Abstract
Purpose :
In clinical trials, the intracameral bimatoprost SR implant lowers intraocular pressure (IOP) well beyond cessation of drug release by the implant. Since matrix metalloprotease (MMP) activity underlies topical bimatoprost effects on IOP, we hypothesized that long-term effects of bimatoprost SR was due to effects of dramatically elevated outflow tissue levels of unmetabolized bimatoprost (amide, not bimatoprost free acid (BFA)) on MMP activity in outflow pathway cells.
Methods :
Human outflow pathway cells (trabecular meshwork, TM, n=7; ciliary muscle, CM, n=6; scleral fibroblasts, SF as controls, n=4) in culture were treated with either implant tissue levels of bimatoprost (10–1000 µM) or topical tissue levels of BFA (0.1–10 µM). Cells were exposed to drug for 24 hours, and MMP gene expression was measured by PCR array and MMP1 protein by ELISA.
Results :
Compared to all other treatments, implant levels of bimatoprost (1000 µM) significantly altered expression of the greatest number of genes in all cell types (e.g.: n=11 partially overlapping genes in TM and CM cells, p<0.05,). Despite these significant effects, there was noticeable strain to strain differences in responses to implant levels of bimatoprost. By comparison, only two genes were significantly altered in TM and CM cells with topical outflow tissue levels of BFA (10 µM). In the one glaucomatous TM cell strain tested, implant levels of bimatoprost had similar effects on most genes compared to normal cells. However, 1000 µM bimatoprost dramatically increased MMP1 and MMP10 expression in glaucomatous TM cells well above average responses of normal TM cells (183.8 vs. 62.9±66.4 fold, and 52.1 vs. 2.89±2.4 fold, respectively), both genes of which were dose-dependently upregulated in normal TM cells, but not CM cells. Similarly, MMP1 protein levels were dose-dependently upregulated in TM, but not CM cells.
Conclusions :
Bimatoprost and BFA had differential effects on MMP gene expression, with a dramatic upregulation in MMP1 in TM cells seen only at “implant levels” of bimatoprost. These preferential effects of high dose bimatoprost on MMP expression on TM cells suggests that increased conventional outflow is due to durable tissue remodeling, underlying long term IOP benefit of implant in some patients.
This is a 2021 ARVO Annual Meeting abstract.