Involvement of Phosphorylation of Myosin Phosphatase by ROCK in Trabecular Meshwork and Ciliary Muscle Contraction

Fukiage, Chiho; Mizutani, K; Kawamoto, Yoko; Azuma, Mitsuyoshi; Shearer, Thomas R.

doi:10.1006/bbrc.2001.5751

Cited by 36 publications

(38 citation statements)

References 14 publications

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“…Rao et al (2001) have shown that ROCK inhibitor, Y-27632 treatment decreased myosin light chain phosphorylation and actomyosin organization in TM cells and Schlemm's canal cells, thereby lowering resistance to out¯ow. It has been shown that phosphorylation of the myosinbinding subunit (MBS) of myosin phosphatase was observed in the contracted TM or ciliary muscle, and the phosphorylation was well correlated with contraction of TM or ciliary muscle (Fukiage et al, 2001). The result in the present study is in good accordance with these previous studies and it is reasonable to conclude that cellular relaxation and loss of cellsubstratum adhesions in TM cells via modulation of myosin light chain phosphorylation could result in alteration of resistance to out¯ow.…”

Section: Discussionsupporting

confidence: 91%

A Myosin Light Chain Kinase Inhibitor, ML-9, Lowers the Intraocular Pressure in Rabbit Eyes

Honjo

Inatani

Kido

et al. 2002

Experimental Eye Research

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Section: Discussionsupporting

confidence: 91%

A Myosin Light Chain Kinase Inhibitor, ML-9, Lowers the Intraocular Pressure in Rabbit Eyes

Honjo

Inatani

Kido

et al. 2002

Experimental Eye Research

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“…14,22 The inhibitors Y-27632 and Y-39983 induce relaxation of carbachol-contracted rabbit CM strips and TM 11,13 and contract monkey TM, exhibiting involvement of phosphorylation of myosin phosphatase by ROCK. 23 Collectively, these findings suggest that TM is a target for the development of new cytoskeletal drugs, including ROCK inhibitors, for new treatment of glaucoma. Based on the findings of the present study, SNJ-1656 can be considered a candidate drug for lowering IOP by increasing conventional outflow with few adverse effects.…”

Section: Commentmentioning

confidence: 99%

Intraocular Pressure–Lowering Effects and Safety of Topical Administration of a Selective ROCK Inhibitor, SNJ-1656, in Healthy Volunteers

Inatani²,

et al. 2008

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To investigate the effects and safety of topical administration of an ophthalmic solution of a selective Rho-associated coiled coil-forming protein kinase (ROCK) inhibitor, SNJ-1656, 0.003% to 0.1%, in healthy male adult volunteers.Design: Randomized, double-masked, group-comparison, phase 1 clinical study. In the initial singleinstillation trial, 45 healthy volunteers were randomly subdivided into 5 groups and treated with SNJ-1656 in concentrations of 0.003%, 0.01%, 0.03%, 0.05%, and 0.1% in stepwise fashion. In the repeated-instillation trial, 36 healthy volunteers were assigned to receive SNJ-1656 ophthalmic solution at the following concentrations and dosages: 0.05% once daily, 0.1% once daily, 0.05% twice daily, or 0.1% twice daily. In our studies, the administration of the solution and subsequent examinations (including intraocular pressure [IOP] measurements) were performed in a double-masked fashion.Results: After single instillation of placebo or SNJ-1656, in concentrations of 0.003%, 0.01%, 0.03%, 0.05%, and 0.1%, the changes in IOP from the baseline were −0.91, −1.18, −1.48, − 2.20 (P = .04 vs placebo), −1.48, and −1.98 mm Hg, respectively, at 2 hours, and −0.63,−0.95, −1.79, −2.26 (P = .01 vs placebo), −1.95, and −3.00 mm Hg (PϽ .001 vs placebo) respectively, at 4 hours. Significant IOP reductions after repeated instillation were also found. On slitlamp examination during the trial, there were no significant adverse findings except hyperemia of the bulbar and palpebral conjunctiva after instillation. Conclusion:This clinical study demonstrated that SNJ-1656 is a safe topical agent effective in reducing IOP in human eyes.

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“…[14][15][16][17] There are two isoforms of ROCK: ROCK-1 and ROCK-2, and they are extensively distributed in various tissues 18 ; for example, in ocular tissues, they are expressed in the ciliary muscles, trabecular meshwork, iris, and retina. 19 The Rho/ ROCK pathway is involved in various neuropathological conditions, such as spinal cord injury, 20 Alzheimer's disease, 21 and demyelinating disease, 22,23 and ophthalmologic diseases, such as glaucoma, 24 corneal endothelial dysfunction, 25 diabetic retinopathy, 26 and age-related macular degeneration. 27 ROCK signaling has therefore attracted interest as a potential therapeutic target for these diseases.…”

mentioning

confidence: 99%

Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma

Akaiwa

Namekata

Azuchi

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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METHODS. Topical administration (5 lL/day) of two different concentrations of ripasudil (0.4% and 2%) were applied to EAAC1 KO mice from 5 to 12 weeks old. Optical coherence tomography, multifocal electroretinograms, the measurement of intraocular pressure (IOP), and histopathology analyses were performed at 5, 8, and 12 weeks old. Retrograde labeling of retinal ganglion cells (RGCs), immunoblot, and immunohistochemical analyses of phosphorylated p38 mitogen-activated protein kinase (MAPK) in the retina were performed at 8 weeks old.RESULTS. Topical ripasudil ameliorated retinal degeneration and improved visual function in EAAC1 KO mice at both 8 and 12 weeks old. Ripasudil reduced IOP and strongly suppressed the phosphorylation of p38 MAPK that stimulates RGC death in EAAC1 KO mice.CONCLUSIONS. These results suggest that, in addition to IOP reduction, ripasudil prevents glaucomatous retinal degeneration by neuroprotection, which is achieved by suppressing celldeath signaling pathways.

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Involvement of Phosphorylation of Myosin Phosphatase by ROCK in Trabecular Meshwork and Ciliary Muscle Contraction

Cited by 36 publications

References 14 publications

A Myosin Light Chain Kinase Inhibitor, ML-9, Lowers the Intraocular Pressure in Rabbit Eyes

A Myosin Light Chain Kinase Inhibitor, ML-9, Lowers the Intraocular Pressure in Rabbit Eyes

Intraocular Pressure–Lowering Effects and Safety of Topical Administration of a Selective ROCK Inhibitor, SNJ-1656, in Healthy Volunteers

Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma

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