A novel ROCK inhibitor, Y-39983, promotes regeneration of crushed axons of retinal ganglion cells into the optic nerve of adult cats

Sagawa, Hiroe; Terasaki, Hiroko; Nakamura, Makoto; Ichikawa, Masahiro; Yata, T.; Tokita, Yoshihito; Watanabe, Masami

doi:10.1016/j.expneurol.2007.02.002

Cited by 62 publications

(44 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Sagawa et al [14] demonstrated that Y-39983 exerted a therapeutic effect on the axonal regeneration of crushed optic nerves and reduced intraocular pressure, which is beneficial for the treatment of glaucoma [15,16]. In the present study, we used a model of EAE to examine the clinical effect of Y-39983 compared to injection of saline in control mice.…”

Section: Discussionmentioning

confidence: 99%

Y-39983, a Selective Rho-Kinase Inhibitor, Attenuates Experimental Autoimmune Encephalomyelitis via Inhibition of Demyelination

Gao

Huang²,

Long³

et al. 2013

Neuroimmunomodulation

View full text Add to dashboard Cite

Objective: Rho-associated kinase (ROCK) is a serine/threonine kinase and a major downstream effector of the small GTP-binding protein, Rho. Rho-ROCK triggers an intracellular signaling cascade that controls actin cytoskeleton and is essential for cell motility and adhesion, neurite outgrowth and retraction. In chronic disabling disease, multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), demyelination and axonal damage are the major pathological changes contributing to neurological disability. We investigated the protective effect of a specific ROCK inhibitor, Y-39983, on demyelination and axonal damage in chronic EAE. Methods: Western blotting for myelin proteins, electron microscopy and solochrome cyanine staining was performed to evaluate demyelination while neurofilament proteins and cytoskeletal proteins including β-actin and β-tubulin were used to determine axonal damage in a chronic mouse model of EAE treated with Y-39983. Results: Y-39983 significantly suppressed clinical symptoms of EAE and prevented its relapse while increasing the amount of myelin proteins. No significant changes in neurofilaments and cytoskeletal proteins were observed compared with control EAE mice. The inhibition of demyelination by Y-39983 was confirmed by solochrome cyanine staining and electron microscopy. To further study the effect of Y-39983 on demyelination in EAE, we tested three major ROCK substrates, including myosin light chain phosphorylation, LIMK2 and collapsin response mediator protein-2. The activity of these molecules was decreased in EAE animals treated with Y-39983. Conclusion: The inhibitory effect of Y-39983 on demyelination is probably due to the inactivation of ROCK substrates, which are important for neurite outgrowth, growth cone collapse and demyelination of oligodendrocytes.

show abstract

Section: Discussionmentioning

confidence: 99%

Y-39983, a Selective Rho-Kinase Inhibitor, Attenuates Experimental Autoimmune Encephalomyelitis via Inhibition of Demyelination

Gao

Huang²,

Long³

et al. 2013

Neuroimmunomodulation

View full text Add to dashboard Cite

show abstract

“…Thus repeated injections of Y39983 seemed to facilitate axon regeneration in the first two weeks after the nerve trauma; perhaps additional administration of the ROCK inhibitor would have been beneficial. However, reduction in activated RhoA levels [89] may reduce the protection to neurons of longer treatments.…”

Section: Optic Nerve Blood Flow Neuroprotection Retinal Detachmentmentioning

confidence: 99%

“…But in addition, the ROCK inhibitor enhanced the number of surviving retinal ganglion cells, thereby preventing axonal degeneration 500 µm from the crush site. In 2007, Sagawa et al [89] compared two ROCK inhibitors in feline retinal cultures. Whereas 10 µM Y39983 facilitated the extension of neurites and glial processes, Y27632 had a similar effect only when the dose was increased to 100 µM.…”

Section: Optic Nerve Blood Flow Neuroprotection Retinal Detachmentmentioning

confidence: 99%

ROCK inhibitors in ocular disease

Halasz

Townes‐Anderson

2016

ADMET DMPK

View full text Add to dashboard Cite

show abstract

“…12 Rho and Rho kinase inhibitions have also been shown to increase retinal ganglion cell survival and axon regeneration. 13,14 On the basis of these various observations, we hypothesized that abnormal regulation of Rho/Rho kinase pathway, which leads to changes in actomyosin contraction, cell adhesive properties, and ECM remodeling, could cause increased resistance within the trabecular pathway and retinal ganglion cell injury that contributes to the pathophysiology of glaucoma. To explore this possibility, we examined immunohistochemically the distribution and staining intensity of Rho GTPase (RhoA), as well as ROCK-1 and ROCK-2, in postmortem human eyes from patients with or without glaucoma.…”

mentioning

confidence: 99%