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Ocular hypotension, actin stress fiber disruption and phagocytosis increase by RKI-1447, a Rho-kinase inhibitor

Dang, Yalong and Wang, Chao and Shah, Priyal and Waxman, Susannah and Loewen, Ralitsa T. and Loewen, Nils A. (2018) Ocular hypotension, actin stress fiber disruption and phagocytosis increase by RKI-1447, a Rho-kinase inhibitor. (Submitted)

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Objective: The Rho GTPase/Rho kinase pathway is an important target in glaucoma treatment. This study investigated the hypotensive effect of RKI-1447, a Rho kinase inhibitor developed for cancer treatment, in a porcine ex vivo pigmentary glaucoma model.
Materials and Methods: Twenty-eight fresh porcine anterior chambers were perfused with pigment medium (1.67×107 pigment particles/ml) for 48 hours before being subjected to the RKI-1447 (n=16) or the vehicle control (n=12). Another twelve eyes with normal medium perfusion served as the control. The intraocular pressure (IOP) was recorded at two-minute intervals and the outflow facility was calculated. To investigate the intracellular mechanism of the IOP reduction, primary trabecular meshwork cells were exposed to RKI-1447 or the vehicle control and then analyzed for changes in cytoskeleton, motility, and phagocytosis.
Results: Compared to the baseline, the perfusion of pigment caused a significant increase in IOP in the RKI-1447 group (P=0.003) at 48 hours. Subsequent treatment with RKI-1447 significantly reduced IOP from 20.14+/-2.59 mmHg to 13.38+/-0.91 mmHg (P=0.02). Pigment perfusion reduced the outflow facility from 0.27+/-0.03 at baseline to 0.18+/-0.02 at 48 hours (P<0.001). This was partially reversed with RKI-1447. RKI-1447 exhibited no apparent changes in the micro- or macroscopic appearance, including histology. Primary TM cells exposed to RKI-1447 showed a significant disruption of the actin cytoskeleton both in the presence and absence of pigment exposure (P<0.001) but no effect on TM migration was observed. Pigment-treated TM cells exhibited a reduction in TM phagocytosis, which RKI reversed.
Conclusions: RKI-1447 is a novel ROCK inhibitor that significantly reduces IOP by disrupting TM stress fibers and increasing TM phagocytosis. These features may make it especially useful for the treatment of secondary glaucomas with an increased phagocytosis load but also for other open angle glaucomas.


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Item Type: Article
Status: Submitted
CreatorsEmailPitt UsernameORCID
Dang, Yalongyad23@pitt.eduYAD23
Wang, Chao
Shah, Priyal
Waxman, Susannah
Loewen, Ralitsa T.rtl13@pitt.eduRTL13
Loewen, Nils A.nal58@pitt.eduNAL580000-0001-7167-1213
Date: 25 January 2018
Schools and Programs: School of Medicine > Ophthalmology
Refereed: No
Article Type: Research Article
Date Deposited: 30 Jan 2018 19:06
Last Modified: 30 Jan 2018 19:06


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