Effects of Y-39983, a Selective Rho-Associated Protein Kinase Inhibitor, on Blood Flow in Optic Nerve Head in Rabbits and Axonal Regeneration of Retinal Ganglion Cells in Rats

Tokushige, Hideki; Waki, Mitsunori; Takayama, Yoshiko; Tanihara, Hidenobu

doi:10.3109/02713683.2011.599106

Cited by 57 publications

(48 citation statements)

References 30 publications

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“…In a 2011 paper by Tokushige et al56 a 0.05% solution of Y-39983 was topically administered to the eyes of six live rabbits. For each of these animals, blood flow in the optic nerve head was significantly improved after treatment, presumably through the relaxation of vascular endothelial smooth muscle 58. Similarly, in 2011, Sugiyama et al48 showed that both intravenous and topical doses of Fasudil (Asahi Kasei Corporation, Tokyo, Japan), a ROCK inhibitor, prevented impairment of optic nerve blood flow by a known nitric oxide synthase inhibitor in rabbits, thereby reinforcing the ability of ROCK inhibitors to mediate normal blood flow in the eye 48.…”

Section: Other Applications Of Rho Kinase Inhibitors In Glaucomamentioning

confidence: 98%

“…Animal studies have demonstrated increased ocular blood flow as well as potential neuroprotective effects, and ROCK inhibitors may also have the potential to reduce postoperative scarring during glaucoma-filtering surgery 48,58–63. In a 2011 paper by Tokushige et al56 a 0.05% solution of Y-39983 was topically administered to the eyes of six live rabbits.…”

Section: Other Applications Of Rho Kinase Inhibitors In Glaucomamentioning

confidence: 99%

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An emerging treatment option for glaucoma: Rho kinase inhibitors

Wang¹,

Chang²

2014

OPTH

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Rho kinase (ROCK) inhibitors are a novel potential class of glaucoma therapeutics with multiple compounds currently in Phase II and III US Food and Drug Administration trials in the United States. These selective agents work by relaxing the trabecular meshwork through inhibition of the actin cytoskeleton contractile tone of smooth muscle. This results in increased aqueous outflow directly through the trabecular meshwork, achieving lower intraocular pressures in a range similar to prostaglandins. There are also animal studies indicating that ROCK inhibitors may improve blood flow to the optic nerve, increase ganglion cell survival, and reduce bleb scarring in glaucoma surgery. Given the multiple beneficial effects for glaucoma patients, ROCK inhibitors are certainly a highly anticipated emerging treatment option for glaucoma.

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Section: Other Applications Of Rho Kinase Inhibitors In Glaucomamentioning

confidence: 98%

Section: Other Applications Of Rho Kinase Inhibitors In Glaucomamentioning

confidence: 99%

An emerging treatment option for glaucoma: Rho kinase inhibitors

Wang¹,

Chang²

2014

OPTH

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show abstract

“…(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. (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.…”

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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“…Accordingly, the suppression of Rho-kinase activity using pharmacological inhibitors like Fasudil and Y-27632 effectively promoted the vasodilation in numerous experimental models [19,20,21], and the clinical use of the former inhibitor yielded promising results for the treatment of several cardiovascular disorders and subarachnoid haemorrhage in humans [22,23]. Recent studies also demonstrated an improvement in ocular blood flow at the optic nerve head in response to different Rho-kinase inhibitors [24,25]. In addition, the selective inhibition of Rho-kinase allowed for the regeneration of the retinal ganglion cell axons in numerous models of optic nerve injury [26,27,28] and prevented the retraction of the photoreceptor axons in an in vitro model of acute retinal detachment [29].…”

Section: Introductionmentioning

confidence: 99%

The Neuroprotective Potential of Rho-Kinase Inhibition in Promoting Cell Survival and Reducing Reactive Gliosis in Response to Hypoxia in Isolated Bovine Retina

Alt

Hilgers

Tura

et al. 2013

Cell Physiol Biochem

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Aims: To investigate the outcomes of Rho-kinase inhibition in the electrophysiological ex vivo model of the isolated perfused vertebrate retina under hypoxia. Methods: Bovine retinas were perfused with an oxygen saturated nutrient solution with or without the Rho-kinase inhibitor H-1152P. The retinas were stimulated repeatedly until stable amplitudes were reached and the electroretinogram was recorded at five minute intervals. Hypoxia was induced for 15, 30, and 45 minutes, after which the oxygen saturation was restored. The extent of the cell damage and glial reactivity was determined by Ethidium homodimer-1 staining, immunohistochemistry, and Western blot. Results: Hypoxia caused a time-dependent reduction of the b-wave amplitudes, which could not be prevented by the H-1152P. Although the Rho-kinase inhibitor maintained higher b-wave amplitudes, these effects did not reach statistical significance. Hypoxia also resulted in an increase in cell damage and the activation of the glial cells in the untreated retinas whereas the administration of H-1152P significantly reduced the extent of these events. Conclusion: H-1152P exerted a neuroprotective effect against necrosis on the isolated bovine retina under hypoxia together with a reduction in glial cell reactivity. However, the inhibitor could not prevent the hypoxia induced retinal dysfunction possibly due to the interference with synaptic modulation.

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Effects of Y-39983, a Selective Rho-Associated Protein Kinase Inhibitor, on Blood Flow in Optic Nerve Head in Rabbits and Axonal Regeneration of Retinal Ganglion Cells in Rats

Cited by 57 publications

References 30 publications

An emerging treatment option for glaucoma: Rho kinase inhibitors

An emerging treatment option for glaucoma: Rho kinase inhibitors

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

The Neuroprotective Potential of Rho-Kinase Inhibition in Promoting Cell Survival and Reducing Reactive Gliosis in Response to Hypoxia in Isolated Bovine Retina

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