Rho-Kinase Inhibitors: The Application and Limitation in Management of Glaucoma
Abstract
1. Introduction
2. Pharmacokinetics and Intraocular Pressure-Lowering Profiles of Marketed Rho Kinase Inhibitors
2.1. Netarsudil (AR-13324)
2.1.1. Pharmacokinetics
2.1.2. IOP Lowering Efficacy
2.2. Ripasudil (K-115)
2.2.1. Pharmacokinetics
2.2.2. IOP Lowering Efficacy
- POAG and OHT: In the prospective observational J-ROCK study and a randomized controlled trial by the K-115 Clinical Study Group, IOP reductions of 3.0–4.5 mmHg over 4 to 8 weeks were achieved by ripasudil 0.4% b.i.d. [14,18]. When employed as an adjunctive treatment with other glaucoma medications, IOP was reduced by 2.6–2.9 mmHg with ripasudil b.i.d. [29,30].
- Secondary glaucoma: In the ROCK-S retrospective cohort study by Futakuchi et al. [31], 332 eyes with secondary glaucoma (including uveitic, exfoliative, and steroid-induced glaucoma) were treated with 0.04% ripasudil. Statistically significant IOP reduction was observed at 1, 2, and 6 months of follow-up, with a maximal reduction of 7.00 ± 8.60 mmHg being achieved at 6 months.
2.3. Fasudil
2.3.1. Pharmacokinetics
2.3.2. IOP Lowering Efficacy
3. Role of Rho Kinase Inhibitors in Ocular Perfusion
4. Modulation of Inflammation and Fibrosis by Rho Kinase Inhibitors
5. Neuroprotective Potential of Rho Kinase Inhibitors
6. Limitation of Rho Kinase Inhibitors
6.1. Ocular Adverse Effect
6.2. Modest IOP Reduction Efficacy
7. Prospects for Rho Kinase Inhibitors
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ATP | Adenosine triphosphate |
ATX | Autotaxin |
Bcl-2 | B-cell lymphoma/leukemia-2 |
CTGF | Connective tissue growth factor |
ECM | Extracellular matrix |
IL | Interleukin |
IOP | Intraocular pressure |
LIMK | LIM domain kinase |
LPA | Lysophosphatidic acid |
NO | Nitric oxide |
OHT | Ocular hypertension |
q.d. | Once daily |
POAG | Primary open angle glaucoma |
ROS | Reactive oxygen species |
RGC | Retinal ganglion cell |
ROCK | Rho kinase |
TM | Trabecular meshwork |
TGF-β | Transforming growth factor-β |
TNF | Tumor necrosis factor |
b.i.d. | Twice daily |
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---|---|---|---|---|
Conventional therapy | Mitomycin-C | Mitomycin-C is an alkylating agent that inhibits cellular proliferation. | Suppresses fibroblast proliferation and inhibits collagen production; significantly lowers IOP in primary trabeculectomy. | Jampel et al. [39] Bindlish et al. [40] |
5-Fluorouracil | 5-Fluorouracil inhibits thymidylate synthase and further halts DNA synthesis in replicating cells. | Inhibit human Tenon’s fibroblast proliferation; improves IOP control after trabeculectomy. | Khaw et al. [42] Rothman et al. [43] | |
ROCK 1 inhibitor | AR12286 | Inhibits TGF 2-β1-induced myofibroblast transdifferentiation, as well as fibronectin and collagen production. | Inhibits conjunctival fibroblast activation; effective at lower concentrations compared to other ROCK inhibitors for antifibrotic effects. | Cheng et al. [45] |
Y-27632 | Inhibits TGF-β1/Smad2,3 signaling, suppressing α-SMA 3, CTGF 4, fibroblast activation, and ECM 5 production. | Inhibits profibrotic signaling in tenon’s fibroblasts; effective in vitro in fibroblast cultures. | Feng et al. [46] |
Mechanism | Molecular Mediators | Cellular Effects | Clinical Relevance | Authors |
---|---|---|---|---|
Anti-apoptotic Signaling | Downregulation: caspase-3, calpain Upregulation: Bcl-2 1, pAkt 2, CRMP2 3 | Reduced cell death, increased cell survival | Potential to prevent retinal cell loss in various degenerative conditions | Koch et al. [52] Wang et al. [53] Zhang et al. [54] |
Inflammatory Modulation | Downregulation: TNF 4, IL-1α 5 | Reduced microglial activation, decreased inflammatory cytokine production | Alleviate chronic inflammation associated with retinal degeneration | Wen et al. [55] Sato et al. [56] |
Oxidative Stress Response | Downregulation: ROS 6 | Protection against oxidative damage, improved cell survival | Mitigate oxidative stress-induced retinal damage in various pathologies | Yamamoto et al. [57] Shaw et al. [58] Quillen et al. [59] |
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Chao, Y.-P.; Chiu, T.-H.; Lu, D.-W. Rho-Kinase Inhibitors: The Application and Limitation in Management of Glaucoma. Biomedicines 2025, 13, 1871. https://doi.org/10.3390/biomedicines13081871
Chao Y-P, Chiu T-H, Lu D-W. Rho-Kinase Inhibitors: The Application and Limitation in Management of Glaucoma. Biomedicines. 2025; 13(8):1871. https://doi.org/10.3390/biomedicines13081871
Chicago/Turabian StyleChao, Yuan-Ping, Ta-Hung Chiu, and Da-Wen Lu. 2025. "Rho-Kinase Inhibitors: The Application and Limitation in Management of Glaucoma" Biomedicines 13, no. 8: 1871. https://doi.org/10.3390/biomedicines13081871
APA StyleChao, Y.-P., Chiu, T.-H., & Lu, D.-W. (2025). Rho-Kinase Inhibitors: The Application and Limitation in Management of Glaucoma. Biomedicines, 13(8), 1871. https://doi.org/10.3390/biomedicines13081871