Effects of Protein Kinase Inhibitor, HA1077, on Intraocular Pressure and Outflow Facility in Rabbit Eyes

Honjo, Megumi; Inatani, Masaru; Kido, Noriaki; Sawamura, Tatsuya; Yue, Beatrice Y.J.T.; Honda, Yoshio; Tanihara, Hidenobu

doi:10.1001/archopht.119.8.1171

Cited by 146 publications

(131 citation statements)

References 42 publications

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“…3). The magnitude of this facility increase is comparable to the 80% facility increase observed in porcine eyes after 3 hrs perfusion (Rao et al, 2001), but was less than the 2-and 3-fold increase observed after 3 hrs in rabbits (Honjo et al, 2001) and after 60-90 min in monkeys (Tian et al, 2005), respectively. Perfusion with tracer microspheres did not appear to influence outflow facility compared to the value immediately prior to tracer perfusion (8 ± 7%, p = 0.31).…”

Section: Outflow Facilitysupporting

confidence: 68%

“…In particular, such drugs include cytochalasin (Johnson, 1997;Kaufman and Erickson, 1982;Tian et al, 1999a), latrunculin (Ethier et al, 2006;Sabanay et al, 2006), H-7 (Bahler et al, 2004;Sabanay et al, 2004) and Y-27632 (Honjo et al, 2001;Rao et al, 2001;Tian and Kaufman, 2005;Waki, 2001), and are therefore important candidates for the next generation of glaucoma therapy. How these potential "glaucoma drugs" work to reduce outflow resistance, however, is much less understood, but determining their mechanism in the trabecular meshwork and their influence on aqueous outflow hydrodynamics is important for developing novel drugs that target specific sites of outflow limitation -namely, the inner wall endothelium of Schlemm's canal and the underlying juxtacanalicular connective tissue (JCT) (Maepea and Bill, 1992).…”

Section: Introductionmentioning

confidence: 99%

“…Inhibiting ROCK with Y-27 decreases MLC phosphorylation by promoting MLC-phosphatase activity (Kaibuchi et al, 1999;Rosenthal et al, 2005), leading to cell relaxation and disassembly of actin stress fibers and focal adhesions in many cell types (Rao et al, 2001), including human trabecular meshwork and Schlemm's canal endothelial cells in vitro (Honjo et al, 2001;Rao et al, 2001). In living rabbits, topical or intracameral delivery of Y-27 decreases IOP by 30-50% within 1-3 hrs (Honjo et al, 2001;Waki et al, 2001), which coincides with a 2-fold increase in trabecular outflow facility (Honjo et al, 2001). In living monkeys, perfusion with 10-100 µM Y-27 dose-dependently increases outflow facility by 2-3 fold within 1-2 hrs (Tian and Kaufman, 2005).…”

Section: Introductionmentioning

confidence: 99%

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The mechanism of increasing outflow facility by rho-kinase inhibition with Y-27632 in bovine eyes

Lü

Overby

Scott

et al. 2008

Experimental Eye Research

117

123

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Rho-kinase inhibitor Y-27632 (Y-27) affects actomyosin cytoskeletal networks and has been shown to significantly increase outflow facility (C) in enucleated porcine and rabbit eyes, as well as in vivo monkey eyes without obvious toxicity. The mechanisms underlying these responses remain largely unknown. In this study, we investigate how Y-27 affects aqueous humor C, the hydrodynamic patterns of outflow, and the morphology of the inner wall (IW) and juxtacanalicular connective tissue (JCT). 12 bovine eyes were perfused at 15 mmHg with Dulbecco's PBS containing 5.5 mM glucose (DPBS) to establish stable baseline C. The anterior chamber was exchanged and perfused with DPBS containing 50 µM Y-27 in 7 eyes, while 5 eyes received DPBS alone. Eyes were then perfused with DPBS containing fluorescent microspheres (0.5 µm; 0.002% v/v) at a fixed volume to deliver equivalent amounts of tracer to label the hydrodynamic filtration patterns. All eyes were perfusionfixed with Karnovsky's fixative. Radial and frontal sections were prepared in all quadrants and confocal images were taken along the IW of the aqueous plexus (AP). The total length (TL) and filtration length (FL) of the IW were measured in ≥16 images/eye, and the average percent effective filtration length (PEFL=FL/TL) was calculated. Sections with AP were processed and examined by light and electron microscopy. The TL of the IW and length exhibiting JCT/IW separation (SL) were measured in ≥16 micrographs/eye, and the average percent separation length (PSL= SL/TL) was also calculated. After Y-27 treatment, C increased from 1.54±0.34 (±SEM) to 2.36±0.54 µL/min/mmHg (58.2±18.9%) while control eyes changed from 1.67±0.41 to 1.71±0.39 µl/min/mmHg (6.0±9.3%) and the percent changes between the Y-27-treated and control eyes were significant (p = 0.03). Control eyes showed segmental distribution of tracer in the trabecular meshwork tending to cluster near collector channel ostia, whereas Y-27-treated eyes showed a more uniform pattern and extensive labeling along the IW. In Y-27-treated eyes, PEFL was 3-fold larger (57.6±3.7%) compared to control eyes (18.2±4.5%; p<0.001). Light microscopic examination revealed that, with Y-27, the IW and JCT were significantly distended compared to control eyes, with discernible separation between the IW and JCT. PSL was 2.8-fold larger in Y-27-treated eyes (59.3±3.6%) than in controls (20.8±2.0%; p<0.001). A significant positive correlation was found between PEFL and PSL (p = 0.003) suggesting that as connectivity between the JCT and IW decreases the available area for aqueous humor drainage Reprint Requests (Corresponding Author): Dr. Haiyan Gong, Department of Ophthalmology, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, Email: hgong@bu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of th...

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Section: Outflow Facilitysupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The mechanism of increasing outflow facility by rho-kinase inhibition with Y-27632 in bovine eyes

Lü

Overby

Scott

et al. 2008

Experimental Eye Research

117

123

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“…These differences might be related to NOS isozymes expressed in different organs. Y27632 has been previously shown to have significant effects on morphology in rat astrocytes when used alone at lower concentrations than that used here (Honjo et al, 2001). However, no significant changes in morphology were observed after Y27632 treatment of mouse astrocytes in the current study.…”

Section: Discussionmentioning

confidence: 74%

Lipocalin-2 Is an Autocrine Mediator of Reactive Astrocytosis

Lee¹,

Park²,

Lee³

et al. 2009

J. Neurosci.

239

238

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Astrocytes, the most abundant glial cell type in the brain, provide metabolic and trophic support to neurons and modulate synaptic activity. In response to a brain injury, astrocytes proliferate and become hypertrophic with an increased expression of intermediate filament proteins. This process is collectively referred to as reactive astrocytosis. Lipocalin 2 (lcn2) is a member of the lipocalin family that binds to small hydrophobic molecules. We propose that lcn2 is an autocrine mediator of reactive astrocytosis based on the multiple roles of lcn2 in the regulation of cell death, morphology, and migration of astrocytes. lcn2 expression and secretion increased after inflammatory stimulation in cultured astrocytes. Forced expression of lcn2 or treatment with LCN2 protein increased the sensitivity of astrocytes to cytotoxic stimuli. Iron and BIM (Bcl-2-interacting mediator of cell death) proteins were involved in the cytotoxic sensitization process. LCN2 protein induced upregulation of glial fibrillary acidic protein (GFAP), cell migration, and morphological changes similar to characteristic phenotypic changes termed reactive astrocytosis. The lcn2-induced phenotypic changes of astrocytes occurred through a Rho-ROCK (Rho kinase)-GFAP pathway, which was positively regulated by nitric oxide and cGMP. In zebrafishes, forced expression of rat lcn2 gene increased the number and thickness of cellular processes in GFAP-expressing radial glia cells, suggesting that lcn2 expression in glia cells plays an important role in vivo. Our results suggest that lcn2 acts in an autocrine manner to induce cell death sensitization and morphological changes in astrocytes under inflammatory conditions and that these phenotypic changes may be the basis of reactive astrocytosis in vivo.

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“…ROCK inhibitors are the first class of glaucoma drugs to increase aqueous humor outflow by working directly on the TM and SC cells, thus lowering IOP. Different ROCK inhibitors (Y-27632, H-1152, and fasudil) have been shown to induce rapid and long-lasting lowering of IOP (within 30 min and lasting for 6-12 h) in various animal models, including rabbit and monkey (39)(40)(41) . The exact mechanism by which Rho inhibitors increase the outflow facility through the conventional pathway is not completely understood.…”

Section: Rock Inhibitorsmentioning

confidence: 99%