An emerging treatment option for glaucoma: Rho kinase inhibitors

Wang, Sean K.; Chang, Robert

doi:10.2147/opth.s41000

Cited by 64 publications

(49 citation statements)

References 65 publications

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“…While inhibitors of GSK-3β have been identified as an important strategy for the treatment of CNS disorders including AD [49], to date, there are few studies investigating whether these molecules could be of benefit for the treatment of glaucoma. Elevated levels of RhoA are reported in the ONH of human eyes with glaucoma [66], and Rho kinase (ROCK) inhibitors are increasingly recognised as a promising therapeutic strategy for the treatment of glaucoma, indicating shared pathology [184]. In addition to the well-established IOP-modulating activity of these agents, ROCK inhibitors have been found to promote RGC axonal regeneration in both murine and feline models of optic nerve crush, a subject recently reviewed by Van de Velde et al [177].…”

Section: Mechanisms Of Rgc and Axonal Deathmentioning

confidence: 99%

Glaucoma: the retina and beyond

Davis¹,

Crawley

Pahlitzsch³

et al. 2016

Acta Neuropathol

234

151

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Over 60 million people worldwide are diagnosed with glaucomatous optic neuropathy, which is estimated to be responsible for 8.4 million cases of irreversible blindness globally. Glaucoma is associated with characteristic damage to the optic nerve and patterns of visual field loss which principally involves the loss of retinal ganglion cells (RGCs). At present, intraocular pressure (IOP) presents the only modifiable risk factor for glaucoma, although RGC and vision loss can continue in patients despite well-controlled IOP. This, coupled with the present inability to diagnose glaucoma until relatively late in the disease process, has led to intense investigations towards the development of novel techniques for the early diagnosis of disease. This review outlines our current understanding of the potential mechanisms underlying RGC and axonal loss in glaucoma. Similarities between glaucoma and other neurodegenerative diseases of the central nervous system are drawn before an overview of recent developments in techniques for monitoring RGC health is provided, including recent progress towards the development of RGC specific contrast agents. The review concludes by discussing techniques to assess glaucomatous changes in the brain using MRI and the clinical relevance of glaucomatous-associated changes in the visual centres of the brain.

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Section: Mechanisms Of Rgc and Axonal Deathmentioning

confidence: 99%

Glaucoma: the retina and beyond

Davis¹,

Crawley

Pahlitzsch³

et al. 2016

Acta Neuropathol

234

151

View full text Add to dashboard Cite

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“…(Challa and Arnold, 2014; Nakajima et al, 2005; Rao et al, 2005; Rao et al, 2001; Wang and Chang, 2014) In addition, Rock inhibitors have been reported to increase ocular blood flow to the optic nerve head, enhancing RGC survival and axon regeneration after ischemic injury. (Sugiyama et al, 2011; Tokushige et al, 2011) Rock inhibitors also reduce scar formation and inflammation following glaucoma filtering surgery.…”

Section: Introductionmentioning

confidence: 99%

“…(Honjo et al, 2007) These data suggest that Rock inhibitors may have additional beneficial effects for the management of glaucoma other than reduction of IOP. (Challa and Arnold, 2014; Wang and Chang, 2014; Yamamoto et al, 2014)…”

Section: Introductionmentioning

confidence: 99%

Topical administration of a Rock/Net inhibitor promotes retinal ganglion cell survival and axon regeneration after optic nerve injury

Shaw

Sang

Wang

et al. 2017

Experimental Eye Research

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Intraocular pressure (IOP)-lowering ophthalmic solutions that inhibit Rho-associated protein kinases (Rock) and norepinephrine transporters (Net) are currently under clinical evaluation. Here we evaluate topical application of one such drug for its effects on retinal ganglion cell (RGC) survival and axon regeneration after optic nerve crush injury. We performed unilateral optic nerve crush on young rats (P18) and topically applied Rock/Net inhibitor AR-13324 or placebo 3 times a day for 14 days. IOP was measured starting 3 days before and up to 9 days after injury. On day 12, cholera toxin B (CTB) was injected intravitreally to trace optic nerve regeneration. On day 14, retinas and optic nerves were collected. The retinas were flat-mounted and stained with RBPMS to quantify RGC survival and the optic nerves were sectioned for optic nerve axon quantification using fluorescent and confocal microscopy. Rock phosphorylation targets implicated in axon growth including cofilin and LIMK were examined by fluorescence microscopy and quantitative western blotting. AR-13324 lowered IOP as expected. RGC survival and optic nerve axon regeneration were significantly higher with Rock/Net inhibitor treatment compared with placebo. Furthermore, topical therapy decreased Rock target protein phosphorylation in the retinas and proximal optic nerves. These data suggest that topical administration of a Rock/Net inhibitor promotes RGC survival and regeneration after optic nerve injury, with associated molecular changes indicative of posterior drug activity. Coordinated IOP lowering and neuroprotective or regenerative effects may be advantageous in the treatment of patients with glaucoma.

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“…The fibrogenic effect caused by TGFβ2 is believed to be mediated, in part, by activated RhoGTPase/Rho-associated kinase (ROCK). ROCK-inhibitors are a novel potential class of glaucoma therapeutics offering distinct applications including reduced IOP, improved ocular blood flow, inhibition of postoperative scarring, and even neuroprotection910. With demonstrated effectiveness in animal models, several ROCK-inhibitors are currently undergoing Phase II and III clinical trials in glaucoma1011.…”

mentioning

confidence: 99%

“…ROCK-inhibitors are a novel potential class of glaucoma therapeutics offering distinct applications including reduced IOP, improved ocular blood flow, inhibition of postoperative scarring, and even neuroprotection910. With demonstrated effectiveness in animal models, several ROCK-inhibitors are currently undergoing Phase II and III clinical trials in glaucoma1011. ROCK inhibitors can affect the contractile properties of HTM cells, α-smooth muscle actin (α-SMA) expression, ECM accumulation in the outflow pathway and aqueous humor outflow9101112.…”

mentioning

confidence: 99%

TGFβ2-induced outflow alterations in a bioengineered trabecular meshwork are offset by a rho-associated kinase inhibitor

Torrejon

Papke

Halman

et al. 2016

Sci Rep

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Members of the transforming growth factor beta (TGFβ) cytokine family have long been associated with affecting several cellular functions, including cell proliferation, differentiation and extracellular matrix (ECM) turnover. Of particular interest to this work, TGFβ2 has been linked to most types of glaucomas as a potential fibrotic agent that can cause elevation of intraocular pressure (IOP). Given that the trabecular meshwork (TM) provides most of aqueous humor outflow resistance in the eye, an in vitro bioengineered human TM (HTM) model has been created and validated by analyzing effects of TGFβ2 on transcellular pressure changes and outflow facility. These changes were correlated with several biological alterations induced by this cytokine, including ECM production and overexpression of HTM-marker myocillin. Furthermore, this TM model has been used to extend current knowledge of gene expression of cytokines involved in TGFβ-induced ECM turnover over time. In particular, the ability for a ROCK-inhibitor to diminish the effect of TGFβ on TM was demonstrated. This work supports the notion that anti-fibrotic activities of ROCK-inhibitors could counteract the elevation of IOP and increased strain observed in glaucomatous TM.

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An emerging treatment option for glaucoma: Rho kinase inhibitors

Cited by 64 publications

References 65 publications

Glaucoma: the retina and beyond

Glaucoma: the retina and beyond

Topical administration of a Rock/Net inhibitor promotes retinal ganglion cell survival and axon regeneration after optic nerve injury

TGFβ2-induced outflow alterations in a bioengineered trabecular meshwork are offset by a rho-associated kinase inhibitor

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