Selective Retina Therapy and Thermal Stimulation of the Retina: Different Regenerative Properties - Implications for AMD Therapy

Abstract BackgroundSelective Retina Therapy (SRT) and Thermal Stimulation of the Retina (TSR) have shown therapeutic effects on Age-related Macular Degeneration (AMD) in mice. We investigate the differences between both laser modalities concerning RPE regeneration. MethodsFor PCR array, 6 eyes of apolipoprotein E and nuclear factor erythroid-derived 2- like 2 knock out mice respectively were treated by neuroretina-sparing TSR or SRT. Untreated litter mates were controls. Eyes were enucleated either 1 or 7 days after laser treatment. For morphological analysis, porcine RPE/choroid organ cultures underwent the same laser treatment and were examined by calcein vitality staining 1 h and 1, 3 or 5 days after irradiation. ResultsTSR did not induce the expression of cell-mediators connected to cell death. SRT induced necrosis associated cytokines as well as inflammation 1 but not 7 days after treatment. Morphologically, 1 hour after TSR, there was no cell damage. One and 3 days after TSR, dense chromatin and cell destruction of single cells was seen. Five days after TSR, there were signs of migration and proliferation. In contrast, one hour after SRT a defined necrotic area within the laser spot was seen. This lesion was closed over days by migration and proliferation of adjacent cells. ConclusionsSRT induces RPE cell death, followed by regeneration within a few days, accompanied by necrosis induced inflammation, RPE proliferation and migration. TSR does not induce immediate RPE cell death; however, migration and mitosis can be seen a few days after laser irradiation, not accompanied by necrosis-associated inflammation.

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Selective retina therapy and thermal stimulation of the retina: different regenerative properties - implications for AMD therapy

BMC Ophthalmology ◽

10.1186/s12886-021-02188-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Elisabeth Richert ◽

Julia Papenkort ◽

Claus von der Burchard ◽

Alexa Klettner ◽

Philipp Arnold ◽

...

Keyword(s):

Cell Death ◽

Laser Treatment ◽

Continuous Wave ◽

Single Cells ◽

Thermal Stimulation ◽

Age Related Macular Degeneration ◽

Therapeutic Effects ◽

Rpe Cells ◽

Selective Retina Therapy ◽

Stimulation Of

Abstract Background Selective Retina Therapy (SRT), a photodisruptive micropulsed laser modality that selectively destroys RPE cells followed by regeneration, and Thermal Stimulation of the Retina (TSR), a stimulative photothermal continuous wave laser modality that leads to an instant sublethal temperature increase in RPE cells, have shown therapeutic effects on Age-related Macular Degeneration (AMD) in mice. We investigate the differences between both laser modalities concerning RPE regeneration. Methods For PCR array, 6 eyes of murine AMD models, apolipoprotein E and nuclear factor erythroid-derived 2- like 2 knock out mice respectively, were treated by neuroretina-sparing TSR or SRT. Untreated litter mates were controls. Eyes were enucleated either 1 or 7 days after laser treatment. For morphological analysis, porcine RPE/choroid organ cultures underwent the same laser treatment and were examined by calcein vitality staining 1 h and 1, 3 or 5 days after irradiation. Results TSR did not induce the expression of cell-mediators connected to cell death. SRT induced necrosis associated cytokines as well as inflammation 1 but not 7 days after treatment. Morphologically, 1 h after TSR, there was no cell damage. One and 3 days after TSR, dense chromatin and cell destruction of single cells was seen. Five days after TSR, there were signs of migration and proliferation. In contrast, 1 h after SRT a defined necrotic area within the laser spot was seen. This lesion was closed over days by migration and proliferation of adjacent cells. Conclusions SRT induces RPE cell death, followed by regeneration within a few days. It is accompanied by necrosis induced inflammation, RPE proliferation and migration. TSR does not induce immediate RPE cell death; however, migration and mitosis can be seen a few days after laser irradiation, not accompanied by necrosis-associated inflammation. Both might be a therapeutic option for the treatment of AMD.

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Novel Programmed Cell Death as Therapeutic Targets in Age-Related Macular Degeneration?

International Journal of Molecular Sciences ◽

10.3390/ijms21197279 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7279 ◽

Cited By ~ 1

Author(s):

Ming Yang ◽

Kwok-Fai So ◽

Wai Ching Lam ◽

Amy Cheuk Yin Lo

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Macular Degeneration ◽

Molecular Mechanisms ◽

Cell Damage ◽

Retinal Pigment ◽

The Elderly ◽

Age Related Macular Degeneration ◽

Severe Visual Loss ◽

Age Related

Age-related macular degeneration (AMD) is a leading cause of severe visual loss among the elderly. AMD patients are tormented by progressive central blurring/loss of vision and have limited therapeutic options to date. Drusen accumulation causing retinal pigment epithelial (RPE) cell damage is the hallmark of AMD pathogenesis, in which oxidative stress and inflammation are the well-known molecular mechanisms. However, the underlying mechanisms of how RPE responds when exposed to drusen are still poorly understood. Programmed cell death (PCD) plays an important role in cellular responses to stress and the regulation of homeostasis and diseases. Apart from the classical apoptosis, recent studies also discovered novel PCD pathways such as pyroptosis, necroptosis, and ferroptosis, which may contribute to RPE cell death in AMD. This evidence may yield new treatment targets for AMD. In this review, we summarized and analyzed recent advances on the association between novel PCD and AMD, proposing PCD’s role as a therapeutic new target for future AMD treatment.

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Thermal Stimulation of the Retina Reduces Bruch's Membrane Thickness in Age Related Macular Degeneration Mouse Models

Translational Vision Science & Technology ◽

10.1167/tvst.7.3.2 ◽

2018 ◽

Vol 7 (3) ◽

pp. 2 ◽

Cited By ~ 16

Author(s):

Jan Tode ◽

Elisabeth Richert ◽

Stefan Koinzer ◽

Alexa Klettner ◽

Claus von der Burchard ◽

...

Keyword(s):

Macular Degeneration ◽

Mouse Models ◽

Thermal Stimulation ◽

Age Related Macular Degeneration ◽

Membrane Thickness ◽

Bruch's Membrane ◽

Bruch’S Membrane ◽

Age Related ◽

Stimulation Of

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Oxidative Stress, Ocular Disease and Diabetes Retinopathy

Current Pharmaceutical Design ◽

10.2174/1381612825666190115121531 ◽

2019 ◽

Vol 24 (40) ◽

pp. 4726-4741 ◽

Cited By ~ 8

Author(s):

Orathai Tangvarasittichai ◽

Surapon Tangvarasittichai

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Cell Death ◽

Protein Modification ◽

Morphological Changes ◽

Corneal Dystrophy ◽

Age Related Macular Degeneration ◽

Ocular Diseases ◽

Retinal Light Damage ◽

Age Related

Background: Oxidative stress is caused by free radicals or oxidant productions, including lipid peroxidation, protein modification, DNA damage and apoptosis or cell death and results in cellular degeneration and neurodegeneration from damage to macromolecules. Results: Accumulation of the DNA damage (8HOdG) products and the end products of LPO (including aldehyde, diene, triene conjugates and Schiff’s bases) were noted in the research studies. Significantly higher levels of these products in comparison with the controls were observed. Oxidative stress induced changes to ocular cells and tissues. Typical changes include ECM accumulation, cell dysfunction, cell death, advanced senescence, disarrangement or rearrangement of the cytoskeleton and released inflammatory cytokines. It is involved in ocular diseases, including keratoconus, Fuchs endothelial corneal dystrophy, and granular corneal dystrophy type 2, cataract, age-related macular degeneration, primary open-angle glaucoma, retinal light damage, and retinopathy of prematurity. These ocular diseases are the cause of irreversible blindness worldwide. Conclusions: Oxidative stress, inflammation and autophagy are implicated in biochemical and morphological changes in these ocular tissues. The development of therapy is a major target for the management care of these ocular diseases.

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Subthreshold laser treatment for reticular pseudodrusen secondary to age-related macular degeneration

Scientific Reports ◽

10.1038/s41598-021-81810-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Giuseppe Querques ◽

Riccardo Sacconi ◽

Francesco Gelormini ◽

Enrico Borrelli ◽

Francesco Prascina ◽

...

Keyword(s):

Macular Degeneration ◽

Laser Treatment ◽

Age Related Macular Degeneration ◽

Short Term ◽

Treated Area ◽

Reticular Pseudodrusen ◽

End Point ◽

Age Related ◽

Subthreshold Laser

AbstractThere is a lack of treatment aimed at the regression of reticular pseudodrusen (RPD) secondary to age-related macular degeneration (AMD). The aim of this prospective, pilot study is to evaluate the safety and short-term efficacy of subthreshold laser treatment (SLT) in patients affected by RPD secondary to dry AMD (dAMD). Twenty eyes of 20 patients (mean age 78.4 ± 6.8 years) with RPD secondary to dAMD were prospectively enrolled. All patients were treated in an extrafoveal area of 1.27 mm2 using end-point management yellow subthreshold laser and followed for 3 months. Best-corrected visual acuity was 0.140 ± 0.09 LogMAR at the baseline and no changes were observed during the follow-up (p = 0.232). No significant worsening was disclosed before and after the treatment analyzing the macular sensitivity of the treated area (p = 0.152). No topical and/or systemic side effects were disclosed during the 3-month follow-up. The distribution among the RPD stages changed after the treatment (p < 0.001). In detail, in the treated area, we observed a significant increase in the number of Stage 1 RPD during the follow-up (p = 0.002), associated with a significant decrease of Stage 3 RPD (p = 0.020). Outer nuclear layer (ONL) thickness analysis showed a significant increase after the treatment associated with RPD regression (p = 0.001). End-point management SLT appears a safe treatment for RPD secondary to dAMD, showing short-term safety outcomes. Our results suggest that SLT could be effective in inducing a RPD regression in terms of RPD stage and ONL thickening.

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VEGF Rescues Cigarette Smoking–Induced Human RPE Cell Death by Increasing Autophagic Flux: Implications of the Role of Autophagy in Advanced Age-Related Macular Degeneration

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.13-12149 ◽

2013 ◽

Vol 54 (12) ◽

pp. 7329 ◽

Cited By ~ 10

Author(s):

Young Kwang Chu ◽

Sung Chul Lee ◽

Suk Ho Byeon

Keyword(s):

Cell Death ◽

Cigarette Smoking ◽

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Advanced Age ◽

Autophagic Flux ◽

Age Related

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Lipofuscin causes atypical necroptosis through lysosomal membrane permeabilization

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2100122118 ◽

2021 ◽

Vol 118 (47) ◽

pp. e2100122118

Author(s):

Chendong Pan ◽

Kalpita Banerjee ◽

Guillermo L. Lehmann ◽

Dena Almeida ◽

Katherine A. Hajjar ◽

...

Keyword(s):

Cell Death ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Physicochemical Characteristics ◽

Age Related Macular Degeneration ◽

Toxic Waste ◽

Pharmacological Intervention ◽

Age Related ◽

Human Disorders ◽

Lipofuscin Granules

Lipofuscin granules enclose mixtures of cross-linked proteins and lipids in proportions that depend on the tissue analyzed. Retinal lipofuscin is unique in that it contains mostly lipids with very little proteins. However, retinal lipofuscin also presents biological and physicochemical characteristics indistinguishable from conventional granules, including indigestibility, tendency to cause lysosome swelling that results in rupture or defective functions, and ability to trigger NLRP3 inflammation, a symptom of low-level disruption of lysosomes. In addition, like conventional lipofuscins, it appears as an autofluorescent pigment, considered toxic waste, and a biomarker of aging. Ocular lipofuscin accumulates in the retinal pigment epithelium (RPE), whereby it interferes with the support of the neuroretina. RPE cell death is the primary cause of blindness in the most prevalent incurable genetic and age-related human disorders, Stargardt disease and age-related macular degeneration (AMD), respectively. Although retinal lipofuscin is directly linked to the cell death of the RPE in Stargardt, the extent to which it contributes to AMD is a matter of debate. Nonetheless, the number of AMD clinical trials that target lipofuscin formation speaks for the potential relevance for AMD as well. Here, we show that retinal lipofuscin triggers an atypical necroptotic cascade, amenable to pharmacological intervention. This pathway is distinct from canonic necroptosis and is instead dependent on the destabilization of lysosomes. We also provide evidence that necroptosis is activated in aged human retinas with AMD. Overall, this cytotoxicity mechanism may offer therapeutic targets and markers for genetic and age-related diseases associated with lipofuscin buildups.

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Therapeutic effects of a novel siRNA-based anti-VEGF (siVEGF) nanoball for the treatment of choroidal neovascularization

Nanoscale ◽

10.1039/c7nr03142d ◽

2017 ◽

Vol 9 (40) ◽

pp. 15461-15469 ◽

Cited By ~ 15

Author(s):

Na-Kyung Ryoo ◽

Jihwang Lee ◽

Hyunjoo Lee ◽

Hye Kyoung Hong ◽

Hyejin Kim ◽

...

Keyword(s):

Macular Degeneration ◽

Choroidal Neovascularization ◽

Developed Countries ◽

Age Related Macular Degeneration ◽

Therapeutic Effects ◽

Anti Vegf ◽

Age Related

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries and is characterized by the development of choroidal neovascularization (CNV).

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Pharmaceutical Induction of PGC-1α Promotes Retinal Pigment Epithelial Cell Metabolism and Protects against Oxidative Damage

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/9248640 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 13

Author(s):

Sangeeta Satish ◽

Hannah Philipose ◽

Mariana Aparecida Brunini Rosales ◽

Magali Saint-Geniez

Keyword(s):

Cell Death ◽

Antioxidant Enzymes ◽

Oxidative Damage ◽

Therapeutic Potential ◽

Retinal Pigment Epithelial Cell ◽

Cell Metabolism ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Age Related

Retinal pigment epithelium (RPE) dysfunction due to accumulation of reactive oxygen species and oxidative damage is a key event in the development of age-related macular degeneration (AMD). Here, we examine the therapeutic potential of ZLN005, a selective PGC-1α transcriptional regulator, in protecting RPE from cytotoxic oxidative damage. Gene expression analysis on ARPE-19 cells treated with ZLN005 shows robust upregulation of PGC-1α and its associated transcription factors, antioxidant enzymes, and mitochondrial genes. Energetic profiling shows that ZLN005 treatment enhances RPE mitochondrial function by increasing basal and maximal respiration rates, and spare respiratory capacity. In addition, ZLN005 robustly protects ARPE-19 cells from cell death caused by H2O2, ox-LDL, and NaIO3 without exhibiting any cytotoxicity under basal conditions. ZLN005 protection against H2O2-mediated cell death was lost in PGC-1α-silenced cells. Our data indicates that ZLN005 efficiently protects RPE cells from oxidative damage through selective induction of PGC-1α and its target antioxidant enzymes. ZLN005 may serve as a novel therapeutic agent for retinal diseases associated with RPE dystrophies.

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