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. 2025 Jun:255:110351.
doi: 10.1016/j.exer.2025.110351. Epub 2025 Mar 20.

Ripasudil does not induce phospholipid accumulation in human corneal epithelial cells

Fumiko Tazoe  1 , Yuichiro Watanabe  2 , Noriyuki Inoue  2 , Mizuho Kanazawa  3 , Atsushi Kasano  3 , Toshihiro Inoue  4
Affiliations
Free article

Ripasudil does not induce phospholipid accumulation in human corneal epithelial cells

Fumiko Tazoe et al. Exp Eye Res. 2025 Jun.
Free article

Abstract

Rho-associated coiled-coil-containing protein kinase (Rho kinase; ROCK) inhibitors represent a novel class of glaucoma medications that lower intraocular pressure by enhancing aqueous humor outflow through the conventional outflow pathway. Netarsudil, a ROCK inhibitor, is known to induce cornea verticillata as an adverse effect in clinical settings. Unlike systemic amiodarone and antimalarials, topical agents do not typically induce the development of this corneal condition. This study investigated whether ripasudil, another ROCK inhibitor, induces cornea verticillata using a Chinese hamster-derived ovary cell line (CHO-K1), SV40 transformed human corneal epithelial cell line (HCE-T), and normal human primary corneal epithelial cells (HCEC-2). CHO-K1, HCE-T, and HCEC-2 were treated with ripasudil, netarsudil, or Y-27632 with varying concentrations (0.1, 0.3, 1, 3, 10, or 30 μM). Ripasudil and Y-27632 did not alter intracellular phospholipid levels at any concentration tested. Conversely, intracellular phospholipid accumulation was observed in cells treated with netarsudil. Netarsudil possesses chemical characteristics similar to those of cationic amphiphilic drugs, which are known to cause phospholipidosis. In contrast, ripasudil and Y-27632 lack these structural features. Our results suggest that ripasudil has a low likelihood of inducing cornea verticillata.

Keywords: Cationic amphiphilic drug; Cornea verticillata; Netarsudil; Phospholipidosis; ROCK inhibitor; Ripasudil; Y-27632.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Fumiko Tazoe reports a relationship with Kowa Company, Ltd. That includes: employment. Yuichiro Watanabe reports a relationship with Kowa Company, Ltd. That includes: employment. Noriyuki Inoue reports a relationship with Kowa Company, Ltd. That includes: employment. Mizuho Kanazawa reports a relationship with Kowa Company, Ltd. That includes: employment. Atsushi Kasano reports a relationship with Kowa Company, Ltd. That includes: employment. Toshihiro Inoue reports a relationship with Kowa Company, Ltd. that includes: consulting or advisory, funding grants, and speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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