Honjo Megumi, Tanihara Hidenobu
Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto, Japan.
Jpn J Ophthalmol. 2018 Mar;62(2):109-126. doi: 10.1007/s10384-018-0566-9. Epub 2018 Feb 14.
Rho-associated protein kinase (ROCK), a ubiquitously expressed signaling messenger and downstream effector of Rho, is activated by several bioactive factors in the aqueous humor (AH). Rho-ROCK signaling regulates a wide spectrum of fundamental cellular events, including cell adhesion, motility, proliferation, differentiation, and apoptosis. Previous studies, including our own, found that ROCK inhibitor lowers intraocular pressure (IOP) via a direct effect on the conventional AH outflow pathway, by regulation of contractile properties, fibrotic activity, and permeability of the trabecular meshwork (TM) and Schlemm's canal (SC) tissues, influencing extracellular matrix (ECM) production. Recently, a novel ROCK inhibitor, ripasudil, has been introduced in Japan. Other ROCK inhibitors are now in clinical trials as new IOP-lowering drugs for glaucoma patients. To date, ripasudil, administered together with other glaucoma medications, has proved safe and efficient in lowering IOP as well as additional effects such as prostaglandin analogs, beta-blockers, and carbonic anhydrase inhibitors, all of which help lower IOP by different mechanisms. In addition, we found that long-term treatment with ripasudil exerted an additional IOP-lowering effect, especially in eyes with high IOP, suggesting that late-onset remodeling of the ECM in glaucomatous eyes may elicit mild and delayed changes in IOP levels. ROCK inhibitors have also shown several additional effects, including increased retinal blood flow, direct protection of neurons against various types of stress, and regulation of wound healing; these benefits may potentially be useful in glaucoma treatment.
Rho相关蛋白激酶（ROCK）是一种广泛表达的信号信使，也是Rho的下游效应器，可被房水中的多种生物活性因子激活。Rho-ROCK信号传导调节广泛的基本细胞事件，包括细胞粘附、运动、增殖、分化和凋亡。包括我们自己的研究在内的先前研究发现，ROCK抑制剂通过对传统房水流出途径的直接作用，调节小梁网（TM）和施莱姆管（SC）组织的收缩特性、纤维化活性和通透性，影响细胞外基质（ECM）产生，从而降低眼压（IOP）。最近，一种新型ROCK抑制剂ripasudil已在日本上市。其他ROCK抑制剂目前正处于临床试验阶段，作为治疗青光眼患者的新型降眼压药物。迄今为止，ripasudil与其他青光眼药物联合使用，已被证明在降低眼压方面是安全有效的，并且还有其他作用，如前列腺素类似物、β受体阻滞剂和碳酸酐酶抑制剂，所有这些药物都通过不同机制帮助降低眼压。此外，我们发现ripasudil长期治疗具有额外的降眼压作用，尤其是在高眼压眼中，这表明青光眼眼中ECM的晚期重塑可能会引起眼压水平的轻微和延迟变化。ROCK抑制剂还显示出其他几种作用，包括增加视网膜血流量、直接保护神经元免受各种类型的应激以及调节伤口愈合；这些益处可能对青光眼治疗有用。
