Currently, corneal blindness is affecting >10 million individuals worldwide, and there is a significant unmet medical need because only 1.5% of transplantation needs are met globally due to a lack of high-quality grafts. In light of this global health disaster, researchers are developing corneal substitutes that can resemble the human cornea in vivo and replace human donor tissue. Thus, this review examines ROCK (Rho-associated coiled-coil containing protein kinases) inhibitors as a potential corneal wound-healing (CWH) therapy by reviewing the existing clinical and nonclinical findings. The systematic review was done from PubMed, Scopus, Web of Science, and Google Scholar for CWH, corneal injury, corneal endothelial wound healing, ROCK inhibitors, Fasudil, Netarsudil, Ripasudil, Y-27632, clinical trial, clinical study, case series, case reports, preclinical study, in vivo, and in vitro studies. After removing duplicates, all downloaded articles were examined. The literature search included the data till January 2023. This review summarized the results of ROCK inhibitors in clinical and preclinical trials. In a clinical trial, various ROCK inhibitors improved CWH in individuals with open-angle glaucoma, cataract, iris cyst, ocular hypertension, and other ocular diseases. ROCK inhibitors also improved ocular wound healing by increasing cell adhesion, migration, and proliferation in vitro and in vivo. ROCK inhibitors have antifibrotic, antiangiogenic, anti-inflammatory, and antiapoptotic characteristics in CWH, according to the existing research. ROCK inhibitors were effective topical treatments for corneal infections. Ripasudil, Y-27632, H-1152, Y-39983, and AMA0526 are a few new ROCK inhibitors that may help CWH and replace human donor tissue.

2015-09-01·Cornea3区 · 医学

Inhibition of Rho-Associated Kinase Prevents Pathological Wound Healing and Neovascularization After Corneal Trauma

3区 · 医学

Article

作者: Ingeborg Stalmans ; Jean-Marie Stassen ; Karolien Castermans ; Evelien Vandewalle ; Davine Sijnave ; Lieve Moons ; Nele Kindt ; Tine Van Bergen

PURPOSE:

To investigate the effect of AMA0526, a specific inhibitor of rho-associated protein kinase (ROCK), on corneal neovascularization (NV) and scarring in different in vitro and in vivo experimental models.

METHODS:

The effect of AMA0526 on cell viability, proliferation, and migration of human umbilical vein endothelial cells was determined. Its in vivo topical effect on NV was investigated in the corneal micropocket mouse model (bevacizumab as a control). The vessel length, clock hours, and NV area were measured on photographs. The effect of AMA0526 on pathological wound healing was investigated in the alkali burn mouse model (dexamethasone as a control). Corneas were scored for corneal opacity (CO) and NV after burn injury. Immunohistochemistry was performed to study inflammation, blood vessel density, and collagen III deposition after 7 days.

RESULTS:

ROCK inhibition significantly inhibited vascular endothelial cell proliferation and migration in vitro in a dose-dependent manner. In the micropocket model, NV was significantly reduced by AMA0526 (37% reduction, P < 0.05) comparable to bevacizumab. CO and NV were reduced after AMA0526, compared with the vehicle (P < 0.05 at all time points from day 3) after chemical burn. AMA0526 resulted in decreased inflammatory cell infiltration (26% reduction, P < 0.01), angiogenesis (47% reduction, P < 0.01), and collagen III deposition (27% reduction, P = 0.009) in the alkali burn model. AMA0526 administration showed results similar to those of dexamethasone with an additional antifibrotic effect.

CONCLUSIONS:

The ROCK inhibitor, AMA0526, efficiently inhibited angiogenesis in vitro, reduced CO and NV, and controlled the complete process of wound healing in vivo. These results warrant further investigation of the therapeutic potential of AMA0526 for corneal NV and scarring.

2015-01-01·Progress in brain research4区 · 医学

Rho kinase inhibitor AMA0526 improves surgical outcome in a rabbit model of glaucoma filtration surgery

4区 · 医学

Review

作者: Van Bergen, Tine ; Kindt, Nele ; Castermans, Karolien ; Van de Velde, Sarah ; Vandewalle, Evelien ; Moons, Lieve ; Stalmans, Ingeborg

PURPOSE:

First, to elucidate the effect of Rho kinase inhibitor, AMA0526, on Human Tenon Fibroblast (HTF) proliferation and transdifferentiation to myofibroblasts. Second, the effects of ROCK inhibition on the wound healing process and surgical outcome were investigated in a rabbit model of glaucoma filtration surgery.

METHODS:

After exposure of HTF to AMA0526 (0.1-25 μM), a water-soluble tetrazolium salt-1 assay and caspase 3/7 activity assay were used to assess its effect on cell proliferation and to elucidate any toxic effects, respectively. Immunohistochemistry of α-smooth muscle actin expression was used to investigate fibroblast-to-myofibroblast differentiation induced by transforming growth factor-beta 1 (TGF-β1) in the presence or absence of the ROCK inhibitor. The effect of topical treatment was studied in a rabbit model of glaucoma filtration surgery. Treatment outcome was studied by performing intraocular pressure (IOP) measurements and clinical investigation of the bleb area and survival. Immunohistological analysis for inflammation (CD45), angiogenesis (CD31), and collagen I was performed at day 8, 14, and 30 after surgery (n=5/time point). Separate control groups treated with vehicle were used as control.

RESULTS:

In vitro results showed that AMA0526 dose dependently inhibited proliferation of HTF (P<0.05) without the induction of caspase 3/7 activity. Incubation of HTF with the AMA0526 inhibited TGF-β1 induced fibroblast-to-myofibroblast differentiation. In the rabbit model, topical treatment significantly improved surgical outcome. Compared to vehicle-treated eyes, AMA0526 resulted in increased bleb area (P<0.0001) and prolonged survival (P=0.0025). IOP remained significantly lower throughout the course of the experiment in the AMA0526 group (P<0.0001). Histological evaluation revealed that blebs treated with the ROCK inhibitor were characterized by reduced inflammation, angiogenesis, and collagen deposition at the site of filtration surgery (P<0.05).

CONCLUSIONS:

AMA0526 had profound effects on HTF proliferation and myofibroblast transition and improved glaucoma filtration surgery outcome by interfering at different levels of the wound healing process. Therefore, these data indicate that ROCK inhibitors may be considered as more physiological agents which specifically target the wound healing process to improve the outcome of glaucoma surgery.

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