Pharmacotherapies for Retinal Detachment

Wubben, Thomas J.; Besirli, Cagri G.; Zacks, David N.

doi:10.1016/j.ophtha.2016.02.040

Cited by 41 publications

(23 citation statements)

References 40 publications

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“…2–5 Cellular exposure to stress initially results in the activation of compensatory pathways that act to restore homeostasis; however, if the stress is chronic or intense enough, then there is activation of death pathways such as apoptosis and necroptosis. 6,7 A major mediator of RPE and photoreceptor death is the Fas/Fas ligand (FasL) system. 7–9 This has been demonstrated in a variety of disease models and appears to be independent of the specific stressor acting on the cell.…”

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confidence: 99%

Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury

Xiao

Yao

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PurposeA major problem in macular degeneration is the inability to reduce RPE and photoreceptor death. These cells die by necroptosis and apoptosis, respectively, but the upstream activator(s) of these death pathways is unknown. In this study, we use the sodium iodate (NaIO3) model of oxidative stress to test the hypothesis that activation of the Fas receptor contributes to the death of the RPE and photoreceptors.MethodsSodium iodate was injected in Brown-Norway rats via femoral vein injection. Both in vivo (fundus photography, optical coherence tomography, and fluorescein angiography) and ex vivo (histology, immunohistochemistry, Western blot, and RT-PCR) analyses of the RPE and retina were conducted at baseline, as well as at various times post NaIO3 injection. The ability of intravitreal injection of Met12, a small peptide inhibitor of the Fas receptor, to prevent RPE and photoreceptor cell death was assessed.ResultsInjection of NaIO3 led to Fas-mediated activation of both necroptosis and apoptosis in the RPE and photoreceptors, respectively. This was accompanied by a significant increase in the number of microglia/macrophages in the outer retina. Met12 significantly reduced the activation of the Fas-mediated death pathways, resulting in reduced RPE and photoreceptor death and a decreased immune response.ConclusionsOur results demonstrate that NaIO3 activates Fas-mediated cell death, both in the RPE and photoreceptor, and that a small peptide antagonist of the Fas receptor, Met12, significantly reduces the extent of this cell death. These findings suggest a role for Fas inhibition to protect the RPE and photoreceptors from death due to oxidative stress.

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confidence: 99%

Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury

Xiao

Yao

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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“…Therefore, pharmacotherapy reducing or slowing degeneration of prcs would be a potential add-on therapy enhancing functional outcomes. Several studies targeting these pathways provide evidences that a neuroprotective strategy might potentially result in prc rescue after RRD 3,4 .…”

Section: Discussionmentioning

confidence: 99%

Neuroprotection with rasagiline in patients with macula-off retinal detachment: A randomized controlled pilot study

Framme

Menke

et al. 2020

Sci Rep

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We aimed to evaluate the neuroprotective efficacy of rasagiline in pseudophakic patients who had surgery for macula-off rhegmatogenous retinal detachment (RRD). This was a 6-month, prospective, randomized, double-blind, placebo-controlled pilot study. Patients presenting with acute macula-off RRD were recruited and randomized 1:1 to receive rasagiline 1 mg/day or placebo for 7 days. Bestcorrected visual acuity (BCVA) and optical coherence tomography were acquired 1 day before as well as 2 days, 3 weeks, 3 months and 6 months after surgery. We screened 26 patients with RRD whereof 23 were eventually included and randomized. The primary outcome was final BCVA. Secondary outcomes included central retinal thickness (CRT) and adverse events (AE). We evaluated photoreceptor cells (prc) recovery through morphological measurements. The baseline characteristics were comparable between groups. BCVA significantly improved in both groups (letters gained: rasagiline 61.5 ± 18.1 vs placebo 55.3 ± 29.2, p = 0.56), but no significant inter-group difference was found at any visit. CRT was stable 3 weeks after surgery onwards, with no inter-group difference. No treatment-emergent AE occurred. Significant prc restoration was observed from 3 weeks to 6 months after surgery, without inter-group difference at either visit. Ellipsoid zone integrity (β = 0.517, p = 0.008) and foveal bulge (β = 0.387, p = 0.038) were significant predictors of good final BCVA. In conclusion, perioperative oral treatment with rasagiline 1 mg/day for 7 days did not show significant benefits on visual or anatomical outcomes in macula-off RRD patients. Rhegmatogenous retinal detachment (RRD) refers to separation of the neurosensory retina from the retinal pigment epithelium (RPE) due to accumulation of subretinal fluid through one or more retinal breaks 1. Currently, surgical repair is the only available treatment. Foveal detachment (macula-off) occurs in 54.5% of all RRD patients and is a major factor influencing visual recovery after successful surgical repair 2. As a result of deprived metabolic supply from the RPE and choroidal vasculature, photoreceptor (prc) death is the ultimate cause of vision loss after RRD 3. This is particularly relevant in the macula, where the density of prc is the highest and maximal visual acuity is achieved. Arguably, visual acuity recovery is significantly limited due to prc loss. Apoptosis was believed to be the major cause involved in prc death. However, recent evidence demonstrated that non-apoptotic forms of cell death (autophagy and necrosis), mitochondrial outer membrane permeabilization and inflammation raised by the interaction between dying cells and phagocytes all play a role in prc death after RRD 4. Accordingly, strategies targeting these pathways may be effective in prc rescue after RRD. Rasagiline [N-propargyl-1-(R)-aminoindan] is a second-generation propargylamine pharmacophore that selectively and irreversibly inhibits monoamine oxidase B (MAO-B). It has been an approved drug for the treatment of Parkinson's d...

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“…Apoptotic, necroptotic and autophagic pathways have been implicated in the process of photoreceptor cell death after RD (Dong et al ., ; Murakami et al ., ; Liu et al ., ; Wubben et al ., ). While inhibition of downstream death effectors is partly and transiently effective, the overall efficacy does not meet the clinical demand (Murakami et al ., ; Wubben et al ., ). Therefore, development of alternative strategies for photoreceptor protection is necessary.…”

Section: Introductionmentioning

confidence: 99%

Modulation of α‐adrenoceptor signalling protects photoreceptors after retinal detachment by inhibiting oxidative stress and inflammation

Yang

She

et al. 2019

British J Pharmacology

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Background and Purpose Currently available treatments do not halt progression of photoreceptor death and subsequent visual impairment related to retinal detachment (RD) which is observed in various retinal disorders. This study investigated the neuroprotective effects of two adrenoceptor ligands, the α1‐adrenoceptor antagonist doxazosin and the α2‐adrenoceptor agonist guanabenz, against photoreceptor cell death in RD. Experimental Approach We used a model of experimental RD in Brown‐Norway rats induced by subretinal injection of sodium hyaluronate. Oxidative stress biomarkers and cytokine production were quantified with elisa. Protein expression levels and immunofluorescent labelling were determined in rats with RD and controls for mechanistic elucidation. The effects of systemic (i.p.) administration of doxazosin or guanabenz on photoreceptor apoptosis, retinal histology and electroretinography were evaluated in rats with RD and compared to the effects in vehicle controls. Key Results Photoreceptors were the major source of RD‐induced ROS overproduction in the rat retina through the regulation of NADPH oxidase. Systemic administration of doxazosin or guanabenz decreased the RD‐induced production of ROS and proinflammatory cytokines, including IL‐1β and the chemokine CCL2, and suppressed retinal gliosis, resulting in attenuation of photoreceptor death and preservation of retinal structures and functions in RD. Conclusions and Implications Our findings point to α‐adrenoceptors as novel therapeutic targets to provide photoreceptor protection and suggest that both doxazosin and guanabenz, two FDA‐approved drugs, could be further explored to treat retinal diseases.

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Pharmacotherapies for Retinal Detachment

Cited by 41 publications

References 40 publications

Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury

Protective Effect of Met12, a Small Peptide Inhibitor of Fas, on the Retinal Pigment Epithelium and Photoreceptor After Sodium Iodate Injury

Neuroprotection with rasagiline in patients with macula-off retinal detachment: A randomized controlled pilot study

Modulation of α‐adrenoceptor signalling protects photoreceptors after retinal detachment by inhibiting oxidative stress and inflammation

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