The Anti-Inflammatory Effect of Ripasudil (K-115), a Rho Kinase (ROCK) Inhibitor, on Endotoxin-Induced Uveitis in Rats

Uchida, Tsuneko; Honjo, Megumi; Yamagishi, Reiko; Aihara, Makoto

doi:10.1167/iovs.17-22679

Cited by 31 publications

(24 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Moreover, in UG patients, the average anterior segment cell score was significantly decreased from baseline after ripasudil treatment, suggesting a possible anti-inflammatory effect of ripasudil in uveitis. Uchida et al demonstrated the therapeutic effect of ripasudil in an endotoxin-induced rat uveitis model 12 , in which ripasudil inhibited LPS-induced nuclear translocation of Nuclear factor-kappa beta (NF-κB), adhesion molecules, and proinflammatory mediators, including monocyte chemotactic protein-1 (MCP-1), a key chemokine in chronically inflamed eyes 25 . Kusuhara et al reported IOP-lowering effects of ripasudil in 21 UG eyes 21 , in which IOP reductions from baseline were -3, -4, and -4 mmHg at 1, 3, and 6 months, respectively, after ripasudil initiation.…”

Section: Discussionmentioning

confidence: 99%

Intraocular pressure-lowering effects of ripasudil in uveitic glaucoma, exfoliation glaucoma, and steroid-induced glaucoma patients: ROCK-S, a multicentre historical cohort study

Futakuchi

Morimoto

Ikeda

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

ROCKS study group collaborators † To evaluate the efficacy and safety of ripasudil for treatment of secondary glaucoma, a historical cohort study was conducted at 18 centres in Japan. Adults (age ≥20 years) who needed additional IOP reduction and received topical 0.4% ripasudil between 2014 and 2018 due to three secondary glaucoma subtypes, including uveitic glaucoma (UG), exfoliation glaucoma (EG) or steroid-induced glaucoma (SG) were assessed for mean IOP change from baseline prior to additional treatment with ripasudil. We further evaluated the IOP change in each glaucoma subtype, baseline characteristics of each cohort, course of uveitis-induced inflammation in UG eyes, and proportion of patients in each cohort with adverse events. In 332 eyes from 332 patients eligible for this study, the mean overall IOP reductions from baseline at 1, 3, and 6 months were −5.86 ± 9.04 mmHg (−19.4 ± 25.1%), −6.18 ± 9.03 mmHg (−20.0 ± 27.1%), and −7.00 ± 8.60 mmHg (−23.4 ± 25.6%), respectively. These changes were all statistically significant. Of 332 eyes, 109 eyes had UG, 181 had EG, and 42 eyes had SG. The IOPlowering effects of ripasudil in UG and SG were significantly greater than those of EG at every time point. This finding could have been related to higher baseline IOP levels in UG and SG. UG patients exhibited significant decreases in mean cell score of the anterior segment after ripasudil treatment. No severe adverse events were reported. These findings suggest that treatment with ripasudil is a safe and effective therapeutic modality for IOP reduction in secondary glaucoma. The Rho protein contributes to various physiological events in many organs and tissues. Rho and its effector molecule Rho-associated kinase (ROCK) are involved in diverse cellular functions, including stress fibre formation, focal adhesion, cell contraction, motility and polarity 1-3. Rho/ROCK signalling molecules are present in the aqueous outflow pathway 4,5 , and regulate aqueous humour outflow, contributing to the pathologies of some subtypes of glaucoma 6,7. Rho/ROCK inhibition lowers intraocular pressure (IOP) primarily by increasing aqueous humour outflow directly through the conventional pathway, which is comprised of the trabecular meshwork (TM) and Schlemm's canal (SC) 8-11. ROCK inhibitors have been shown to induce alterations in cell shape, contraction, motility, attachment and extracellular matrix production in TM and SC cells 10. Moreover, several recent studies have demonstrated anti-inflammatory effects of ROCK inhibitors such as ripasudil 12,13 , including inhibition of immune cell infiltration and inflammatory cytokine production.

show abstract

Section: Discussionmentioning

confidence: 99%

Intraocular pressure-lowering effects of ripasudil in uveitic glaucoma, exfoliation glaucoma, and steroid-induced glaucoma patients: ROCK-S, a multicentre historical cohort study

Futakuchi

Morimoto

Ikeda

et al. 2020

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recently, several new glaucoma therapies targeting reconstruction of TM biomechanics are being developed for clinical application. 26 , 27 Our PhS-OCT technique may potentially be a promising tool to detect the presence of a TM abnormalities and optimize the selection of the operative site for minimally invasive glaucoma surgery (MIGS).…”

Section: Discussionmentioning

confidence: 99%

Quantification of Pulse-Dependent Trabecular Meshwork Motion in Normal Humans Using Phase-Sensitive OCT

Chen

Song

Johnstone

et al. 2018

Invest. Ophthalmol. Vis. Sci.

View full text Add to dashboard Cite

PurposeThe purpose of this study was to characterize the pulsatile motion of trabecular meshwork (TM) in normal subjects and demonstrate its changes in accommodation with phase-sensitive optical coherence tomography (PhS-OCT).MethodsA new PhS-OCT laboratory prototype was designed to measure pulsatile TM motion in 13 healthy humans. Two sets of images were captured in 10 subjects, first with best corrective refraction and the other with an additional 3.0 diopters of accommodation. In each image, both maximum velocity (MV) and cumulative displacement (CD) in two selected regions of TM, the internal (IMV and ICD) and external (EMV and ECD) region, were measured.ResultsFor all parameters the intraclass correlation coefficient was >0.75. Neither MV nor CD was significantly different between eyes in individual subjects (PIMV = 0.967, PEMV = 0.391, PICD = 0.603, PECD = 0.482). In 26 eyes, with best corrective refraction, the EMV was higher than the IMV (23.9 ± 9.8 vs. 18.9 ± 8.08 μm/s; P = 0.0001), as was the ECD compared with the ICD (0.340 ±0.125 vs. 0.264 ± 0.111 μm; P = 0.000004). With accommodation, MV and CD significantly increased (PIMV = 0.0003, PEMV = 0.0003, PICD = 0.019, and PECD = 0.007), whereas MV and CD in the external region were still larger than those in the internal area (PEMV vs. IMV = 0.009, PECD vs. ICD = 0.023).ConclusionsThis study demonstrates the differences in TM motion between the internal and external regions of TM and displays its change with accommodation. The findings and good reproducibility suggest PhS-OCT helps to understand TM function in regulation of IOP, and, with further refinements, it may be useful in clinical management of glaucoma.

show abstract

“…Like other ROCK inhibitors that share similar structures, ripasudil inhibits ROCK activity by suppressing transfer of the terminal phosphate from ATP to their substrates. The anti-inflammatory and anti-fibrotic activities of ripasudil were reported in previous studies [ 9 ]. The inhibitory effect of ripasudil was higher than that of other ROCK inhibitors such as fasudil and Y-27632.…”

Section: Introductionmentioning

confidence: 68%

“…The deactivation of eNOS leads to reduction of Bcl2 expression, facilitating cell death [ 8 ]. Moreover, eNOS was reported to attenuate inflammation by suppressing NF-κB activation [ 9 ]. Thus, we hypothesized that LPS induces activation of the RhoA/ROCK signaling pathway, which further reduces eNOS activity in PMVECs.…”

Section: Introductionmentioning

confidence: 99%

Ripasudil Attenuates Lipopolysaccharide (LPS)-Mediated Apoptosis and Inflammation in Pulmonary Microvascular Endothelial Cells via ROCK2/eNOS Signaling

2018

View full text Add to dashboard Cite

BackgroundMicrovascular endothelial inflammation and apoptosis are responsible for septic acute lung injury (ALI). Ripasudil is a novel Rho/Rho kinase (ROCK) inhibitor which shows therapeutic effects on several vascular diseases. The aim of this study was to investigate the protective effects and correlated molecular mechanisms of ripasudil on lipopolysaccharide-induced inflammation and apoptosis of pulmonary microvascular endothelial cells (PMVECs).Material/MethodsCultured PMVECs were exposed to lipopolysaccharide (LPS). Ripasudil at various concentrations was used to treat the cells. Several cells were also co-administrated with the endothelial nitric oxide synthase (eNOS) inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Cell viability was assessed by MTT assay. Terminal dUTP transferase nick-end labeling (TUNEL) assay was used to detect the apoptosis. The colorimetric method was used to measure the activity of eNOS and ROCK2. Protein phosphorylation and expression were assessed by Western blotting.ResultsRipasudil attenuated the LPS-induced inflammation and apoptosis in PMVECs, which was reversed by L-NAME. Ripasudil suppressed ROCK2 activity and further increased the eNOS activity. Ripasudil treatment increased the phosphorylation of eNOS, increased the expression level of Bcl2, and decreased the expression level of active caspase3 in LPS-treated PMVECs. Moreover, the ripasudil treatment also inhibited the nuclear translocation of NF-κB and further suppressed the levels of interleukin (IL) 6 and tumor necrosis factor (TNF) α. The co-treatment with L-NAME, however, impaired the anti-apoptotic and anti-inflammatory effects of ripasudil on PMVECs without affecting ROCK2.ConclusionsThe novel ROCK2 inhibitor ripasudil suppressed LPS-induced apoptosis and inflammation in PMVECs by regulating the ROCK2/eNOS signaling pathway.

show abstract

The Anti-Inflammatory Effect of Ripasudil (K-115), a Rho Kinase (ROCK) Inhibitor, on Endotoxin-Induced Uveitis in Rats

Cited by 31 publications

References 40 publications

Intraocular pressure-lowering effects of ripasudil in uveitic glaucoma, exfoliation glaucoma, and steroid-induced glaucoma patients: ROCK-S, a multicentre historical cohort study

Intraocular pressure-lowering effects of ripasudil in uveitic glaucoma, exfoliation glaucoma, and steroid-induced glaucoma patients: ROCK-S, a multicentre historical cohort study

Quantification of Pulse-Dependent Trabecular Meshwork Motion in Normal Humans Using Phase-Sensitive OCT

Ripasudil Attenuates Lipopolysaccharide (LPS)-Mediated Apoptosis and Inflammation in Pulmonary Microvascular Endothelial Cells via ROCK2/eNOS Signaling

Contact Info

Product

Resources

About