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

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 (1.67×10 7 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.

Outflow Enhancement by Three Different ab Interno Trabeculectomy Procedures in a Porcine Anterior Segment Model

“…Third, EVP was likely close to zero in the perfusion model; however, it is higher in glaucoma patients [31,32]. However, the widespread use of porcine eyes in glaucoma research by our group [18,[37][38][39][40][41][42][43][44] and others [45][46][47][48][49][50][51][52][53] and in glaucoma surgery models [16,41,[54][55][56] validates and justifies its use in this study. In particular, outflow enhancement by trabecular ablation [14,16] or trabecular bypass surgery [16] demonstrated a behavior highly similar to human eyes.…”

Outflow enhancement by three different ab interno trabeculectomy procedures in a porcine anterior segment model

“…Third, EVP was likely close to zero in the perfusion model; however, it is higher in glaucoma patients [30,31]. However, the widespread use of porcine eyes in glaucoma research by our group [12,17,20,27,[35][36][37][38] and others [39][40][41][42][43][44][45][46][47] and in glaucoma surgery models [11][12][13]15] validates and justifies its use in this study. In particular, outflow enhancement by trabecular ablation [13,15] or trabecular bypass surgery [15] demonstrated a behavior highly similar to human eyes.…”

Intraocular Pressure Reduction in a Pigmentary Glaucoma Model by Goniotome Ab Interno Trabeculectomy

“…We recently found that a Rho-kinase inhibitor can relax the contracted cytoskeleton and normalize outflow in an ex vivo PG model. 19 In the present study, we hypothesized that trabecular excision with an I&A-equipped dual-blade device could also restore outflow by removing the pathology. We have extensive experience studying outflow in experimental systems, 20,21 including gene transfer, [22][23][24][25][26][27][28] disease modeling 5,7,19 and surgical outflow enhancement, 14,15,18,[29][30][31][32] but this is the first study of a microsurgical intervention for glaucoma in an ex vivo model of glaucoma.…”