Abstract
PurposeTo investigate the effects of Ripasudil (K-115), a Rho-kinase inhibitor, in a porcine model of pigmentary glaucoma.MethodsIn vitro trabecular meshwork (TM) cells and ex vivo perfused eyes were subjected to pigment dispersion followed by K-115 treatment (PK115). PK115 was compared to controls (C) and pigment (P). Cytoskeletal alterations were assessed by F-actin labeling. TM cell phagocytosis of fluorescent targets was evaluated by flow cytometry. Cell migration was studied with a wound-healing assay. Intraocular pressure was continuously monitored and compared to after the establishment of the pigmentary glaucoma model and after treatment with K-115.ResultsThe percentage of cells with stress fibers increased in response to pigment but declined sharply after treatment with K-115 (P: 32.8% ± 2.9%; PK115: 11.6% ± 3.3%, P < 0.001). Phagocytosis first declined but recovered after K-115 (P: 25.7% ± 2.1%, PK115: 33.4% ± 0.8%, P <0.01). Migration recuperated at 12 hours with K-115 treatment (P: 19.1 ± 4.6 cells/high-power field, PK115: 42.5 ± 1.6 cells/high-power field, P < 0.001). Ex vivo, eyes became hypertensive from pigment dispersion but were normotensive after treatment with K-115 (P: 20.3 ± 1.2 mm Hg, PK115: 8.9 ± 1.7 mm Hg; P < 0.005).ConclusionsIn vitro, K-115 reduced TM stress fibers, restored phagocytosis, and restored migration of TM cells. Ex vivo, K-115 normalized intraocular pressure.Translational RelevanceThis ex vivo pigmentary glaucoma model provides a readily available basis to investigate new drugs such as the rho-kinase inhibitor studied here.
Highlights
Pigment dispersion syndrome (PDS) is characterized by the shedding of pigmented debris from the iris pigment epithelium and its ectopic accumulation throughout the anterior segment of the eye but primarily in the trabecular meshwork (TM) [1]
Pigmentary glaucoma is caused by the dispersion of pigment from the posterior side of the iris and ciliary processes that accumulates in the TM
In earlier studies with primary porcine TM cells [3]and porcine anterior segment perfusion model [4], we found that pigmentary debris caused an increase of TM cell stress fibers, reduced phagocytosis, and mobility, and led to a persistent intraocular pressure (IOP) elevation [17]
Summary
Pigment dispersion syndrome (PDS) is characterized by the shedding of pigmented debris from the iris pigment epithelium and its ectopic accumulation throughout the anterior segment of the eye but primarily in the trabecular meshwork (TM) [1]. Pigmentary glaucoma, a common secondary open-angle glaucoma, can develop due to PDS. It is characterized by heavy pigmentation of the TM, increased intraocular pressure (IOP), and characteristic glaucomatous optic neuropathy [2]. Miotics lower IOP and reduce the underlying pigment dispersion by minimizing friction between zonules and the iris. This is poorly tolerated in non-presbyopic patients due to myopization [7]. Rho-kinase inhibitors are a more recent class of glaucoma medications that increase the outflow facility by relaxing the TM cytoskeleton [8,9,10,11]and dilating the distal outflow tract [12]. Tanihara et al found that a 0.4% solution of K-115 lowered the IOP by around 20% from a low baseline of 19 mmHg [16]
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