoid or mineralocorticoid activity. Our objective was to extend these observations to another species, the rat. We induced neovascularization by cauterizing rat corneas with silver nitrate/potassium nitrate; drugs were applied topically four times per day for 4 days in most experiments. Submicron sized emulsions of lipid-soluble dexamethasone and the angiostatic steroids 17 α-hydroxyprogesterone (1 or 10 mg ml-1) and cortexolone (1 or 10 mg ml-1) were prepared by lecithin encapsulation of drug microcrystals. The vehicle for water-soluble hydrocortisone 21-phosphate (HCP)±β-CD (Molecusol; Pharmatec, Inc) was 10% Tween 20 in Tris-buffered 0·9% saline. Angiogenesis was significantly inhibited only by 1 mg ml-1 dexamethasone (-63·2% when compared with controls), 0·5 mg ml-1 HCP+1 mg ml-1 β-CD (-33·4%), and 1 mg ml-1 HCP (-40·2%). HCP (0·5 mg ml-1) or β-CD (1 or 2 mg ml-1) alone had no significant effect on neovascularization; the inhibition by 1·0 mg ml-1 HCP was not potentiated by 2 mg ml-1 β-CD. We also tested HCP and tetrahydro-S (TH-S) using 1·5% hydroxypropyl methylcellulose vehicle and β-CD from Takeda Chemical Industries. Ltd., to simulate the procedure of Folkman and coworkers. Neovascularization was inhibited by 0·5 mg ml-1 HCP (-45·1%), but this inhibition was not potentiated by 1 mg ml-1 β-CD. TH-S (1 mg ml-1) alone or combined with β-CD (0·5 mg ml-1) did not inhibit angiogenesis when applied for either 4 or 10 days. Our results suggest that inhibition of corneal neovascularization by angiostatic steroids is influenced by species and/or the angiogenic stimulus since we were unable to reproduce the beneficial effect reported for most of these compounds. However, the moderate inhibition of corneal neovascularization by HCP, which has only slight glucocorticoid activity when compared to dexamethasone, supports Folkman's contention that angiostatic, glucocorticoid, and mineralocorticoid activities are separable.