Involvement of RhoA and possible neuroprotective effect of fasudil, a Rho kinase inhibitor, in NMDA-induced neurotoxicity in the rat retina

Kitaoka, Yuka; Kitaoka, Yasushi; Kumai, Toshio; Lam, Tsun Ip; Kuribayashi, K.; Isenoumi, Kazuyuki; Munemasa, Yasunari; Motoki, Masamitsu; Kobayashi, Shinichi; Ueno, Satoki

doi:10.1016/j.brainres.2004.05.070

Cited by 91 publications

(60 citation statements)

References 46 publications

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“…22,34 In this study, our TUNEL staining could confirm an increase of apoptotic cells in the inner retina of the OIR model, which corresponds with a previous report. 35 Topical 0.8% ripasudil treatment did not affect the number of apoptotic cells in the inner as well as the outer retina.…”

Section: Discussionsupporting

confidence: 78%

Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K-115) Eye Drop in Retinal Angiogenesis and Hypoxia

Yamaguchi

Nakao

Arita

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. In this study, we investigated the therapeutic potential of a Rho-associated coiledcoil-containing protein kinase (ROCK) inhibitor ripasudil (K-115) eye drop on retinal neovascularization and hypoxia.METHODS. In vitro, human retinal microvascular endothelial cells (HRMECs) were pretreated with ripasudil and then stimulated with VEGF. ROCK activity was evaluated by phosphorylation of myosin phosphatase target protein (MYPT)-1. Endothelial migration and cell viability were assessed by cell migration and MTT assay, respectively. The concentration of ripasudil in the retina was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). In vivo, normal saline, 0.4%, or 0.8% ripasudil were administered three times a day to mice with oxygen-induced retinopathy (OIR). The areas of neovascularization and avascular retina were also quantified with retinal flat-mounts at postnatal day (P) 15, P17, or P21. The retinal hypoxic area was evaluated using hypoxia-sensitive drug pimonidazole by immunohistochemistry at P17. The vascular normalization was also evaluated by immunohistochemistry at P17. RESULTS.Ripasudil but not fasudil significantly reduced VEGF-induced MYPT-1 phosphorylation in HRMECs at 30 lmol/L. Ripasudil significantly inhibited VEGF-induced HRMECs migration and proliferation. The concentration of ripasudil in the retina was 3.8 to 10.4 lmol/ L and 6.8 to 14.8 lmol/L after 0.4% and 0.8% ripasudil treatment, respectively. In the 0.4% and 0.8% ripasudil treated OIR mice, the areas of neovascularization as well as avascular area in the retina was significantly reduced compared with those of saline-treated mice at P17 and P21. Pimonidazole staining revealed that treatment with 0.4% and 0.8% ripasudil significantly inhibited the increase in the hypoxic area compared with saline. 0.8% ripasudil could cause intraretinal vascular sprouting and increase retinal vascular perfusion.CONCLUSIONS. Novel ROCK inhibitor ripasudil eye drop has therapeutic potential in the treatment of retinal hypoxic neovascular diseases via antiangiogenic effects as well as vascular normalization.

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Section: Discussionsupporting

confidence: 78%

Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K-115) Eye Drop in Retinal Angiogenesis and Hypoxia

Yamaguchi

Nakao

Arita

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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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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“…Moreover, membrane blebbing and nuclear disintegration during apoptosis is dependent on ROCKmediated regulation of the actin myosin cytoskeleton (31,32). Some laboratories have written these obvious discrepancies off as being tissue and cell type dependent, however even within a category of cells such as neurons, obvious contradictions are reported with Rho/ROCK signaling being pro-survival (33)(34)(35)(36) or pro-apoptotic (37-43) depending on the reporting group.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological inhibition of Rho-kinase (ROCK) signaling enhances cisplatin resistance in neuroblastoma cells

Street

Routhier²,

Spencer³

et al. 2010

Int J Oncol

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Abstract. The role of the RhoA/Rho kinase (ROCK) signaling pathway in cell survival remains a very controversial issue, with its activation being pro-apoptotic in many cell types and anti-apoptotic in others. To test if ROCK inhibition contributes to tumor cell survival or death following chemotherapy, we treated cisplatin damaged neuroblastoma cells with a pharmacological ROCK inhibitor (Y27632) or sham, and monitored cell survival, accumulation of a chemoresistant phenotype, and in vivo tumor formation. Additionally, we assayed if ROCK inhibition altered the expression of genes known to be involved in cisplatin resistance. Our studies indicate that ROCK inhibition results in increased cell survival, acquired chemoresistance, and enhanced tumor survival following cisplatin cytotoxicity, due in part to altered expression of cisplatin resistance genes. These findings suggest that ROCK inhibition in combination with cisplatin chemotherapy may lead to enhanced tumor chemoresistance in neuroblastoma.

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Involvement of RhoA and possible neuroprotective effect of fasudil, a Rho kinase inhibitor, in NMDA-induced neurotoxicity in the rat retina

Cited by 91 publications

References 46 publications

Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K-115) Eye Drop in Retinal Angiogenesis and Hypoxia

Vascular Normalization by ROCK Inhibitor: Therapeutic Potential of Ripasudil (K-115) Eye Drop in Retinal Angiogenesis and Hypoxia

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

Pharmacological inhibition of Rho-kinase (ROCK) signaling enhances cisplatin resistance in neuroblastoma cells

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