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

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.

Development of a new strategy of visual field testing for macular dysfunction in patients with open angle glaucoma.

PURPOSE: To explore methods of automated visual field (VF) examination for the assessment of macular function. METHOD: We used a VF examination (AP-7000 automatic perimeter, Kowa, Japan) to examine macular function in 53 eyes from 29 patients with open angle glaucoma. We measured the mean total deviation (c-MD) of 16 points in the central VF located in a 2-degree-interval 4 × 4 array with various stimulus sizes (Goldmann sizes III, II, and I). The retinal nerve fiber layer (RNFL) thickness, ganglion cell complex (GCC), and ganglion cell layer plus inner plexiform layer (GCL + IPL) were measured with the 3D OCT-2000 System (Topcon, Japan). The c-MDs of various stimulus sizes were compared with the OCT parameters using the Spearman rank correlation. RESULTS: The average examination time was 93.5 ± 23.5 s and the c-MD values were -11.8 ± 8.2 (stimulus size III), -11.9 ± 9.5 (stimulus size II), and -12.3 ± 9.6 dB (stimulus size I). The c-MD (stimulus size III) and averaged total deviations of the Humphrey Field Analysis 10-2 program were significantly correlated (ρ = 0.91). The C-MD values for stimulus size III were significantly correlated with the OCT parameters (RNFL: ρ = 0.59; GCC: ρ = 0.65; and GCL + IPL: ρ = 0.64). The correlation coefficient between the c-MD and the GCC was better for stimulus sizes II and I (ρ = 0.69) than for stimulus size III (ρ = 0.65). CONCLUSION: The C-MD values for the 16 measured central VF points were significantly correlated with macular structure, and the smaller stimulus sizes of the automated VF test had a higher correlation coefficient of within 8°.