Abstract
Purpose: :
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.
Methods: :
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.
Results: :
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.
Conclusions: :
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.
Keywords: wound healing • corticosteroids • extracellular matrix