ROCK inhibitors in ocular disease

Halasz, Eva; Townes‐Anderson, Ellen

doi:10.5599/admet.4.4.331

Cited by 6 publications

(10 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fortuitously, a number of ROCK inhibitors are being tested for ocular use in clinical trials. 49 Their binding constants, half-lives, off-target effects, solubility, and so forth vary. If these drugs prove useful in patient treatment, they can be repurposed and tested as agents for retinal protection.…”

Section: Discussionmentioning

confidence: 99%

Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment

Townes‐Anderson

Wang

Halasz

et al. 2017

Trans. Vis. Sci. Tech.

Self Cite

View full text Add to dashboard Cite

PurposeRetinal detachment disrupts the rod-bipolar synapse in the outer plexiform layer by retraction of rod axons. We showed that breakage is due to RhoA activation whereas inhibition of Rho kinase (ROCK), using Y27632, reduces synaptic damage. We test whether the ROCK inhibitor fasudil, used for other clinical applications, can prevent synaptic injury after detachment.MethodsDetachments were made in pigs by subretinal injection of balanced salt solution (BSS) or fasudil (1, 10 mM). In some animals, fasudil was injected intravitreally after BSS-induced detachment. After 2 to 4 hours, retinae were fixed for immunocytochemistry and confocal microscopy. Axon retraction was quantified by imaging synaptic vesicle label in the outer nuclear layer. Apoptosis was analyzed using propidium iodide staining. For biochemical analysis by Western blotting, retinal explants, detached from retinal pigmented epithelium, were cultured for 2 hours.ResultsSubretinal injection of fasudil (10 mM) reduced retraction of rod spherules by 51.3% compared to control detachments (n = 3 pigs, P = 0.002). Intravitreal injection of 10 mM fasudil, a more clinically feasible route of administration, also reduced retraction (28.7%, n = 5, P < 0.05). Controls had no photoreceptor degeneration at 2 hours, but by 4 hours apoptosis was evident. Fasudil 10 mM reduced pyknotic nuclei by 55.7% (n = 4, P < 0.001). Phosphorylation of cofilin and myosin light chain, downstream effectors of ROCK, was decreased with 30 μM fasudil (n = 8–10 explants, P < 0.05).ConclusionsInhibition of ROCK signaling with fasudil reduced photoreceptor degeneration and preserved the rod-bipolar synapse after retinal detachment.Translational RelevanceThese results support the possibility, previously tested with Y27632, that ROCK inhibition may attenuate synaptic damage in iatrogenic detachments.

show abstract

Section: Discussionmentioning

confidence: 99%

Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment

Townes‐Anderson

Wang

Halasz

et al. 2017

Trans. Vis. Sci. Tech.

Self Cite

View full text Add to dashboard Cite

show abstract

“…ROCK1, is highly expressed in lung, liver, spleen, and kidney [ 106 , 107 , 108 , 109 ]. Both ROCK isomers are also present in ocular tissues and aberrant regulation of ROCK levels plays a role in the pathogenesis of corneal wound healing, glaucoma, diabetic retinopathy, and AMD [ 110 , 111 , 112 ].…”

Section: Rho Kinase and Rock Pathwaysmentioning

confidence: 99%

“…ROCKs can be activated by the GTP-bound form of Rho and the activated form then phosphorylates downstream targets [ 110 ]. Binding of Rho-GTP opens the loop formation of the enzyme, and the activated form then phosphorylates downstream targets ( Figure 2 ).…”

Section: Rho Kinase and Rock Pathwaysmentioning

confidence: 99%

“…The C-terminus of the ROCK protein is a self-inhibiting region of kinase activity, including the RBD region and the PH region. In the inactive state, the RBD and PH regions of the C-terminus of the ROCK protein interact with the kinase domain to form a self-inhibiting loop ( Figure 2 ) [ 106 , 107 , 108 , 109 , 110 ].…”

Section: Rho Kinase and Rock Pathwaysmentioning

confidence: 99%

“…In addition, the activation of the Rho/ROCK signalling pathway regulates the NF-κB signalling pathway, which upregulates inflammatory genes, fibronectin and transcription factor AP-1 activation and accumulation of glomerular matrix proteins. Upregulation of Rho/ROCK pathway also results in the dephosphorylation of endothelial nitric oxide synthase (eNOS), which induces endothelial cell apoptosis and vasoconstriction [ 110 , 111 , 112 , 114 ].…”

Section: Rho Kinase and Rock Pathwaysmentioning

confidence: 99%

See 2 more Smart Citations

Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema

Mateos-Olivares

García-Onrubia

Valentín-Bravo

et al. 2021

Cells

View full text Add to dashboard Cite

Diabetic macular oedema (DMO) is one of the leading causes of vision loss associated with diabetic retinopathy (DR). New insights in managing this condition have changed the paradigm in its treatment, with intravitreal injections of antivascular endothelial growth factor (anti-VEGF) having become the standard therapy for DMO worldwide. However, there is no single standard therapy for all patients DMO refractory to anti-VEGF treatment; thus, further investigation is still needed. The key obstacles in developing suitable therapeutics for refractory DMO lie in its complex pathophysiology; therefore, there is an opportunity for further improvements in the progress and applications of new drugs. Previous studies have indicated that Rho-associated kinase (Rho-kinase/ROCK) is an essential molecule in the pathogenesis of DMO. This is why the Rho/ROCK signalling pathway has been proposed as a possible target for new treatments. The present review focuses on the recent progress on the possible role of ROCK and its therapeutic potential in DMO. A systematic literature search was performed, covering the years 1991 to 2021, using the following keywords: “rho-Associated Kinas-es”, “Diabetic Retinopathy”, “Macular Edema”, “Ripasudil”, “Fasudil” and “Netarsudil”. Better insight into the pathological role of Rho-kinase/ROCK may lead to the development of new strategies for refractory DMO treatment and prevention.

show abstract

Improving outcomes in retinal detachment: the potential role of rho-kinase inhibitors

Halasz¹,

Townes‐Anderson²,

Zarbin

2020

Current Opinion in Ophthalmology

View full text Add to dashboard Cite

Purpose of review Retinal detachment initiates a series of events that lead to degenerative changes in retinal synaptic architecture as well as the well-known phenomena of gliosis and photoreceptor apoptosis. Retinal reattachment does not always result in complete visual recovery, even if the fovea is not directly involved in the detachment. Rho-kinase (ROCK) inhibitors may mitigate some of these deleterious changes including disruption of synaptic architecture, photoreceptor apoptosis, and initiation of the epithelial-mesenchymal transition that characterizes proliferative vitreoretinopathy (PVR). This review focuses on the use of ROCK inhibitors to modulate synaptic disjunction. Recent findings ROCK inhibition prevents retinal detachment-induced photoreceptor synaptic terminal retraction (i.e., synaptic disjunction), thereby diminishing the damage of the first synapse in the visual pathway. ROCK inhibition also reduces retinal detachment-induced photoreceptor apoptosis and suppresses PVR progression in preclinical models. Summary Inhibition of ROCK may help to optimize visual recovery after retinal detachment surgery or iatrogenic detachments during cell transplantation or viral subretinal injection and might play a role in reducing the risk of PVR after retinal detachment surgery.

show abstract

ROCK inhibitors in ocular disease

Abstract: Rho kinases (ROCKs)

Cited by 6 publications

References 80 publications

Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment

Fasudil, a Clinically Used ROCK Inhibitor, Stabilizes Rod Photoreceptor Synapses after Retinal Detachment

Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema

Improving outcomes in retinal detachment: the potential role of rho-kinase inhibitors

Contact Info

Product

Resources

About