RhoA Inactivation Prevents Photoreceptor Axon Retraction in an In Vitro Model of Acute Retinal Detachment

Fontainhas, Aurora M.; Townes‐Anderson, Ellen

doi:10.1167/iovs.10-5744

Cited by 44 publications

(65 citation statements)

References 52 publications

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“…Retinal detachment has been explored in vitro previously [28], but to our knowledge the present work represents the first example in which reattachment has been performed and showed to arrest pathological events in a manner emulating clinical detachment and surgical reattachment. Using this model, we for the first time have shown that lack of tissue support may be an important instigator of RRD pathology, and that its restitution may at least be partially responsible for treatment effects seen clinically.…”

Section: Müller Cell Activationmentioning

confidence: 98%

In vitro biomechanical modulation—retinal detachment in a box

Ghosh

Arnér

Taylor

2015

Graefes Arch Clin Exp Ophthalmol

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Section: Müller Cell Activationmentioning

confidence: 98%

In vitro biomechanical modulation—retinal detachment in a box

Ghosh

Arnér

Taylor

2015

Graefes Arch Clin Exp Ophthalmol

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“…While rods rapidly started to retract their synaptic terminals towards their cell bodies thereby breaking their synaptic connection to horizontal and bipolar cells, cones exhibited degenerative signs later. Cones did not show retraction [95], but instead changed the shape of their terminals [94]. Similar changes were described in human retina [96].…”

Section: Optic Nerve Blood Flow Neuroprotection Retinal Detachmentmentioning

confidence: 66%

“…However, rods maintained their morphology and showed no axonal retraction with 100 µM Y27632 pretreatment [97] and in similar conditions with even lower concentrations (10, 30, 100 µM) in a dose-dependent manner [98]. An in vitro retinal detachment model in porcine eyes demonstrated that RhoA activity increased immediately after detachment [94,99]; recent experiments, therefore, have explored short time periods after the detachment injury. Porcine retinal explants treated with 1, 10 and 100 µM of Y27632 significantly reduced the number of the rod synaptic terminals which retracted into the outer nuclear layer, moreover six hour-delayed administrations of 100 µM Y27632 also reduced synaptic breakage [94].…”

Section: Optic Nerve Blood Flow Neuroprotection Retinal Detachmentmentioning

confidence: 95%

“…For retinal detachment the goal is to prevent structural remodeling and plasticity in order to decrease disruption of synapses [94]. Photoreceptor degeneration was shown to be one of the early changes after detachment in the feline retina [95].…”

Section: Optic Nerve Blood Flow Neuroprotection Retinal Detachmentmentioning

confidence: 99%

“…RhoA was shown to be present in the inner and the outer retina of salamanders [97], and pigs [94]. From both in vitro and in vivo experiments, the RhoA-ROCK pathway was shown to take part in structural remodeling of photoreceptors, including rod axon retraction and cone neuritic outgrowth.…”

Section: Optic Nerve Blood Flow Neuroprotection Retinal Detachmentmentioning

confidence: 99%

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ROCK inhibitors in ocular disease

Halasz

Townes‐Anderson

2016

ADMET DMPK

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Using Rho Kinase Inhibitors for Retinal Detachment

2017

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To the Editor We applaud the efforts by Simunovic and colleagues 1 to examine the issue of structural and functional recovery of the retina after an iatrogenic macular detachment. An injection of adeno-associated viral vector that encoded Rab escort protein 1 into 5 patients with choroidermeia yielded mixed results: visual acuity was restored among all patients, but sensitivity and color discrimination did not improve consistently. As this study assesses recovery only up to 1 month after reattachment, it is possible that many or all of the residual abnormalities noted after macular detachment will reverse. One factor that may limit visual recovery, however, is detachment-induced synaptic retraction.Following short-term rhegmatogenous detachments in adult pigs, we have found that within 2 hours after a detachment, rod axon terminals withdraw from their bipolar postsynaptic partners towards their cell somas in the outer nuclear layer. 2 Thus, the first synapse of the visual pathway is disrupted quickly. Synaptic disruption after detachment was first reported in 1983 and has since been described for both rod and cone cells, as well as after reattachment; however, our observation of the rapidity of the damage is new. 3 Moreover, we found that synaptic disjunction occurs not only in the detached retina, but also in regions many millimeters away. Thus, detachment affects large areas of retina outside the area of iatrogenic detachment even if the photoreceptors are otherwise healthy. 2 We have investigated the mechanism of the axon retraction and determined that the activation of the RhoA pathway is involved. 4 We have demonstrated that using a Rho kinase (ROCK) inhibitor at the time of detachment can dramatically reduce the amount of axon retraction of rod photoreceptors by 40% to 50%. 2,5 We do not know whether synaptic retraction after retinal detachment improves neuronal survival after detachment or has adverse effects on retinal function, but preclinical studies indicate that retraction persists to some degree even after retinal reattachment. 3 If reduced sensitivity and color discrimination among these patients does not improve with time, one possible explanation is that outer synaptic layer retractioninduced damage is associated with the detachment. We are conducting experiments to determine whether recovery after iatrogenic macular detachment (for retinal gene therapy or any other purpose) can be improved by adding a ROCK inhibitor as a subretinal bleb is created. If ROCK inhibition proves useful, combining ROCK inhibitors with the therapeutic intervention (eg, gene or cell therapy) might augment visual recovery.

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RhoA Inactivation Prevents Photoreceptor Axon Retraction in an In Vitro Model of Acute Retinal Detachment

Abstract: Thus, RhoA and downstream Rho kinase activity constitute part of the mechanism that produces rod axonal retraction in retinal explants. Treatments that manipulate RhoA signaling may promote synaptic stability after retinal detachment.

Cited by 44 publications

References 52 publications

In vitro biomechanical modulation—retinal detachment in a box

In vitro biomechanical modulation—retinal detachment in a box

ROCK inhibitors in ocular disease

Using Rho Kinase Inhibitors for Retinal Detachment

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