Rho-associated kinase inhibitors: A novel glaucoma therapy
Introduction
Glaucoma is estimated to be the second leading cause of vision loss in the world, with an estimated 60.5 million people affected worldwide (Quigley and Broman, 2006). Despite the high prevalence, relatively little progress has been made in glaucoma management over the past several decades. Lowering intraocular pressure (IOP) is the classic treatment approach for glaucoma and is the only therapy that has been shown to be effective in large-scale clinical studies. Medications, mainly topical eye drops, are generally used first to reduce IOP. When these are insufficient, more invasive therapies, such as laser iridotomy and/or filtration surgeries, are performed. Unfortunately, the lowering of IOP following successful filtration surgery can be temporary because of excess scarring at the surgical site. Severe vision loss often results in these cases.
Glaucoma is a multifactorial disease and elevated IOP is not the only risk factor for the development and progression of glaucoma. Therefore, novel treatment strategies, such as protecting retinal ganglion cells or increasing retinal blood flow, have been explored. Memantine, a neuroprotectant that has shown promise in animal glaucoma models, only resulted in insignificant delays in glaucoma progression in clinical trials (Osborne, 2009). Still, this drug established the need and desire for glaucoma therapeutics that do not affect IOP.
In the study that first introduced Rho-associated kinase (ROCK) inhibitors as potential glaucoma therapeutics, we showed that the selective ROCK inhibitor Y-27632 (Uehata et al., 1997) lowered rabbit IOP (Honjo et al., 2001b). These compounds directly affect trabecular meshwork (TM, Fig. 1) and Schlemm's canal (SC) cells in vitro, which are different therapeutic targets than commercially available glaucoma drugs. Because of this, ROCK inhibitors have recently gained interest and are now the focus of several ongoing clinical trials. Moreover, accumulating evidence shows that ROCK inhibitors have favorable effects because of their ability to lower IOP in a novel way, but also because of neuroprotection. Interestingly, ROCK inhibitors also reduce tissue scarring after filtration surgery.
Section snippets
Tissue composition and function of aqueous outflow structures
Intraocular pressure depends on the balance between the inflow and outflow of aqueous humor. In glaucoma patients, IOP is elevated because of an increase in outflow resistance. Two aqueous humor outflow pathways exist in the eye. Aqueous mainly flows through the TM and SC to the episcleral vein, but an auxiliary uveoscleral pathway through the iris root and ciliary muscle exists, with fluid leaving the eye through the choroidal circulation or orbital tissues (Fig. 2). An increased resistance to
Molecular mechanisms by which ROCK inhibitors increase outflow facility
Most IOP-lowering drugs currently in clinical use suppress aqueous humor production (sympathomimetics, β-adrenergic receptor antagonists, carbonic anhydrase inhibitors) or enhance uveoscleral outflow (prostaglandin analogs; Brubaker, 2003). Pilocarpine, a miotic agent, increases conventional outflow through the TM and SC and also causes ciliary muscle contraction. This widens the spaces of the TM, thereby decreasing flow resistance and increasing aqueous humor outflow (Kaufman and Barany, 1976
Side effects of ROCK inhibitors
Rho kinase inhibitors can increase blood flow by inhibiting calcium sensitization and relaxing vascular smooth muscles (Uehata et al., 1997). From a therapeutic point of view, vasodilating conjunctival vessels would manifest as conjunctival hyperemia (Tanihara et al., 2008, Williams et al., 2011). This harmless cosmetic side effect does not affect vision, but would likely reduce patient satisfaction and compliance. To reduce the cosmetic implications of conjunctival hyperemia, a once-daily
Future directions
In this paper, we review the background, molecular mechanisms, and side effects of ROCK inhibitors. As stated in the opening paragraph, several clinical trials with ROCK inhibitors are currently underway. We reported that the topical ROCK inhibitor, Y-39983, when used twice daily, dramatically lowered IOP in healthy volunteers (Fig. 7; Tanihara et al., 2008). In addition, another ROCK inhibitor, AR-12286, safely lowered IOP in a recent clinical study (Williams et al., 2011), but approval for
Acknowledgments
This work was supported in part by JSPS KAKENHI Grant Number 23390403 and 23791994.
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Percentage of work contributed by each author in the production of the manuscript is as follows: Toshihiro Inoue, 80%; Hidenobu Tanihara, 20%.