The novel Rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma
| Autor: | Kotaro Yamamoto, Kazuko Omodaka, Ryu Morin, Noriko Himori, Kazuichi Maruyama, Toru Nakazawa, Yu Yokoyama, Yukihiro Shiga |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Retinal Ganglion Cells Cell Survival Administration Oral Pharmacology medicine.disease_cause Real-Time Polymerase Chain Reaction Neuroprotection Thiobarbituric Acid Reactive Substances Lipid peroxidation chemistry.chemical_compound Mice TBARS medicine Animals Rho-associated protein kinase Sulfonamides Transcription Factor Brn-3A rho-Associated Kinases NADPH oxidase biology Dose-Response Relationship Drug Fasudil Glaucoma Isoquinolines Mice Inbred C57BL Disease Models Animal Oxidative Stress medicine.anatomical_structure chemistry Biochemistry Retinal ganglion cell Gene Expression Regulation biology.protein RNA Thy-1 Antigens Oxidative stress |
| Zdroj: | Investigative ophthalmologyvisual science. 55(11) |
| ISSN: | 1552-5783 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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