title: Rho-Associated Kinase Inhibitor Eye Drop (Ripasudil) Transiently Alters the Morphology of Corneal Endothelial Cells.
abstract: OBJECTIVE
  Ripasudil (Glanatec), a selective Rho-associated coiled coil-containing protein kinase (ROCK) inhibitor, was approved in Japan in September 2014 for the treatment of glaucoma and ocular hypertension. The purpose of this study was to investigate the effect of ripasudil eye drops on corneal endothelial morphology, as ROCK signaling is known to modulate the actin cytoskeleton.
  
  
  METHODS
  Morphological changes in the corneal endothelium were evaluated in human subjects by specular and slit-lamp microscopy, following topical administration of ripasudil. We also used a rabbit model to evaluate the effect of ripasudil on clinical parameters of the corneal endothelium. Twenty-four hours after ripasudil application, corneal specimens were evaluated by phalloidin staining, immunohistochemical analysis, and electron microscopy.
  
  
  RESULTS
  Specular microscopy revealed morphological changes in human eyes, and slit-lamp microscopy showed guttae-like findings. The rabbit model showed morphological changes similar to those seen in human eyes after ripasudil administration. Electron microscopy demonstrated that these alterations are due to the formation of protrusions along the cell-cell borders, but this formation is transient. Expression of corneal endothelial function-related markers was not disrupted; corneal thickness and corneal volume were not changed; and no cell death was observed following ripasudil administration.
  
  
  CONCLUSIONS
  Ripasudil induces transient guttae-like findings in humans, most likely due to protrusion formation along intracellular borders caused by the reduction in actomyosin contractility of the corneal endothelial cells. No severe adverse effects were observed. Physicians should be aware that ROCK inhibitors can cause these guttae-like findings, to avoid misdiagnosing patients as having Fuchs endothelial corneal dystrophy. (www.umin.ac.jp/ctr number, UMIN000018340.).
authors.affiliation: Department of Biomedical Engineering Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Okumura
authors.affiliation: Department of Biomedical Engineering Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Okazaki
authors.affiliation: Department of Biomedical Engineering Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Inoue
authors.affiliation: Department of Biomedical Engineering Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakano
authors.affiliation: Biomedical and Life Sciences, School of Health and Medicine, Lancaster University, Lancaster, United Kingdom.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Fullwood
authors.affiliation: Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kinoshita
authors.affiliation: Department of Biomedical Engineering Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Koizumi
mesh_terms: D000328:Adult; D000818:Animals; D004728:Endothelium, Corneal / Q000187:drug effects / Q000648:ultrastructure*; D005260:Female; D005642:Fuchs' Endothelial Dystrophy / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007546:Isoquinolines / Q000008:administration & dosage*; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D009883:Ophthalmic Solutions; D011817:Rabbits; D013449:Sulfonamides / Q000008:administration & dosage*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D007546:Isoquinolines; C584679:K-115; D009883:Ophthalmic Solutions; D013449:Sulfonamides; D054460:rho-Associated Kinases