Preprint Article Version 1 This version is not peer-reviewed

Ocular Hypotension, Actin Stress Fiber Disruption and Phagocytosis Increase by RKI-1447, a Rho-Kinase Inhibitor

Version 1 : Received: 1 February 2018 / Approved: 5 February 2018 / Online: 5 February 2018 (03:39:57 CET)

How to cite: Dang, Y.; Wang, C.; Shah, P.; Waxman, S.; Loewen, R.T.; Loewen, N.A. Ocular Hypotension, Actin Stress Fiber Disruption and Phagocytosis Increase by RKI-1447, a Rho-Kinase Inhibitor. Preprints 2018, 2018020026 (doi: 10.20944/preprints201802.0026.v1). Dang, Y.; Wang, C.; Shah, P.; Waxman, S.; Loewen, R.T.; Loewen, N.A. Ocular Hypotension, Actin Stress Fiber Disruption and Phagocytosis Increase by RKI-1447, a Rho-Kinase Inhibitor. Preprints 2018, 2018020026 (doi: 10.20944/preprints201802.0026.v1).

Abstract

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.

Subject Areas

pig eye perfusion model; pigmentary glaucoma; ocular hypertension; ocular hypotension; phagocytosis; rho-kinase inhibitor

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