Y-27632, a Rho-associated protein kinase inhibitor, attenuates neuronal cell death after transient retinal ischemia

Hirata, Akira; Inatani, Masaru; Inomata, Yasuya; Yonemura, Naoko; Kawaji, Takahiro; Honjo, Megumi; Tanihara, Hidenobu

doi:10.1007/s00417-007-0666-6

Cited by 49 publications

(31 citation statements)

References 55 publications

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“…RhoA inhibition using C3 exoenzyme and suppression of RhoA expression by shRNA increases axonal outgrowth and RGC survival in various animal models of glaucomatous damage (Bertrand et al, 2007; Bertrand et al, 2005; Drummond et al, 2014; Koch et al, 2014). Similarly, different Rho kinase inhibitors including HA1007 (fasudil), Y-39983 (SJN-1656), ripasudil (K-115) and Y-27632 were found to exhibit neuroprotection by promoting axonal outgrowth and RGC survival in different animal models (Bermel et al, 2009; Hirata et al, 2008; Kitaoka et al, 2004; Sagawa et al, 2007; Sugiyama et al, 2011; Van de Velde et al, 2015; Yamamoto et al, 2014; Yu et al, 2015; Yu et al, 2016). Fasudil and Y-39983 have also been shown to increase blood flow to the optic nerve head in rabbits (Sugiyama et al, 2011; Tokushige et al, 2011).…”

Section: Effects Of Rho Gtpase and Rho Kinase Signaling On Optic Nmentioning

confidence: 99%

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Rao

Pattabiraman

Kopczynski

2017

Experimental Eye Research

142

166

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Glaucoma is a leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is considered to be a predominant risk factor for primary open angle glaucoma, the most prevalent form of glaucoma. Although the etiological mechanisms responsible for increased IOP are not completely clear, impairment in aqueous humor (AH) drainage through the conventional or trabecular pathway is recognized to be a primary cause in glaucoma patients. Importantly, lowering of IOP has been demonstrated to reduce progression of vision loss and is a mainstay of treatment for all types of glaucoma. Currently however, there are limited therapeutic options available for lowering IOP especially as it relates to enhancement of AH outflow through the trabecular pathway. Towards addressing this challenge, bench and bedside research conducted over the course of the last decade and a half has identified the significance of inhibiting Rho kinase for lowering IOP. Rho kinase is a downstream effector of Rho GTPase signaling that regulates actomyosin dynamics in numerous cell types. Studies from several laboratories have demonstrated that inhibition of Rho kinase lowers IOP via relaxation of the trabecular meshwork which enhances AH outflow. By contrast, activation of Rho GTPase/Rho kinase signaling in the trabecular outflow pathway increases IOP by altering the contractile, cell adhesive and permeability barrier characteristics of the trabecular meshwork and Schlemm’s canal tissues, and by influencing extracellular matrix production and fibrotic activity. This article, written in honor of the late David Epstein, MD, summarizes findings from both basic and clinical studies that have been instrumental for recognition of the importance of the Rho/Rho kinase signaling pathway in regulation of AH outflow, and in the development of Rho kinase inhibitors as promising IOP- lowering agents for glaucoma treatment.

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Section: Effects Of Rho Gtpase and Rho Kinase Signaling On Optic Nmentioning

confidence: 99%

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Rao

Pattabiraman

Kopczynski

2017

Experimental Eye Research

142

166

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“…On the basis of the results of these experiments, many investigators have studied various agents that can attenuate tissue damage by suppressing leukocyte-endothelial interactions in the postischemic retina. Antithrombin III [83,84], tacrolimus (FK506) [85], argatroban (direct thrombin inhibitor) [86], statin [87,88], Rho-associated protein kinase inhibitor [89], superoxide dismutase [90], thalidomide [91], selectin ligands/inhibitor (SKK-60060) [92], triamcinolone acetonide [93], ischemic preconditioning [94,95], platelet depression [81], and 17β-estradiol [96] are reported to reduce leukocyte accumulation in the postischemic retina and thereby reduce neural damage.…”

Section: Leukocyte-endothelial Interactions In Pathological Conditionsmentioning

confidence: 99%

Evaluation of Leukocyte-Endothelial Interactions in Retinal Diseases

Tsujikawa

Ogura

2011

Ophthalmologica

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Purpose: We reviewed various methodologies for studying leukocyte-retinal endothelial interactions in vivo, and summarized the information obtained from studies employing these methods. Procedures: Fluorescence dye-enhanced scanning laser ophthalmoscopy facilitates study of leukocyte-cell interactions in the retinal microcirculation. Results: Various methods such as adaptive optics scanning laser ophthalmoscopy (AO-SLO), acridine orange digital angiography, and intravital microscopy provided evidence of the mechanisms of leukocyte recruitment in the retina and of their importance in the pathogenesis of various retinal diseases. Conclusions: Leukocyte behavior can be easily examined in the retina in vivo because the optical media is transparent. SLO substantially contributes to visualizing leukocyte-endothelial interactions in retinal vessels, although most of the methods employing SLO could only be used for animal studies. AO-SLO noninvasively demonstrates the movement of each leukocyte in the parafoveal capillaries in humans. Message: AO-SLO could be useful in investigating the leukocyte-retinal endothelial interactions in various diseases in humans.

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“…In addition, the selective inhibition of Rho-kinase allowed for the regeneration of the retinal ganglion cell axons in numerous models of optic nerve injury [26,27,28] and prevented the retraction of the photoreceptor axons in an in vitro model of acute retinal detachment [29]. Moreover, an increase in retinal cell survival in response to the Rho-kinase inhibition has recently been demonstrated under different injury paradigms in the retina including NMDA-induced neurotoxicity, serum deprivation, optic nerve crush, and transient retinal ischemia [28,30,31,32,33,34]. These findings altogether highlight the involvement of Rho-kinase at a convergence point of diverse pathological events that can be associated with hypoxia.…”

Section: Introductionmentioning

confidence: 99%

The Neuroprotective Potential of Rho-Kinase Inhibition in Promoting Cell Survival and Reducing Reactive Gliosis in Response to Hypoxia in Isolated Bovine Retina

Alt

Hilgers

Tura

et al. 2013

Cell Physiol Biochem

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Aims: To investigate the outcomes of Rho-kinase inhibition in the electrophysiological ex vivo model of the isolated perfused vertebrate retina under hypoxia. Methods: Bovine retinas were perfused with an oxygen saturated nutrient solution with or without the Rho-kinase inhibitor H-1152P. The retinas were stimulated repeatedly until stable amplitudes were reached and the electroretinogram was recorded at five minute intervals. Hypoxia was induced for 15, 30, and 45 minutes, after which the oxygen saturation was restored. The extent of the cell damage and glial reactivity was determined by Ethidium homodimer-1 staining, immunohistochemistry, and Western blot. Results: Hypoxia caused a time-dependent reduction of the b-wave amplitudes, which could not be prevented by the H-1152P. Although the Rho-kinase inhibitor maintained higher b-wave amplitudes, these effects did not reach statistical significance. Hypoxia also resulted in an increase in cell damage and the activation of the glial cells in the untreated retinas whereas the administration of H-1152P significantly reduced the extent of these events. Conclusion: H-1152P exerted a neuroprotective effect against necrosis on the isolated bovine retina under hypoxia together with a reduction in glial cell reactivity. However, the inhibitor could not prevent the hypoxia induced retinal dysfunction possibly due to the interference with synaptic modulation.

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Y-27632, a Rho-associated protein kinase inhibitor, attenuates neuronal cell death after transient retinal ischemia

Abstract: Our data suggest that inhibition of Rho/ROCK signaling offers neuroprotective therapy against postischemic neural damage, by regulating leukocyte infiltration in the neural tissue.

Cited by 49 publications

References 55 publications

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Role of the Rho GTPase/Rho kinase signaling pathway in pathogenesis and treatment of glaucoma: Bench to bedside research

Evaluation of Leukocyte-Endothelial Interactions in Retinal Diseases

The Neuroprotective Potential of Rho-Kinase Inhibition in Promoting Cell Survival and Reducing Reactive Gliosis in Response to Hypoxia in Isolated Bovine Retina

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