A Rho-Associated Kinase Inhibitor Protects Permeability in a Cell Culture Model of Ocular Disease, and Reduces Aqueous Flare in Anterior Uveitis.
Recent clinical and experimental studies have reported favorable results when using Rho-associated kinase (ROCK) inhibitors for ocular disease, and in cell culture. Disruption of the human, nonpigmented ciliary epithelial cells (HNPCECs) that comprise the blood-aqueous barrier (BAB) induces anterior uveitis; these cells therefore provide a useful cell model of ocular disease. In this study, we examined the effects of ROCK inhibitors in anterior uveitis and in HNPCECs.



Aqueous flare values and intraocular pressures (IOPs) were determined in patients with anterior uveitis, 2 weeks after administration of ripasudil hydrochloride hydrate, a commercial ROCK inhibitor used to treat glaucoma or ocular hypertension. We also investigated the effects of Y-27632, a second ROCK inhibitor, in HNPCECs following exposure to matrix metalloproteinases (MMPs) and human tumor necrosis factor-alpha (TNF-α).



Patients with anterior uveitis, glaucoma, or ocular hypertension, referred to the Aichi Medical University from February to July 2015, were enrolled. Thirty eyes from 25 outpatients were studied. Aqueous flare values and IOPs were significantly decreased 2 weeks after ripasudil hydrochloride hydrate treatment, with no adverse events. In a cultured HNPCEC monolayer, permeability was markedly increased following exposure to MMPs-1, 3, 9, and TNF-α, with these effects attenuated by exposure to Y-27632. In cultured HNPCECs, Y-27632 provoked a marked alteration in cytoskeletal morphology without a significant change in expression levels of claudin-1 and occludin.



ROCK inhibitors may confer favorable effects in anterior uveitis, possibly due to a reorganized BAB, although the relevant mechanisms remain unclear.
1 Department of Ophthalmology, Aichi Medical University , Nagakute, Japan .
Hiroshi
H
Yamada
2 Department of Biochemistry and Molecular Biology, School of Nursing and Health, Aichi Prefectural University , Nagoya, Japan .
Masahiko
M
Yoneda
3 Department of Pathology, Aichi Medical University , Nagakute, Japan .
Shingo
S
Inaguma
4 Department of Clinical Trial and Clinical Epidemiology, Faculty of Medicine, University of Tsukuba , Tsukuba, Japan .
Masahiko
M
Gosho
5 Department of Advanced Medicine, National Center for Geriatrics and Gerontology , Obu, Japan .
Yusuke
Y
Murasawa
5 Department of Advanced Medicine, National Center for Geriatrics and Gerontology , Obu, Japan .
Zenzo
Z
Isogai
1 Department of Ophthalmology, Aichi Medical University , Nagakute, Japan .|6 Department of Ophthalmology, Asai Hospital , Seto, Japan .
Masahiro
M
Zako
D000328:Adult; D000368:Aged; D001082:Aqueous Humor / Q000187:drug effects*; D001623:Betamethasone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D018929:Cell Culture Techniques; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005901:Glaucoma / Q000188:drug therapy / Q000473:pathology; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009798:Ocular Hypertension / Q000188:drug therapy / Q000473:pathology; D009883:Ophthalmic Solutions / Q000008:administration & dosage / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012189:Retrospective Studies; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D014606:Uveitis, Anterior / Q000188:drug therapy* / Q000473:pathology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D007546:Isoquinolines; C584679:K-115; D009883:Ophthalmic Solutions; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C028994:betamethasone sodium phosphate; D001623:Betamethasone; D054460:rho-Associated Kinases
anterior uveitis; aqueous flare; inhibitor of Rho-associated kinase; intraocular pressure; nonpigmented ciliary epithelium