The anti-inflammatory effect of BOL-303242-X compared with classical GC has been shown in a number of ocular cells and a monocytic cell line, THP-1.
35 The anti-inflammatory action of BOL-303242-X was comparable to that of DEX or triamcinolone acetonide in inhibiting key inflammatory cytokines such as IL-1β, IL-6, IL-8, monocyte chemotactic protein-1 (MCP-1), and TNF-α in all the cell types studied and intracellular adhesion molecule-1 (ICAM-1) in human retinal endothelial cells. Furthermore, BOL-303242-X inhibited the phosphorylation of the transcriptional factors NF-κB, p38, and JNK.
35 In the present study, we also evaluated the anti-inflammatory properties of BOL-303242-X compared with DEX in a model of postoperative inflammation, the paracentesis-induced inflammation model. The rabbit paracentesis model is a relevant system that mimics ocular trauma induced during surgery in the anterior segment with breakdown of the blood-aqueous barrier. In this model, animals respond to GC treatment by showing inhibition of clinical signs indicating an inflammatory response and biomarkers of inflammation such as PGE
2. The anti-inflammatory activity of DEX in experimental postoperative inflammation and downregulation of PGE
2 has been previously demonstrated in postsurgical (vitrectomy or lensectomy) rabbit inflammation models.
55 Therefore, this animal model represents a good platform for screening anti-inflammatory agents,
55 particularly those that modulate GR activity. Pretreatment with BOL-303242-X improved clinical anti-inflammatory outcomes in the paracentesis model. In addition, more objective measures of inflammation, which include flare, levels of PGE
2, and infiltration of inflammatory cells in aqueous humor, were also favorably affected by treatment with the compound. More important, the data indicate that BOL-303242-X is as effective as DEX in improving inflammatory readouts in this model, demonstrating that the compound shows full efficacy when looking at its anti-inflammatory properties. However, DEX was ineffective in reducing levels of PGE
2. The discrepancy between these data and findings by Scheib et al.
55 may be due to the duration of our study and the time points at which the samples were assayed. The differences observed between BOL-303242-X or DEX may be due to differences in ligand-receptor interaction and morphologic changes that may result in the inhibition of specific inflammatory mediators; however, it is also possible that there are differences in the PK properties of BOL-303242-X and DEX that could result in different concentrations attained in the target tissue.