Preprint Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 6 July 2018 / Approved: 9 July 2018 / Online: 9 July 2018 (11:27:28 CEST)

How to cite: Dang, Y.; Wang, C.; Shah, P.; Waxman, S.; Loewen, R.T.; Loewen, N.A. RKI-1447, a Rho-Kinase Inhibitor Causes Ocular Hypotension, Actin Stress Fiber Disruption and Increased Phagocytosis. Preprints 2018, 2018070131 (doi: 10.20944/preprints201807.0131.v1). Dang, Y.; Wang, C.; Shah, P.; Waxman, S.; Loewen, R.T.; Loewen, N.A. RKI-1447, a Rho-Kinase Inhibitor Causes Ocular Hypotension, Actin Stress Fiber Disruption and Increased Phagocytosis. Preprints 2018, 2018070131 (doi: 10.20944/preprints201807.0131.v1).

Abstract

Purpose: This study investigated the hypotensive effect of RKI-1447, a Rho kinase inhibitor, in a porcine ex vivo pigmentary glaucoma model. Methods: Twenty-eight porcine anterior chambers were perfused with medium supplemented with 1.67 × 107 pigment particles/mL for 48 hours before treatment with RKI-1447 (n = 16) or vehicle control (n = 12). Intraocular pressure (IOP) was recorded and outflow facility was calculated. Primary trabecular meshwork cells were exposed to RKI-1447 or vehicle control; effects on the cytoskeleton, motility, and phagocytosis were evaluated. Result: Compared to 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 caused no apparent histological changes in the micro- or macroscopic TM appearance. RKI-1447-treated primary TM cells showed significant disruption of the actin cytoskeleton both in the presence and absence of pigment (P < 0.001) but no effect on TM migration was observed. Pigment-treated TM cells exhibited a reduction in TM phagocytosis, which RKI-1447 reversed. Conclusion: RKI-1447 significantly reduces IOP by disrupting TM stress fibers and increasing TM phagocytosis. These features may make it useful for the treatment of secondary glaucomas with an increased phagocytic load.

Subject Areas

pigmentary glaucoma; ROCK kinase inhibitor; RKI-1447; trabecular meshwork; phagocytosis; cytoskeleton

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