Protective effect of rapamycin in models of retinal degeneration

Niu, Zhanyu; Shi, Yu; Li, Jiande; Qiao, Shufan; Du, Shanyi; Chen, Linchi; Tian, Huanbing; Li, Wei; Cao, Hanwen; Wang, Ji; Gao, Lan

doi:10.1016/j.exer.2021.108700

Cited by 5 publications

(4 citation statements)

References 49 publications

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“…RAPA prevented neurodegradation and reduced retinal thickness in animal models of retinal degeneration. In DR, RAPA also showed the same protective effects on the retina [31,[36][37][38]. In this study, we found that RAPA signi cantly improved the inhibition of autophagy in RMCs induced by high glucose.…”

Section: Discussionmentioning

confidence: 54%

Resveratrol Improves Diabetic Retinopathy via Regulating MicroRNA-29b/Specificity Protein 1/Apoptosis Pathway by Enhancing Autophagy

Zeng,

Wan,

Sun

et al. 2024

Preprint

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Therapeutic targeting of retinal Müller cells (RMCs) has garnered tremendous attention for early prevention and treatment of diabetic retinopathy (DR). The microRNA-29b (miR-29b)/specificity protein 1 (SP1) pathway is critical for RMCs survival in hyperglycemic environments, and miR-29b downregulation and SP1 upregulation contribute to RMCs apoptosis during early DR stages. Resveratrol (RSV), a natural plant polyphenol, can inhibit RMCs apoptosis by regulating miR-29b/SP1 expression, playing an important role in early DR protection. However, how RSV affects high-glucose-stimulated miR-29b downregulation and SP1 upregulation in early DR remains poorly understood. Here, we show that RSV increased autophagosome formation and LC3-I/LC3-II and Beclin-1 levels while decreasing P62 level, thereby promoting autophagy and inhibiting dysregulation of miR-29b/SP1 pathway expression and RMCs apoptosis in DR rat retinal tissues and high glucose-cultured RMCs. This is supported by findings that autophagy inducer rapamycin (RAPA) enhances the effect of RSV on inhibiting high-glucose-induced dysregulation of miR-29b/SP1 expression and apoptosis of RMCs in DR rat retinal tissues and high glucose-cultured RMCs. Inhibition of autophagy with 3-methyladenine (3-MA) attenuates the effect of RSV on inhibiting high-glucose-induced dysregulation of miR-29b/SP1 expression and apoptosis of RMCs in DR rat retinal tissues and high glucose-cultured RMCs. In summary, these results suggest that RSV further inhibits the apoptosis of RMCs by activating autophagy and regulating the early miR-29b downregulation and SP1 upregulation induced by high glucose, thereby inhibiting the progression of DR. Our findings suggest that RSV has great potential in the early prevention and treatment of DR.

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Section: Discussionmentioning

confidence: 54%

Resveratrol Improves Diabetic Retinopathy via Regulating MicroRNA-29b/Specificity Protein 1/Apoptosis Pathway by Enhancing Autophagy

Zeng,

Wan,

Sun

et al. 2024

Preprint

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“…Another study observed that autophagy inhibition using either 3-methyladenine (3-MA; PI3K inhibitor) or Bafilomycin A1 (lysosomal acidification, autolysosome fusion inhibitor) further sensitizes ARPE-19 cells to SI-induced cell death [ 18 ]. Rapamycin, a traditional autophagy inducer, has accordingly shown neuroprotective benefits against SI treatment in vitro [ 34 ] and in vivo [ 39 ]. Even though current research highlights promising results regarding lifespan extension and therapeutic potential, the use of rapamycin in the clinic and its putative side effects are still being debated [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration

Jiménez-Loygorri,

Viedma-Poyatos,

Gómez-Sintes

et al. 2024

Mol Neurodegeneration

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Background Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands in our bodies that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status and constant photooxidative damage from incoming light, the retina requires a tightly-regulated housekeeping system that involves autophagy. The natural polyphenol Urolithin A (UA) has shown neuroprotective benefits in several models of aging and age-associated disorders, mostly attributed to its ability to induce mitophagy and mitochondrial biogenesis. Sodium iodate (SI) administration recapitulates the late stages of AMD, including geographic atrophy and photoreceptor cell death. Methods A combination of in vitro, ex vivo and in vivo models were used to test the neuroprotective potential of UA in the SI model. Functional assays (OCT, ERGs), cellular analysis (flow cytometry, qPCR) and fine confocal microscopy (immunohistochemistry, tandem selective autophagy reporters) helped address this question. Results UA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA. Treatment with UA restored autophagic flux and triggered PINK1/Parkin-dependent mitophagy, as previously reported in the literature. Autophagy blockage caused by SI was caused by severe lysosomal membrane permeabilization. While UA did not induce lysosomal biogenesis, it did restore upcycling of permeabilized lysosomes through lysophagy. Knockdown of the lysophagy adaptor SQSTM1/p62 abrogated viability rescue by UA in SI-treated cells, exacerbated lysosomal defects and inhibited lysophagy. Conclusions Collectively, these data highlight a novel putative application of UA in the treatment of AMD whereby it bypasses lysosomal defects by promoting p62-dependent lysophagy to sustain proteostasis. Graphical Abstract

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“…Rapamycin not only protected ARPE-19 cells from an acute lethal dose of H 2 O 2 but also rescued the autophagy activity, leading to a reduction in ROS generation and lipofuscin-like granule accumulation upon long-term oxidative stress. Besides the in vitro model, rapamycin also played a key role in attenuating an inflammatory response and oxidative stress in sodium-iodate (NaIO 3 )-induced retinal degeneration in mice as well [ 21 ].…”

Section: Mtor In Ocular Neurodegenerative Diseasesmentioning

confidence: 99%

“…The neuroprotective roles of rapamycin may be a novel therapeutic pathway in ocular neurodegenerative diseases, such as diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma, which share common pathophysiological mechanisms, especially increased and prolonged oxidative stress, which would ultimately result in retinal neuronal death [ 11 , 12 , 13 , 14 ]. Recently, a large number of studies have been conducted to elucidate the neuroprotective role of rapamycin and its underlying mechanism(s) in the treatment of ocular degenerative diseases [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ]. For instance, a study has shown that rapamycin ameliorated high-glucose-induced ROS formation and inflammatory injury in retinal pigment epithelial (RPE) cells [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

mTOR Signalling Pathway: A Potential Therapeutic Target for Ocular Neurodegenerative Diseases

et al. 2022

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Recent advances in the research of the mammalian target of the rapamycin (mTOR) signalling pathway demonstrated that mTOR is a robust therapeutic target for ocular degenerative diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma. Although the exact mechanisms of individual ocular degenerative diseases are unclear, they share several common pathological processes, increased and prolonged oxidative stress in particular, which leads to functional and morphological impairment in photoreceptors, retinal ganglion cells (RGCs), or retinal pigment epithelium (RPE). mTOR not only modulates oxidative stress but is also affected by reactive oxygen species (ROS) activation. It is essential to understand the complicated relationship between the mTOR pathway and oxidative stress before its application in the treatment of retinal degeneration. Indeed, the substantial role of mTOR-mediated autophagy in the pathogenies of ocular degenerative diseases should be noted. In reviewing the latest studies, this article summarised the application of rapamycin, an mTOR signalling pathway inhibitor, in different retinal disease models, providing insight into the mechanism of rapamycin in the treatment of retinal neurodegeneration under oxidative stress. Besides basic research, this review also summarised and updated the results of the latest clinical trials of rapamycin in ocular neurodegenerative diseases. In combining the current basic and clinical research results, we provided a more complete picture of mTOR as a potential therapeutic target for ocular neurodegenerative diseases.

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Protective effect of rapamycin in models of retinal degeneration

Cited by 5 publications

References 49 publications

Resveratrol Improves Diabetic Retinopathy via Regulating MicroRNA-29b/Specificity Protein 1/Apoptosis Pathway by Enhancing Autophagy

Resveratrol Improves Diabetic Retinopathy via Regulating MicroRNA-29b/Specificity Protein 1/Apoptosis Pathway by Enhancing Autophagy

Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration

mTOR Signalling Pathway: A Potential Therapeutic Target for Ocular Neurodegenerative Diseases

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