Rho kinase inhibitors

From EyeWiki


Rho is a group of small GTP-binding proteins[1]. These proteins aid in regulation of cell structure, motility, division, and apoptosis. Rho kinases (ROCKs) are effectors of the Rho pathways (Rho activates ROCKs)[2][3]. There are two identified types of ROCKs referred to as ROCK1[4] and ROCK2[5]. Both are serine/tyrosine kinases. One of the main functions of ROCKs is to aid in reorganization of the actin cytoskeleton[6]. Cell growth, movement, and death can occur through this reorganization[7]. ROCKs are ubiquitous and expressed in all tissue types, although the concentration of the particular isoform may vary by tissue[7].

ROCKs are expressed in the cornea, and appear to be involved in corneal healing and cell differentiation[8][9]. Corneal endothelial cells (CEC) are responsible for maintaining the clarity of the cornea and express ROCKs[10][11]. The use of ROCK inhibitors (RKIs) has been shown to improve corneal wound healing and endothelial regeneration[12][13]. Because of this, RKIs are a promising therapeutic agent for corneal disease, but have also found applications in glaucoma and vitreoretinal disease.


Rho kinase plays a part in the guanine nucleotide exchange factors, factors that cycle between the bound and unbound conformations of GTP1[4]. Rho kinase specifically works downstream of RhoA protein, a Rho GTPase. Guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs) switch RhoA between its active GTP bound conformation and inactive GDP bound conformation[14][15].

Activated RhoA turns on a coiled-coil serine/threonine kinase called Rho kinase[14][15]. The two isoforms of ROCK, ROCK1 (ROKβ) and ROCK2 (ROKα), have similar effects but may also have different effects depending on the isoform[14][15]. Once active, Rho kinase phosphorylates myosin light chain, myosin phosphatase substrate 1, LIM kinase, CP1-17, calponin and the ERM proteins[14]. These factors serve a number of cellular roles including cell adhesion, actomyosin contraction, cell migration, and cell proliferation[7][14]. These factors have a critical role in outflow of aqueous humor[15]. As mentioned previously, ROCK has recently been shown to affect the corneal layers through cell proliferation, cell migration, including wound healing and progression through the cell cycle[7].

Indications for Rho Kinase Inhibitors in Ophthalmology

In the setting of corneal endothelial disease, both topical and anterior chamber injections with RKIs have been found to be beneficial[7]. In Fuchs endothelial corneal dystrophy (FECD), a form of anterior segment dysgenesis, use of ROCK inhibitor (Y-27632) eye drops have been successful in preserving corneal clarity and visual acuity[16]. The use of RKI eye drops (Ripasudil hydrochloride hydrate) as a salvage treatment for patients who have failed central descemetorhexis has also been found to be successful in a subset of patients[17]. These findings support a pharmacologic approach to a commonly surgical problem in CEC disease. In conjunction with other topical glaucoma therapies, RKIs have been shown to be effective in diseases of increased intraocular pressure (IOP) in both animal and human models[18][19]. Such diseases include ocular hypertension (predisposes patient to glaucoma) and primary open-angle glaucoma (POAG)[7]. The mechanism of ROCK inhibitors’ ability to decrease IOP is through direct action on the trabecular meshwork and Schlemm’s canal cells (increases permeability), which play a large role in the resistance of aqueous humor outflow[18]. RKIs also decrease reactive oxidative species damage to the trabecular meshwork which is a known component of glaucoma pathophysiology[20]. The ROCK pathway has also been implicated in retinal disease such as diabetic retinopathy. It is known that Rho and ROCK are expressed in central nervous tissue and retinal ganglion cells which may promote vasoconstriction through endothelin-1[21]. Therefore, use of RKIs promotes vasodilation and improved retinal blood flow, especially to the optic nerve head[7][21].

Commonly Used Rho Kinase Inhibitors

Two commonly used RKIs are Ripasudil (K-115) and Netarsudil(AR-13503)[15]. Ripasudil has been clinically approved to treat glaucoma in Japan. Side effects of Ripasudil include dose-dependent conjunctival hyperemia and non-dose dependent conjunctival hemorrhage[22]. It has not shown any other ophthalmological side effects. Netarsudil is both an RKI and a norepinephrine transport inhibitor. As a norepinephrine transport inhibitor, it decreases the reuptake of norepinephrine increasing its effects on the body and the alpha-adrenergic receptors[23]. It has also been clinically approved to treat glaucoma, specifically in the United States, and its intraocular pressure lowering effect has been shown to increase with latanoprost[7]. Side effects of Netarsudil include conjunctival hyperemia and corneal verticillata, instillation site pain, and conjunctival hemorrhages[15].

Rho kinase inhibitors have also been shown to treat corneal endothelial dysfunction[24]. They inhibit apoptosis and increase proliferation of monkey corneal endothelial cells, and these effects may be seen in humans[13]. Recent studies have shown that topical application of RKIs as eyedrops has also successfully treated Fuchs’ endothelial dystrophy and endothelial damage after cataract surgery, although more tests are necessary[24]. The mechanism proposed for increased cell cycle growth with corneal endothelial cells involve increased cyclin D levels which suppress phosphorylation of cyclin-dependent kinase inhibitor 1B, p27/kip115[24]. Both factors regulate cell division in corneal cells; however these effects may only be seen in younger patients[15][25].

Because of these properties, topical ripasudil is often given in conjunction with the descemet stripping only(DSO) procedure. Patients treated with topical ripasudil recovered vision more quickly and had higher endothelial cell density at 3,6 and 12 months.[26]

There have been two proposed methods of delivery of ROCK inhibitors to heal the corneal endothelium, including topical eye drops and an anterior chamber injection with cultured endothelial cells.[27]


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