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J.L. Edelman, D. Lutz, M.R. Castro; Glucocorticoid Receptor Binding and Anti–Angiogenic/Anti–Vasopermeability Effects of the Synthetic Steroid, 9–Dehydro Cortexolone Acetate . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3943.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: To determine the glucocorticoid receptor binding affinity and anti–angiogenic/anti–vasopermeability activity of the anti–angiogenic synthetic steroid 9–dehydro cortexolone acetate (anecortave acetate). Methods: 9–dehydro cortexolone acetate (4, 9(11)–pregnadien–17, 21–diol–3, 20–dione acetate) and its deacetylated congener (9–dehydro cortexolone; anecortave) were purchased from Steraloids, Inc. Glucocorticoid receptor (GR) binding affinity was determined by displacement of 3H–dexamethasone in human HeLa S3 cells using 10 nM – 10 µM anecortave or anecortave acetate. Corneal neovascularization was initiated by central cornea chemical cautery in rats, and the extent of new vessel growth was measured by intravascular FITC–dextran fluorescence on day 4. Anecortave acetate was administered topically three times daily in suspension (0.1% – 2.5%). Blood–retinal barrier breakdown was induced in rabbits by intravitreal injection of 500 ng VEGF–165, and retinal leakage was measured two days later by subjective scoring of fluorescein angiograms. In this rabbit model, 1 mg anecortave acetate or the glucocorticoid triamcinolone acetonide was injected into the vitreous in a sterile saline suspension. The GR antagonist mifepristone (50 mg/kg/day) was administered by subcutaneous injection. Results: Anecortave and anecortave acetate bind to the GR with Ki values of 160 nM and 209 nM, respectively. In a rat model of corneal angiogenesis, anecortave acetate (up to 2.5% topically, t.i.d.) failed to inhibit new blood vessel growth. In the same study, 0.1% dexamethasone inhibited corneal angiogenesis by ∼80%. In rabbits, intravitreal anecortave acetate (1 mg) inhibited VEGF–induced retinal leakage by 71%, and this inhibitory effect was significantly reversed by the GR antagonist mifepristone. In the same model, 1 mg triamcinolone acetonide completely blocked VEGF–induced vascular leakage for >1 month. These results in rabbits suggest that anecortave acetate (or anecortave) activates GR signaling, or alternatively, that anecortave acetate may be metabolized within the rabbit eye (but not the rat eye) to an active glucocorticoid. Conclusions: The anti–angiogenic steroid anecortave acetate binds to the glucocorticoid receptor in vitro, and significantly inhibits VEGF–mediated retinal vascular leakage in vivo. Its in vivo activity may be due to the conversion of anecortave acetate to an active glucocorticoid within the rabbit eye.
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