Rho-Kinase Inhibitors as Emerging Targets for Glaucoma Therapy

Abstract

Glaucoma, the leading cause of irreversible blindness worldwide, is a chronic and progressive optic neuropathy characterized by damage to the optic and retinal nerve fiber layers, which can lead to permanent loss of peripheral or central vision. Reduction of intraocular pressure (IOP) is the only known modifiable risk factor for preventing and treating glaucoma. Rho kinase (ROCK) inhibitors are a new class of glaucoma drugs with a novel mechanism of action and good safety profile. They exert neuroprotective effects, act on the trabecular tissue, increase the outflow of aqueous humor, and reduce intraocular pressure. However, they also cause local adverse reactions, including common conjunctival congestion and subconjunctival bleeding; however, most are self-limiting and temporary. Netarsudil (0.02%), a ROCK inhibitor, relaxes the trabecular meshwork, increases the outflow of aqueous humor, reduces scleral venous pressure, and directly decreases IOP. Conjunctival congestion can be reduced if netarsudil is administered at night. The combination of these medications is always more effective than the single drug. Ripasudil (0.4%), another ROCK inhibitor, also lowers IOP; however, conjunctival hyperemia is the most common adverse drug reaction. The purpose of this review is to summarize the effects and adverse reactions of ROCK inhibitors in the experimental trial stage and in clinical treatment in recent years, providing suggestions for future clinical drug use, and research and development to reduce the side effects of these drugs, maximize the potential for reducing IOP, and improve the therapeutic effect.

Apoptosis in glaucoma: A new direction for the treatment of glaucoma (Review)

“…Therefore, a strategy to improve survivin expression may be a useful for treating glaucoma. Recently, ROCK inhibitors have been identified as a new class of drugs that directly target TM cells to reduce IOP ( 250 , 251 ). In a transgenic mouse model, ROCKi was reported to reduce IOP by promoting cell proliferation and phagocytosis of TM cell, reducing actin cross-linking and cell adhesion interactions ( 74 , 250 , 252 ).…”

The Application of Rho Kinase Inhibitors in the Management of Glaucoma

“…In humans, both ROCK1 and ROCK2 are expressed in the eye but differ in other tissue distributions. ROCK1 is mainly expressed in non-neural tissues like the heart, lung, and skeletal muscle, while ROCK2 is primarily expressed in the brain [ 20 ].…”

“…Additionally, the use of ROCK inhibitors also lead to similar positive outcomes in rabbit models [ 25 , 34 ]. As such, Rho/ROCK inhibitors may benefit glaucoma patients through non-IOP-dependent mechanisms, such as neuroprotection, by improving blood flow to the optic nerve and increasing ganglion cell survival [ 14 , 20 ]. However, most of the hypotheses regarding neuroprotection and improved blood flow are based on findings from animal models.…”

“…The in vivo animal model studies also revealed similar findings. They suggested that ROCK inhibitors have therapeutic potential in reducing scar formation after glaucoma filtration surgeries by inhibiting the transdifferentiation of fibroblasts into myofibroblasts and extracellular matrix deposition in rabbit and rat models [ 20 , 38 , 39 , 40 ]. In real-world clinical practice, further research is needed to determine if ROCK inhibitors exhibit similar anti-fibrosis properties.…”