Abstract
Purpose :
Deepening of upper eyelid sulcus (DUES) is one of the cosmetic adverse events caused by topical administration of FP receptor agonists for the treatment of glaucoma. Recent findings suggested that DUES is induced by atrophy of orbital fat in the eyelid by inhibiting adipogenesis through FP receptor stimulation. Omidenepag isopropyl (OMDI), the prodrug of a selective, non-prostaglandin, EP2 receptor agonist, is being developed as a new IOP-lowering topical agent for glaucoma. Here, we investigated the effects of omidenepag (OMD), a pharmacologically active form of OMDI, on adipocyte differentiation in comparison with FP agonists, using 3T3-L1 cells.
Methods :
3T3-L1 preadipocytes were cultured with a differentiation medium for 10 days. Differentiation into adipocytes was assessed by Oil Red O-stained area of the cells at day 10 and by evaluating the alteration of adipogenic transcription factors, pparγ, c/ebpα and c/ebpβ using quantitative real-time PCR at day 2, 4 and 10 after the induction of differentiation. OMD (0.1, 1, 10 and 40 µM), latanoprost free acid (LAT-A, 0.1 µM) or prostaglandin F2α (PGF2α, 0.1 µM) were used to treat the cultured cells during the adipogenesis. Oil Red O-stained area and gene expression patterns in the OMD or FP agonists groups were compared with the control group without an agent using various statistical methods.
Results :
Accumulation of lipid droplets stained with Oil Red O was observed inside the cells in the control group at day 10, confirming the differentiation of 3T3-L1 cells to adipocytes. Whereas LAT-A and PGF2α significantly inhibited the accumulation of lipid droplets, OMD showed no effect on the accumulation, even at high concentrations up to 40 µM. LAT-A and PGF2α significantly suppressed the elevation of pparγ, c/ebpα and c/ebpβ expressions observed during the adipocyte differentiation. In contrast, OMD showed no obvious effects on these gene expressions.
Conclusions :
OMD did not affect the adipocyte differentiation in 3T3-L1 cells. Long term evidence in patients is needed, but these data suggest that OMDI does not induce DUES in glaucoma patients due to the different profile of OMD on gene expression related to adipogenesis in the eyelid fat tissue, unlike existing FP agonists.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.