Abstract
Purpose :
Accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) causes elevated intraocular pressure (IOP) in POAG patients. However, there are few eye drops targeting TM. Therefore, we investigated compounds that act on ECM of the TM. To develop novel therapeutic agents that affect the TM, we focused on Activin receptor-like kinase 5 (ALK5) inhibitors. ALK5/smad pathway is important for the production of ECM. The purpose of this study was to clarify the effects of ALK5 inhibitor on murine IOP and human trabecular meshwork cells (HTMCs).
Methods :
To investigate the compound that acts on ECM of the TM, HTMCs were added to various chemical compounds known as suppressing ECM accumulation. These cells were incubated for 72 hours. The expression of ECM was measured by using Western blotting and RT-PCR. Normal mice were treated topically with ALK5 inhibitor (SB431542) or Rho-associated coiled-coil-containing protein kinase inhibitor (Y-27632). At 1-24 hours after topical treatment, the animals were anesthetized and IOP was measured using a rebound tonometer. The effect of drug application was calculated as the difference in IOP between the treated eye and the contralateral control eye in each mouse. SB431542 or Y-27632 was administered chronically (three consecutive days; once daily). The pressures in both eyes were recorded before each dose.
Results :
ALK5 inhibitor suppressed the expression and production of fibronectin and collagen1 in HTMC. In addition, staining of the cytoskeleton with phalloidin showed that SB431542 did not affect the cytoskeleton. The effect on mouse IOP showed that a single dose of SB431542 reduced IOP by -1.704 ± 0.466 mmHg, -1.167 ± 0.383 mmHg, and -1.044 ± 0.331 mmHg at 6, 12, and 24 hours after topical administration. Moreover, in multiple doses, the IOP-lowering effect was sustained and enhanced.
Conclusions :
The long-term IOP-lowering effect inhibition of ALK5 is the advantage of SB431542, which is not observed in existing drugs. Therefore, ALK5 inhibitor may be a novel therapeutic strategy for lowering IOP.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.