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Rho kinase inhibitors for treatment of glaucoma.

ABSTRACT: Affecting 60 million patients, glaucoma is the second leading cause of blindness worldwide. Despite the availability of multiple medical and surgical treatments with effective intraocular pressure lowering, many patients still progress to become visually handicapped from glaucoma due to therapeutic failure. There is therefore a great need for novel therapies to improve the standard of care, and Rho kinase (ROCK) inhibitors represent a promising new class of drugs for treatment of glaucoma. ROCK inhibitors act by increasing facility of fluid outflow from the eye, thereby reducing intraocular pressure. ROCK inhibitors also have a vasodilatory effect on conjunctival vessels, which can lead to eye redness, a less than desirable cosmetic side effect for patients that would use this medication. Although there is promising data to support the clinical potential of this class of drug, the occurrence of conjunctival hyperemia remains a potential deterrent for use by patients. Studies are underway to assess alternative dosing strategies, delivery methods and prodrug formulations that may circumvent this unwanted side effect. This review provides an up-to-date account of the basic scientific data, as well as nonclinical and clinical studies to support use of ROCK inhibitors for treatment of glaucoma.

SUBMITTER: Mandell KJ

PROVIDER: S-EPMC6319899 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Rho kinase inhibitors for treatment of glaucoma.

Mandell Kenneth J KJ Kudelka Matthew R MR Wirostko Barbara B

Expert review of ophthalmology 20110101 6

Affecting 60 million patients, glaucoma is the second leading cause of blindness worldwide. Despite the availability of multiple medical and surgical treatments with effective intraocular pressure lowering, many patients still progress to become visually handicapped from glaucoma due to therapeutic failure. There is therefore a great need for novel therapies to improve the standard of care, and Rho kinase (ROCK) inhibitors represent a promising new class of drugs for treatment of glaucoma. ROCK ...[more]

PMID: 30613208

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Project description:In an elegant example of bench-to-bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of intraocular pressure (IOP) regulation. The critical discovery that pharmacologic manipulation of the cytoskeleton of outflow pathway cells decreased outflow resistance placed a spotlight on the Rho kinase pathway that was known to regulate the cytoskeleton. Ultimately, a search for Rho kinase inhibitors led to the discovery of several molecules of therapeutic interest, leaving us today with 2 new ocular hypotensive agents approved for clinical use: ripasudil in Japan and netarsudil in the United States. These represent members of the first new class of clinically useful ocular hypotensive agents since the US Food and Drug Administration approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower IOP in patients with glaucoma and ocular hypertension represents a triumph in translational research. Rho kinase inhibitors are effective alone or when combined with other known ocular hypotensive medications. They also offer the possibility of neuroprotective activity, a favorable impact on ocular blood flow, and even an antifibrotic effect that may prove useful in conventional glaucoma surgery. Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages, and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact. The objectives of this review are to describe the basic science underlying the development of Rho kinase inhibitors as a therapy to lower IOP and to summarize the results of the clinical studies reported to date. The neuroprotective and vasoactive properties of Rho kinase inhibitors, as well as the antifibrotic properties, of these agents are reviewed in the context of their possible role in the medical and surgical treatment of glaucoma.

Project description:Glaucoma, the most perilous disease leading to blindness is a result of optical neuropathy. Accumulation of aqueous humor in the posterior chamber due to a large difference in the rate of formation and its drainage in the anterior chamber causes an increase in intraocular pressure (IOP) leading to damage of nerve cells. A literature survey has revealed that inhibition of the Rho guanosine triphosphatases (rho GTPase) pathway by specific inhibitors leads to the relaxation of contractile cells involved in the aqueous outflow pathway. Relaxation of the strained contractile cells results in increased outflow thereby releasing IOP. In the present study molecular docking has been used to screen twenty seven bioactive (17 natural compounds and 10 conventional drugs) compounds that may play a significant role in relaxing contractile cells by inhibiting rho-GTPase protein. Docking results showed that among all-natural bioactive compounds Cyanidin and Delphinidine have a good binding affinity (- 8.4 kcal/mol) than the top screened conventional drug molecule Mitomycin, (- 6.3 kcal/mol) when docked with rho-GTPase protein. Cyanidin and Delphinidin belong to anthocyanidin, a glycoside form of anthocyanins from Vaccinium myrtillus L. and Punica granatum. The resembling potential of Cyanidin and Delphinidin concerning the drug Mitomycin was confirmed through simulation analysis. Molecular dynamics study (MDS) for 100 ns, showed that the rho GTPase-Delphinidine complex structure was energetically more stable than rho GTPase-Cyaniding complex in comparison to rho GTPase-Mitomycin complex. The comparative study of both the selected hits (Cyanidin and Delphinidin) was assessed by RMSD, RMSF, Rg, SASA, H-bond, PCA MM/PBSA analysis. The analysis revealed that Delphinidine is more potent to inhibit the rho GTPase as compare to Cyaniding and available conventional drugs in terms of stability and binding free energy. Based on the results, these molecules have good pharmacokinetic and pharmacodynamics properties and will prove to be a promising lead compound as a future drug for Glaucoma.

Project description:Neurofibrillary tangles, one of the pathological hallmarks of Alzheimer's disease, consist of highly phosphorylated tau proteins. Tau protein binds to microtubules and is best known for its role in regulating microtubule dynamics. However, if tau protein is phosphorylated by activated major tau kinases, including glycogen synthase kinase 3β or cyclin-dependent kinase 5, or inactivated tau phosphatase, including protein phosphatase 2A, its affinity for microtubules is reduced, and the free tau is believed to aggregate, thereby forming neurofibrillary tangles. We previously reported that pitavastatin decreases the total and phosphorylated tau protein using a cellular model of tauopathy. The reduction of tau was considered to be due to Rho-associated coiled-coil protein kinase (ROCK) inhibition by pitavastatin. ROCK plays important roles to organize the actin cytoskeleton, an expected therapeutic target of human disorders. Several ROCK inhibitors are clinically applied to prevent vasospasm postsubarachnoid hemorrhage (fasudil) and for the treatment of glaucoma (ripasudil). We have examined the effects of ROCK inhibitors (H1152, Y-27632, and fasudil [HA-1077]) on tau protein phosphorylation in detail. A human neuroblastoma cell line (M1C cells) that expresses wild-type tau protein (4R0N) by tetracycline-off (TetOff) induction, primary cultured mouse neurons, and a mouse model of tauopathy (rTG4510 line) were used. The levels of phosphorylated tau and caspase-cleaved tau were reduced by the ROCK inhibitors. Oligomeric tau levels were also reduced by ROCK inhibitors. After ROCK inhibitor treatment, glycogen synthase kinase 3β, cyclin-dependent kinase 5, and caspase were inactivated, protein phosphatase 2A was activated, and the levels of IFN-γ were reduced. ROCK inhibitors activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Collectively, these results suggest that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including Alzheimer's disease.

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Rho kinase inhibitors for treatment of glaucoma.

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Rho kinase inhibitors for treatment of glaucoma.

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