Hello everyone
I have some doubts about the short-term mechanisms of action of Rho kinase inhibitors on corneal endothelial cells. Can someone help me? I am not finding the information I need in the literature.
As you may know, Y-27632 has been extensively evaluated in pre-clinical studies aimed at the treatment of corneal endothelial lesions. The inhibition of the ROCK signaling pathway with Y-27632 results in inhibition of myosin light chain (MLC) phosphorylation, with subsequent inhibition of apoptosis of corneal endothelial cells. The literature shows that 100 hours after treatment with Y-27632, endothelial cell cultures show totally collapsed stress fibers and a significant reduction in the apoptotic index. However, I wonder what happens within the first 15-30 minutes after exposure of the cell to the Rho kinase inhibitor? Is any significant effect expected on cell metabolism or activities in such a short period of time? Finally, considering the rational clinical use of Y-27632 and possible ocular adverse effects (ocular hypotension, intense hyperemia, etc.) of its instillation, is inhibition of Rho/ROCK advantageous in which situations that affect the corneal endothelium? Would you use Y-27632 only to prevent cell loss in a healthy corneal endothelium?
Hi Marcela,
I can't say for the first 15-30 minutes, but I can definitely say that changes should be apparent within an hour. See the following paper on a ROCK inhibitor series I worked on:
Article AMA0076, a Novel, Locally Acting Rho Kinase Inhibitor, Poten...
Changes intraocular pressure are visible within an hour. Which means that the trabecular meshwork cells have already been affected for some time at that point. Also, in human trabecular meshwork cells, changes in cell morphology and in the cytoskeleton could be seen after one hour of exposure to the test compound.
Best,
Sandro
Following Dr. Bolands' citation Netarsudil -ROCK inhibitor is available for clinical use in Open agle glaucoma with special IOP-lowering mechanism of action
Hello, thank you all for the contribution. I'm reading the paper.
I am sending to your attention the following impactful papers
9 Jaffe AB, Hall A. Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 2005;21:247–69. 10 Zeng P, Pi RB, Li P, et al. Fasudil hydrochloride, a potent ROCK inhibitor, inhibits corneal neovascularization after alkali burns in mice. Mol Vis 2015;21:688–98. 11 Yin J, Yu FS, Fs Y. Rho kinases regulate corneal epithelial wound healing. Am J Physiol Cell Physiol 2008;295:C378–C387. 12 Sijnave D, Van Bergen T, Castermans K, et al. Inhibition of Rho-associated kinase prevents pathological wound healing and neovascularization after corneal trauma. Cornea 2015;34:1120–9. 13 Zhou Q, Duan H, Wang Y, et al. ROCK inhibitor Y-27632 increases the cloning efficiency of limbal stem/progenitor cells by improving their adherence and ROSscavenging capacity. Tissue Eng Part C Methods 2013;19:531–7. 14 Okumura N, Koizumi N, Ueno M, et al. The new therapeutic concept of using a rho kinase inhibitor for the treatment of corneal endothelial dysfunction. Cornea 2011;30(Suppl 1):S54–9. 15 Okumura N, Koizumi N, Ueno M, et al. ROCK inhibitor converts corneal endothelial cells into a phenotype capable of regenerating in vivo endothelial tissue. Am J Pathol 2012;181:268–77. 16 Galvis V, Tello A, Gutierrez ÁJ. Human corneal endothelium regeneration: effect of ROCK inhibitor. Invest Ophthalmol Vis Sci 2013;54:4971–3. 17 Siu GD, Young AL, Jhanji V. Alternatives to corneal transplantation for the management of bullous keratopathy. Curr Opin Ophthalmol 2014;25:347–52. 18 Koizumi N, Okumura N, Kinoshita S. Development of new therapeutic modalities for corneal endothelial disease focused on the proliferation of corneal endothelial cells using animal models. Exp Eye Res 2012;95:60–7. 19 Okumura N, Inoue R, Okazaki Y, et al. Effect of the Rho Kinase Inhibitor Y-27632 on corneal endothelial wound healing. Invest Ophthalmol Vis Sci 2015;56:6067–74. 20 Pipparelli A, Arsenijevic Y, Thuret G, et al. ROCK inhibitor enhances adhesion and wound healing of human corneal endothelial cells. PLoS One 2013;8:e62095. 21 Okumura N, Koizumi N, Kay EP, et al. The ROCK inhibitor eye drop accelerates corneal endothelium wound healing. Invest Ophthalmol Vis Sci 2013;54:2493–502. 22 Okumura N, Okazaki Y, Inoue R, et al. Effect of the Rho-associated kinase inhibitor eye drop (Ripasudil) on corneal endothelial wound healing. Invest Ophthalmol Vis Sci 2016;57:1284–92. 23 Chan W, Akhbanbetova A, Quantock AJ, et al. Topical delivery of a Rho-kinase inhibitor to the cornea via mucoadhesive film. Eur J Pharm Sci 2016;91:256–64
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