BOL-303242-X, a novel selective glucocorticoid receptor agonist, with full anti-inflammatory properties in human ocular cells

[摘要] Purpose: BOL-303242-X is a novelselective glucocorticoid receptor agonist under clinical evaluation forthe treatment of inflammatory skin and eye diseases. Data from in vitroand in vivo studies suggest an improved side-effect profile of thiscompound compared to classical glucocorticoids. The aim of this studywas to determine the anti-inflammatory effect of BOL-303242-X in ocularcells. Methods: Four primary human ocular cellcultures, including human conjunctival fibroblasts (HConFs), humancorneal epithelial cells (HCEpiCs), human optic nerve astrocytes(HONAs), and human retinal endothelial cells (HRECs), as well as ahuman monocytic cell line, THP-1, were challenged with eitherlipopolysacharide (LPS) or interleukin-1ß (IL-1ß). Luminex technologywas used to determine the effect of BOL-303242-X on LPS- orIL-1ß-induced cytokine release and intercellular adhesion molecule-1(ICAM-1) levels. Effects of BOL-303242-X on nuclear factor kappa B(NFκB) and mitogen-activated protein kinase (MAPK) in HCEpiCs were alsoassessed by measuring inhibitory kappa B protein-α (IκB-α),phosphorylated p65 NFκB, and MAPK levels by western blotting.Dexamethasone (DEX) or triamcinolone acetonide (TA) was used as thecontrol. Results: LPS or IL-1ß induced multiplecytokine release in all cell types studied. BOL-303242-X significantlyreduced LPS- or IL-1ß-induced inflammatory cytokine release in adose-dependent manner, including granulocyte colony-stimulating factor(G-CSF), IL-1ß, IL-6, IL-8, IL-12p40, monocyte chemotactic protein-1(MCP-1), and tumor necrosis factor-α (TNF-α). BOL-303242-X showedactivity and potency comparable to that observed for DEX or TA. Astatistically significant inhibitory effect of BOL-303242-X wasobserved at doses ranging from 1 to 100 nM in HConFs, HCEpiCs, HONAs,and THP-1. The IC50 values for these effects were in the lownM range. BOL-303242-X also significantly reduced LPS-induced IL-1ßrelease and ICAM-1 levels in HRECs. Furthermore, BOL-303242-X inhibitedIL-1ß-induced decreases in IκB-α levels, as well as IL-1ß-inducedphosphorylation of NFκB, p38, and c-Jun-N-terminal kinase (JNK) MAPKsin HCEpiCs. Conclusions: BOL-303242-X acts as apotent anti-inflammatory agent in various primary human ocular cellswith similar activity and potency compared to classical steroids.Results also suggest that MAPK (p38 and JNK) and NFκB signalingpathways are involved in the anti-inflammatory properties ofBOL-303242-X in HCEpiCs. An improved side effect profile of this novelSEGRA compound has been reported recently. Thus, BOL-303242-X mayprovide a new option for the treatment of ophthalmic conditions with aninflammatory component.

[学科分类] 生物化学/生物物理