The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma

Kotaro Yamamoto, Kazuichi Maruyama, Noriko Himori, Kazuko Omodaka, Yu Yokoyama, Yukihiro Shiga, Ryu Morin, Toru Nakazawa

Research output: Contribution to journalArticlepeer-review

79 Citations (Scopus)

Abstract

PURPOSE: To investigate the effect of K-115, a novel Rho kinase (ROCK) inhibitor, on retinal ganglion cell (RGC) survival in an optic nerve crush (NC) model. Additionally, to determine the details of the mechanism of K-115's neuroprotective effect in vivo and in vitro.

METHODS: ROCK inhibitors, including K-115 and fasudil (1 mg/kg/d), or vehicle were administered orally to C57BL/6 mice. Retinal ganglion cell death was then induced with NC. Retinal ganglion cell survival was evaluated by counting surviving retrogradely labeled cells and measuring RGC marker expression with quantitative real-time polymerase chain reaction (qRT-PCR). Total oxidized lipid levels were assessed with a thiobarbituric acid-reactive substances (TBARS) assay. Reactive oxygen species (ROS) levels were assessed by co-labeling with CellROX and Fluorogold. Expression of the NADPH oxidase (Nox) family of genes was evaluated with qRT-PCR.

RESULTS: The survival of RGCs after NC was increased 34 ± 3% with K-115, a significantly protective effect. Moreover, a similar effect was revealed by the qRT-PCR analysis of Thy-1.2 and Brn3a, RGC markers. Levels of oxidized lipids and ROS also increased with time after NC. NC-induced oxidative stress, including oxidation of lipids and production of ROS, was significantly attenuated by K-115. Furthermore, expression of the Nox gene family, especially Nox1, which is involved in the NC-induced ROS production pathway, was dramatically reduced by K-115.

CONCLUSIONS: The results indicated that oral K-115 administration delayed RGC death. Although K-115 may be mediated through Nox1 downregulation, we found that it did not suppress ROS production directly. Our findings show that K-115 has a potential use in neuroprotective treatment for glaucoma and other neurodegenerative diseases.

Original languageEnglish
Pages (from-to)7126-7136
Number of pages11
JournalInvestigative ophthalmology & visual science
Volume55
Issue number11
DOIs
Publication statusPublished - 2014 Nov 1

Keywords

  • Nox
  • ROCK
  • glaucoma
  • neuroprotection
  • oxidative stress
  • retinal ganglion cell

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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