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Editors Selection IGR 16-4
Basic Reseach: RHO-kinase inhibitor
Comment by Baohe Tian & Paul Kaufman on:
12242 Contribution of ROCK in contraction of trabecular meshwork: Proposed mechanism for regulating aqueous outflow in monkey and human eyes, Nakajima E; Nakajima T; Minagawa Y et al., Journal of Pharmaceutical Sciences, 2005; 94: 701-708
Cellular contractility in the trabecular meshwork (TM), mediated by the actin cytoskeleton, is an important regulator of aqueous outflow and a potential glaucoma therapeutic target.1 TM relaxation increases outflow facility by expanding the draining surface of the meshwork.2 However, ciliary muscle (CM) relaxation decreases the TM outflow function normally maintained by tonic CM contraction.3 Therefore, cytoskeletal drugs that relax TM but not CM may have a more favorable therapeutic profile. Nakajima et al. (647) report that the levels of mRNAs for ROCK and ROCK substrates are higher in TM than in CM in monkey or human tissues, and that the Rho kinase inhibitor Y-39983 substantially inhibits carbachol-induced contraction in TM, but only slightly in CM. The outflow facility increasing, IOP lowering effects of cytoskeletal drugs in general, and cell contractility inhibitors acting on the Rho/ROCK/MLCK pathways in particular, have been reported extensively, and in models that are far closer to the clinical world than what has been used here.1,2,4-7 Several classes of such compounds have been proposed as potential glaucoma therapy,8,9 and indeed are in development for this purpose. Nonetheless, the data reported by Nakajima et al. are interesting and support Y-39983 as potentially another good clinical candidate for a TM-selective anti-glaucoma medication.
References
- Tian B, Geiger B, Epstein DL, Kaufman PL. Cytoskeletal involvement in the regulation of aqueous humor outflow. Invest Ophthalmol Vis Sci. 2000;41:619-623.
- Sabanay I, Gabelt BT, Tian B, Kaufman PL, Geiger B. H-7 effects on structure and fluid conductance of monkey trabecular meshwork. Arch Ophthalmol. 2000,118:955-962.
- Kiland JA, Croft MA, Gabelt BT, Kaufman PL. Atropine reduces but does not eliminate the age-related decline in perfusion outflow facility in monkeys. Exp Eye Res. 1997;64:831-835.
- Tian B, Kaufman PL, Volberg T, Gabelt BT, Geiger B. H-7 disrupts the actin cytoskeleton and increases outflow facility. Arch Ophthalmol. 1998;116:633-643
- Honjo M, Tanihara H, Inatani M, Kido N, Sawamura T, Yue BYJT, Shuh N, Honda Y. Effects of rho associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility. Invest Ophthalmol Vis Sci. 2001;42:137-144.
- Rao PV, Deng P-F, Kumar J, Epstein DL. Modulation of aqueous humor outflow facility by the rho kinase specific inhibitor Y-27632. Invest Ophthalmol Vis Sci. 2001;42:1029-1037Invest Ophthalmol Vis Sci. 2000;41:619-623.
- Tian B, Kaufman PL. Effects of the rho kinase inhibitor Y-27632 and the phosphatase inhibitor calyculin A on outflow facility in monkeys. Exp Eye Res. 2005;80:215-225.
- Tian B, Wang R-F, Podos SM, Kaufman PL. Effects of topical H-7 on outflow facility, intraocular pressure and corneal thickness in monkeys. Arch Ophthalmol. 2004;122:1171-1177.
- Okka M, Tian B, Kaufman PL. Effect of low-dose latrunculin B on anterior segment physiologic features in the monkey eye. Arch Ophthalmol. 2004;122:1482-1488.
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