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Effects of the Rho-Kinase Inhibitor Y-27632 on Extraocular Muscle Surgery in Rabbits.

ABSTRACT: To evaluate the effect of the Rho-kinase inhibitor Y-27632 on postoperative inflammation and adhesion following extraocular muscle surgery in rabbits.The superior rectus muscle reinsertion was performed on both eyes of 8 New Zealand white rabbits. After reinsertion, the rabbits received subconjunctival injections of the Rho-kinase inhibitor and saline on each eye. To assess acute and late inflammatory changes, Ki-67, CD11β+, and F4/80 were evaluated and the sites of muscle reattachment were evaluated for a postoperative adhesion score and histopathologically for collagen formation.F4/80 antibody expression was significantly different in the Rho-kinase inhibitor-injected group at both postoperative day 3 and week 4 (p = 0.038, 0.031). However, Ki-67 and CD11β+ were not different the between two groups. The difference in the SRM/conjunctiva adhesion score between the two groups was also significant (p = 0.034). Conclusion. Intraoperative subconjunctival injection of the Rho-kinase inhibitor may be effective for adjunctive management of inflammation and fibrosis in rabbit eyes following extraocular muscle surgery.

SUBMITTER: Moon JS

PROVIDER: S-EPMC5549496 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Cardiovascular effects of a novel potent and highly selective azaindole-based inhibitor of Rho-kinase.

Project description:Background and purposeRho-kinase (ROCK) has been implicated in the pathophysiology of altered vasoregulation leading to hypertension. Here we describe the pharmacological characterization of a potent, highly selective and orally active ROCK inhibitor, the derivative of a class of azaindoles, azaindole 1 (6-chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-phenyl}pyrimidine-2,4-diamine).Experimental approachPharmacological characterization of azaindole 1 was performed with human recombinant ROCK in vitro. Vasodilator activity was determined using isolated vessels in vitro and different animal models in vivo.Key resultsThis compound inhibited the ROCK-1 and ROCK-2 isoenzymes with IC50 s of 0.6 and 1.1 nM in an ATP-competitive manner. Although ATP-competitive, azaindole 1 was inactive against 89 kinases (IC50>10 microM) and showed only weak activity against an additional 21 different kinases (IC50=1-10 microM). Only the kinases TRK und FLT3 were inhibited by azaindole 1 in the sub-micromolar range, albeit with IC50 values of 252 and 303 nM, respectively. In vivo, azaindole 1 lowered blood pressure dose-dependently after i.v. administration in anaesthetized normotensive rats. In conscious normotensive and spontaneously hypertensive rats azaindole 1 induced a dose-dependent decrease in blood pressure after oral administration without inducing a significant reflex increase in heart rate. In anaesthetized dogs, azaindole 1 induced vasodilatation with a moderately elevated heart rate.Conclusions and implicationsAzaindole 1 is representative of a new class of selective and potent ROCK inhibitors and is a valuable tool for the elucidation of the role of ROCK in the cardiovascular system.

| S-EPMC2095102 | biostudies-literature

Human keratinocytes are efficiently immortalized by a Rho kinase inhibitor.

Project description:Primary human keratinocytes are useful for studying the pathogenesis of many different diseases of the cutaneous and mucosal epithelia. In addition, they can form organotypic tissue equivalents in culture that can be used as epidermal autografts for wound repair as well as for the delivery of gene therapy. However, primary keratinocytes have a finite lifespan in culture that limits their proliferative capacity and clinical use. Here, we report that treatment of primary keratinocytes (originating from 3 different anatomical sites) with Y-27632, a Rho kinase inhibitor, greatly increased their proliferative capacity and resulted in efficient immortalization without detectable cell crisis. More importantly, the immortalized cells displayed characteristics typical of primary keratinocytes; they had a normal karyotype and an intact DNA damage response and were able to differentiate into a stratified epithelium. This is the first example to our knowledge of a defined chemical compound mediating efficient cell immortalization, and this finding could have wide-ranging and profound investigational and medical applications.

| S-EPMC2898606 | biostudies-literature

TRANSCRIPTOMIC PROFILING OF ASTROCYTES TREATED WITH THE RHO KINASE INHIBITOR FASUDIL REVEALS CYTOSKELETAL AND PRO-SURVIVAL RESPONSESTRANSFORMATION INDUCED BY THE RHO KINASE INHIBITOR FASUDIL.

Project description:Analysis of genome wide gene expression changes over a time course of 24 hours induced by the Rho kinase inhibitor Fasudil in primary mouse astrocyte cultures.

2011-05-10 | GSE25829 | GEO

TRANSCRIPTOMIC PROFILING OF ASTROCYTES TREATED WITH THE RHO KINASE INHIBITOR FASUDIL REVEALS CYTOSKELETAL AND PRO-SURVIVAL RESPONSESTRANSFORMATION INDUCED BY THE RHO KINASE INHIBITOR FASUDIL.

Project description:Analysis of genome wide gene expression changes over a time course of 24 hours induced by the Rho kinase inhibitor Fasudil in primary mouse astrocyte cultures. Total RNA was extracted from primary astrocyte cultures prepared from mouse forebrain from 1.5 day old mice and treated with Fasudil or vehicle control for 2, 6, 12 or 24 hours.

2011-05-10 | E-GEOD-25829 | biostudies-arrayexpress

Central Angiotensin-II Increases Blood Pressure and Sympathetic Outflow via Rho Kinase Activation in Conscious Rabbits.

Project description:Elevated sympathetic tone and activation of the renin-angiotensin system are pathophysiologic hallmarks of hypertension, and the interactions between these systems are particularly deleterious. The importance of Rho kinase as a mediator of the effects of angiotensin-II (AngII) in the periphery is clear, but the role of Rho kinase in sympathoexcitation caused by central AngII is not well established. We hypothesized that AngII mediates its effects in the brain by the activation of the RhoA/Rho kinase pathway. Chronically instrumented, conscious rabbits received the following intracerebroventricular infusion treatments for 2 weeks via osmotic minipump: AngII, Rho kinase inhibitor Fasudil, AngII plus Fasudil, or a vehicle control. AngII increased mean arterial pressure over the course of the infusion, and this effect was prevented by the coadministration of Fasudil. AngII increased cardiac and vascular sympathetic outflow as quantified by the heart rate response to metoprolol and the depressor effect of hexamethonium; coadministration of Fasudil abolished both of these effects. AngII increased baseline renal sympathetic nerve activity in conscious animals and impaired baroreflex control of sympathetic nerve activity; again Fasudil coinfusion prevented these effects. Each of these end points showed a statistically significant interaction between AngII and Fasudil. Quantitative immunofluorescence of brain slices confirmed that Rho kinase activity was increased by AngII and decreased by Fasudil. Taken together, these data indicate that hypertension, elevated sympathetic outflow, and baroreflex dysfunction caused by central AngII are mediated by Rho kinase activation and suggest that Rho kinase inhibition may be an important therapeutic target in sympathoexcitatory cardiovascular diseases.

| S-EPMC5063718 | biostudies-literature

Rho kinase inhibitor enables cell-based therapy for corneal endothelial dysfunction.

Project description:The corneal endothelium maintains corneal transparency; consequently, its dysfunction causes severe vision loss. Tissue engineering-based therapy, as an alternative to conventional donor corneal transplantation, is anticipated to provide a less invasive and more effective therapeutic modality. We conducted a preclinical study for cell-based therapy in a primate model and demonstrated regeneration of the corneal endothelium following injection of cultured monkey corneal endothelial cells (MCECs) or human CECs (HCECs), in combination with a Rho kinase (ROCK) inhibitor, Y-27632, into the anterior chamber. We also evaluated the safety and efficacy of Good Manufacturing Practice (GMP)-grade HCECs, similar to those planned for use as transplant material for human patients in a clinical trial, and we showed that the corneal endothelium was regenerated without adverse effect. We also showed that CEC engraftment is impaired by limited substrate adhesion, which is due to actomyosin contraction induced by dissociation-induced activation of ROCK/MLC signaling. Inclusion of a ROCK inhibitor improves efficiency of engraftment of CECs and enables cell-based therapy for treating corneal endothelial dysfunction as a clinically relevant therapy.

| S-EPMC4870691 | biostudies-literature

Thrombospondin-1 mediates Rho-kinase inhibitor-induced increase in outflow-facility.

Project description:Rho-kinase (ROCK) inhibitors, a novel class of anti-glaucoma agents, act by increasing the aqueous humor outflow through the conventional trabecular meshwork pathway. However, the downstream signaling consequences of the ROCK inhibitor are not completely understood. Our data show that Y39983, a selective ROCK inhibitor, could induce filamentous actin remodeling, reduced cell motility (as measured by cell migration), and transepithelial resistance in primary human TM (hTM) cells. After 2 days Y39983 treatment of hTM cells, a proteomic study identified 20 proteins whose expression was significantly altered. Pathway analysis of those proteins revealed the involvement of the p53 pathway, integrin signaling pathway, and cytoskeletal pathway regulation by Rho GTPase. Thrombospondin-1 (TSP1), a matricellular protein that is increased in glaucoma patients, was downregulated fivefold following Y39983 treatment. More importantly, both TSP1 antagonist leucine-serine-lysine-leucine (LSKL) and small interfering RNA (siRNA) reduced TSP1 gene and protein expressions as well as hTM cell migration. In the presence of Y39983, no further inhibition of cell migration resulted after LSKL and TSP1 siRNA knockdown. Likewise, LSKL triggered a dose-dependent increase in outflow facility in ex vivo mouse eyes, to a similar extent as Y39983 (83.8% increase by Y39983 vs. 71.2% increase by LSKL at 50 µM). There were no additive effects with simultaneous treatment with LSKL and Y39983, supporting the notion that the effects of ROCK inhibition were mediated by TSP1.

| S-EPMC9292191 | biostudies-literature

Rho kinase inhibitor for primary open-angle glaucoma and ocular hypertension.

Project description: Not available

| S-EPMC9185806 | biostudies-literature

Effect of Rho-associated kinase inhibitor on cryopreservation of hES cells

2011-11-15 | GSE21796 | GEO

Effect of Rho-associated kinase inhibitor on cryopreservation of hES cells

Project description:After thawing, the mechanism of apoptosis advancing in human ES cells was invesitigated mainly by Gene conpath analysis. As time passed after thawing, nuclear fragmented cells increased more and more in cR-/mR- and cR+/mR-, but in cR+/mR+ and cR-/mR+, thawed cells formed cluster markedly, which was seen among three cell lines. Flow cytometry using TUNEL assay supported final colony formation ratio, which defined that such cell death was due to apoptosis. Gene map analysis 12 hours later after thawing of cR-/mR- showed activation of IL-1? & its receptor IL-1R and TGF-? & its receptor ACVR1C required for activation of caspase-8, initiation of caspase-8 and 10 and marked activation of ARHGDIB promoting actin reorganization comparing to cR+/mR+. Recovered cell lines in any condition did not lose proliferation and pluripotency regardless of ROCK inhibitor treatment.?These results showed apoptotic events after thawing were more marked in cR- and advanced through autoenhanced cascaded mechanism followed by initiation of self-cytokain activity, and were suppressed by ROCK inhibitor Y-27632. To investigate the protective mechanism caused by a novel cryo-technique of human embryonic stem (hES) cells using ROCK inhibitor Y-27632 against the cell death due to cryopreservation and thawing with Gene map analysis in addition to estimations of survival rate, apoptosis, undifferentiated states and pluripotency, the dissociated hES cells were cryopreserved in a freezing container in the following four conditions: addition of 10µM of Y-27632 to 1: cryoprotection solution and post-thawing medium (cR+/mR+), 2: only addition to cryoprotection (cR+/mR-), 3: only addition to post-thawing medium (cR-/mR+), 4: no addition to any medium (cR-/mR-).

2011-11-15 | E-GEOD-21796 | biostudies-arrayexpress

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