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S. P. Bartels, X. Xi, G. Lehmann, S. E. Feldon, R. P. Phipps; BOL-303242-X, a Selective Glucocorticoid Receptor Agonist (SEGRA), Inhibits TGF-β-Induced Cellular Levels of Collagen Type I, -Smooth Muscle Actin, and Tissue Transglutaminase in Human Tenon's Capsule Fibroblasts (HTF). Invest. Ophthalmol. Vis. Sci. 2009;50(13):470.
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Excessive scarring of the filtering bleb is the most important cause of failure after glaucoma surgery. Transforming growth factor-β (TGF-β) may promote scarring by stimulating Type I collagen (COL), -smooth muscle actin (SMA) and tissue transglutaminase (tTGase) production. Therefore, we assessed the effects of BOL-303242-X, a selective glucocorticoid receptor agonist (SEGRA), on COL, SMA, and tTGase protein levels after a TGF-β challenge in HTF.
Control and TGF-β-challenged HTF were treated with BOL-303242-X (0.1-10 µM) or vehicle for up to 5 days. Levels of COL, SMA, tTGase and GAPDH were assessed by Western blots and cell metabolic activity was assessed in response to the treatments using the Alamar Blue assay.
Incubation of HTF from 6 different donors with TGF-β (5 ng/ml) for 5 days increased COL, tTGase, SMA protein levels by 8-, 4- and 29-fold, respectively. Co-administration of BOL-303242-X was associated with a dose-dependent decrease in levels of COL (p<0.05) and SMA (p<0.05) at concentrations ≥ 3 µM. While there was a trend toward reduction of tTGase, the effect did not achieve statistical significance. Cell metabolic activity was increased at day 1, 3 and 5 in TGF-β stimulated HTF (1.39-, 2.03-, and 1.64-fold respectively; n=3). Co-administration of BOL-303242-X was associated with no change compared to TGF-β-stimulated HTF.
BOL-303242-X is being developed as an ocular anti-inflammatory drug. BOL-303242-Xuniquely interacts with the glucocorticoid receptor to trigger the anti-inflammatory activity while limiting the activity that is known to cause side effects.The results from these studies suggest that in addition to reducing post-surgical inflammation and the risk of intraocular pressure, BOL-303242-X may be useful in preventing scar formation when used after trabeculectomy surgery.
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