Ripasudil in a model of pigmentary glaucoma

Wang, Chao; Dang, Yalong; Waxman, Susannah; Hong, Ying; Shah, Priyal; Loewen, Ralitsa T.; Xia, Xiaobo; Loewen, Nils A.

doi:10.1101/2020.05.04.076760

Cited by 2 publications

(3 citation statements)

References 34 publications

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“…ROCK inhibitors H1152, Y27632, and fasudil-reduced smooth muscle actin (SMA) expression (68 to 85%) and collagen gel contraction (27 to 36%) by scleral fibroblasts. The Rho-kinase inhibitor Ripasudil also demonstrated IOP-lowering effect in PDG by reducing trabecular meshwork stress fibers and restored migration of trabecular meshwork cells (Wang et al 2020) [26].…”

Section: Discussionmentioning

confidence: 99%

Ultrastructural analysis of explanted CyPass microstents and correlation with clinical findings

Hübner

Schlötzer‐Schrehardt

Weller

et al. 2022

Graefes Arch Clin Exp Ophthalmol

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Purpose The purpose of this study was to obtain insight into cellular processes after CyPass microstent implantation into the supraciliary space. With this knowledge, we expected to find some reason for surgical failure. Methods Nine CyPass microstents of 8 patients with primary open-angle glaucoma (n = 1), pseudoexfoliation glaucoma (n = 5), uveitic glaucoma (n = 1), and posttraumatic open-angle glaucoma (n = 1) were explanted due to recurrence of IOP elevation, corneal decompensation, or persistent hypotony. The explants were processed for light and transmission electron microscopy. Results Fibrotic material, consisting of collagen fibrils, microfibrils, pseudoexfoliation fibrils produced by activated fibroblasts, was detected in the stent lumen of 4/5 pseudoexfoliation glaucoma patients and also in posttraumatic open-angle glaucoma. Fibrotic material was also present on the outer surface and within fenestrations of the majority of stents. Complete absence of fibrotic reaction was noticed in 3 of 9 microstents. Conclusion Although MIGS is known to be less invasive than conventional surgery, implants placed in the suprachoroidal space may be adversely affected by a fibrotic tissue reaction resulting in implant failure. Understanding mechanisms and risk factors leading to fibrotic scarring following antiglaucomatous surgery may help to develop novel strategies that improve surgical outcome.

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Section: Discussionmentioning

confidence: 99%

Ultrastructural analysis of explanted CyPass microstents and correlation with clinical findings

Hübner

Schlötzer‐Schrehardt

Weller

et al. 2022

Graefes Arch Clin Exp Ophthalmol

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“…When these functions are not performed sufficiently to maintain normal conditions, the essential role of phagocytosis in keeping TM channels free of obstructive debris is disrupted (Gagen et al, 2013). A previous study found that phagocytosis was disrupted in pathological TM cells, but that one type of ROCKi (RKI-1447) could recover TM phagocytosis to a near reference range (Dang et al, 2019). The results of immunofluorescence and flow cytometry analyses in our study indicate that Y-27632 has a similar effect in promoting phagocytosis by GTM 3 cells, such that it nearly recovered to the level observed in normal TM cells.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we hypothesized that ROCKi also promote the proliferation of TM cells. A recent study found that RKI-1447, a ROCKi, significantly reduces IOP by increasing TM phagocytosis, which is an essential function of TM cells (Dang et al, 2019). Y-27632 is the first ROCKi drug reported to reduce IOP (Honjo et al, 2001), and its IOP-lowering effect was verified in multiple species (Gong and Yang, 2014).…”

Section: Introductionmentioning

confidence: 99%

Rho-Associated Protein Kinase Inhibitor Treatment Promotes Proliferation and Phagocytosis in Trabecular Meshwork Cells

et al. 2020

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Purpose: Continuous reductions in trabecular meshwork (TM) cellularity inhibit aqueous humor (AH) outflow, which is the main cause of primary open-angle glaucoma. Rhoassociated protein kinase inhibitor (ROCKi) targets the TM to reduce intraocular pressure (IOP) and increase AH outflow facility. However, the underlying mechanisms are not entirely clear. Here, we aimed to investigate the effect of a ROCKi (Y-27632) on TM cell proliferation and phagocytosis. Methods: Immortalized human TM (iHTM) cells, glaucomatous TM (GTM 3) cells, and primary human TM (pTM) cells were cultured and identified. The effects of various concentrations of Y-27632 on F-actin cytoskeleton were assessed using immunofluorescence. Cell proliferation effects were evaluated using a cell counting kit-8 (CCK8), cell counting, and Ki67 immunostaining. Cell phagocytosis was evaluated using immunofluorescence and flow cytometry in immortalized TM cells. C57BL/6J and Tg-MYOC Y437H mice were used to investigate the proliferative effects of Y-27632 on TM cells in vivo. The effect of Y-27632 on IOP was monitored for 2 weeks, and the outflow facility was detected 2 weeks after IOP measurement. TM cells in mice were counted using immunohistochemistry. Results: Y-27632 (100 µM) significantly promoted the proliferation of both immortal TM cells and pTM cells. In GTM 3 cells, phagocytosis was significantly greater in the Y-27632 group than in the control group, nearly reaching the level of phagocytosis in iHTM, as determined using immunofluorescence and flow cytometry. In Tg-MYOC Y437H mice, treatment with Y-27632 significantly decreased IOP and increased outflow facility, which greatly influenced the long-term IOP-lowering effect. The number of TM cells in Tg-MYOC Y437H mice was significantly improved after Y-27632 administration. Conclusion: Y-27632 promoted cell proliferation and phagocytosis of TM cells, and its proliferative effect was demonstrated in a transgenic mouse model. These results revealed a new IOP-lowering mechanism of Y-27632 through effects on TM cells, suggesting the potential for a correlation between TM cellularity and long-term recovery of IOP.

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Ripasudil in a model of pigmentary glaucoma

Cited by 2 publications

References 34 publications

Ultrastructural analysis of explanted CyPass microstents and correlation with clinical findings

Ultrastructural analysis of explanted CyPass microstents and correlation with clinical findings

Rho-Associated Protein Kinase Inhibitor Treatment Promotes Proliferation and Phagocytosis in Trabecular Meshwork Cells

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