Solving neurodegeneration: common mechanisms and strategies for new treatments

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: March 21, 2022

Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology site disease pathology. To address these and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus the Melza M. Frank Theodore Barr Foundation collaborated to bring together key opinion leaders experts field for a virtual meeting titled "Solving Neurodegeneration". This "think-tank" style focused uncovering mechanistic roots promising new catalyzed by goal finding treatments glaucoma, world's leading cause irreversible blindness interest three hosting foundations. Glaucoma, which causes vision loss through degeneration optic nerve, likely shares early cellular molecular events with other diseases central nervous system. Here we major areas overlap between system: neuroinflammation, bioenergetics metabolism, genetic contributions, neurovascular interactions. We summarize important discussion points emphasis research that are most innovative treatment neurodegeneration yet require further development. The is highlighted provides unique opportunities collaboration will lead efforts preventing ultimately loss.

Language: Английский

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Topical Drug Delivery to the Posterior Segment of the Eye

Pharmaceutics, Journal Year: 2022, Volume and Issue: 14(1), P. 134 - 134

Published: Jan. 6, 2022

Topical drug delivery to the posterior segment of eye is a very complex challenge. However, topical highly desired, achieve an easy-to-use treatment option for retinal diseases. In this review, we focus on characteristics that are relevant succeed in An overview ocular barriers need be overcome and some animal models study pharmacokinetics given. Furthermore, summary substances were able reach after drop application provided, as well outline investigated systems improve delivery. Some promising results delivered retina suggest diseases might possible future, which warrants further research.

Language: Английский

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Addressing neurodegeneration in glaucoma: Mechanisms, challenges, and treatments

Progress in Retinal and Eye Research, Journal Year: 2024, Volume and Issue: 100, P. 101261 - 101261

Published: March 26, 2024

Glaucoma is the leading cause of irreversible blindness globally. The disease causes vision loss due to neurodegeneration retinal ganglion cell (RGC) projection brain through optic nerve. associated with sensitivity intraocular pressure (IOP). Thus, mainstay treatments seek manage IOP, though many patients continue lose vision. To address directly, numerous preclinical studies develop protective or reparative therapies that act independently IOP. These include growth factors, compounds targeting metabolism, anti-inflammatory and antioxidant agents, neuromodulators. Despite success in experimental models, these approaches fail translate into clinical benefits. Several factors contribute this challenge. Firstly, anatomic structure nerve head differs between rodents, nonhuman primates, humans. Additionally, animal models do not replicate complex glaucoma pathophysiology Therefore, enhance translating findings, we propose two approaches. First, thorough evaluation targets multiple including should precede trials. Second, advocate for combination therapy, which involves using agents simultaneously, especially early potentially reversible stages disease. strategies aim increase chances successful neuroprotective treatment glaucoma.

Language: Английский

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Integration and functionality of human iPSC-derived microglia in a chimeric mouse retinal model

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: Feb. 27, 2025

Microglia, the resident immune cells of central nervous system, play a pivotal role in maintaining homeostasis, responding to injury, and modulating neuroinflammation. However, limitations rodent models accurately representing human microglia have posed significant challenges study retinal diseases. PLX5622 was used eliminate endogenous mice through oral intraperitoneal administration, followed by transplantation induced pluripotent stem cell-derived (hiPSC-microglia, iMG) into explants create novel ex vivo chimeric model containing xenotransplanted (xMG). The number proportion xMG retina were quantified using flat-mounting immunostaining. To evaluate proliferative capacity synaptic pruning ability xMG, expression Ki-67 phagocytosis proteins SV2 PSD95 assessed. stimulated with LPS, single-cell RNA sequencing (scRNA-seq) analyze transcriptomic changes iMG xMG. Mouse IL-34 antibody neutralization experiments performed, behavior degenerative Pde6b−/− examined. We demonstrated that (xMG) successfully migrated localized within mouse retina, adopting homeostatic morphologies. Our approach achieved over 86% integration microglia, which maintained key functions including proliferation, responsiveness, 14-day culture period. scRNA-seq revealed shift microglial signatures compared monoculture iMG, indicating transition more vivo-like phenotype. In mice, exhibited activation toward degenerated photoreceptors. This provides powerful platform for studying context, offering insights advancing research diseases developing potential therapeutic strategies. Future applications this include patient-derived iPSCs investigate disease-specific behaviors, thereby enhancing our understanding microglia-related pathogenesis.

Language: Английский

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Glaucoma and Antioxidants: Review and Update

Antioxidants, Journal Year: 2020, Volume and Issue: 9(11), P. 1031 - 1031

Published: Oct. 22, 2020

Glaucoma is a neurodegenerative disease characterised by the progressive degeneration of retinal ganglion cells. Oxidative stress has been related to cell death in this disease. Theoretically, deleterious consequence can be reduced antioxidants substances. The aim review assemble studies published relation antioxidant supplementation and its effects on glaucoma offer reader an update field. With purpose, we have included animal models clinical trials. Although there are variable results, with may promising therapy glaucoma.

Language: Английский

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Uptake and Distribution of Administered Bone Marrow Mesenchymal Stem Cell Extracellular Vesicles in Retina

Cells, Journal Year: 2021, Volume and Issue: 10(4), P. 730 - 730

Published: March 25, 2021

Cell replacement therapy using mesenchymal (MSC) and other stem cells has been evaluated for diabetic retinopathy glaucoma. This approach significant limitations, including few integrated, aberrant growth, surgical complications. Mesenchymal Stem Exosomes/Extracellular Vesicles (MSC EVs), which include exosomes microvesicles, are an emerging alternative, promoting immunomodulation, repair, regeneration by mediating MSC’s paracrine effects. For the clinical translation of EV therapy, it is important to determine cellular destination time course uptake in retina following administration. Here, we tested fate EVs vivo rat retinas, ex retinal explant, primary cells. Intravitreally administered fluorescent were rapidly cleared from vitreous. Retinal ganglion (RGCs) had maximal fluorescence at 14 days post administration, microglia 7 days. Both explant model, most no deeper than inner nuclear layer. astrocytes, microglia, mixed neurons vitro endocytosed a dose-dependent manner. Thus, our results indicate that intravitreal suited treatment diseases affecting retina. Modification surface should be considered maintaining vitreous prolonged delivery.

Language: Английский

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Role of toll-like receptor 4 in diabetic retinopathy

Pharmacological Research, Journal Year: 2021, Volume and Issue: 175, P. 105960 - 105960

Published: Oct. 28, 2021

Language: Английский

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miRNA Studies in Glaucoma: A Comprehensive Review of Current Knowledge and Future Perspectives

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(19), P. 14699 - 14699

Published: Sept. 28, 2023

Glaucoma, a neurodegenerative disorder that leads to irreversible blindness, remains challenge because of its complex nature. MicroRNAs (miRNAs) are crucial regulators gene expression and associated with glaucoma other diseases. We aimed review discuss the advantages disadvantages miRNA-focused molecular studies in through discussing their potential as biomarkers for early detection diagnosis; offering insights into pathways mechanisms; utility respect personalized medicine, therapeutic potential, non-invasive monitoring. Limitations, such variability, small sample sizes, specificity, limited accessibility ocular tissues, also addressed, underscoring need robust protocols collaboration. Reproducibility validation establish credibility miRNA research findings, integration bioinformatics tools database creation is valuable component comprehensive approach investigate aberrations patients glaucoma. Overall, has provided significant mechanisms disease, biomarkers, diagnostic tools, targets. However, addressing challenges variability tissue essential, further investigations will contribute deeper understanding functional significance miRNAs

Language: Английский

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Glaucoma Animal Models beyond Chronic IOP Increase

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 906 - 906

Published: Jan. 11, 2024

Glaucoma is a complex and multifactorial disease defined as the loss of retinal ganglion cells (RGCs) their axons. Besides an elevated intraocular pressure (IOP), other mechanisms play pivotal role in glaucoma onset progression. For example, it known that excitotoxicity, immunological alterations, ischemia, oxidative stress contribute to neurodegeneration disease. To study these effects discover novel therapeutic approaches, appropriate animal models are needed. In this review, we focus on various beyond IOP. We introduce genetically modified mice, e.g., optineurin E50K knock-in or glutamate aspartate transporter (GLAST)-deficient mouse. Excitotoxicity can be mimicked by injecting analogue N-methyl-D-aspartate intravitreally, which leads rapid RGC degeneration. explore contribution immune system, experimental autoimmune model serve useful tool. Here, immunization with antigens led glaucoma-like damage. The ischemic mechanism inducing high IOP for certain amount time rodents, followed reperfusion. Thereby, damage retina optic nerve occurs rapidly after ischemia/reperfusion. Lastly, discuss importance crush systems normal-tension glaucoma. summary, increase utilized.

Language: Английский

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Ferroptosis as a potential therapeutic target for age-related macular degeneration

Drug Discovery Today, Journal Year: 2024, Volume and Issue: 29(4), P. 103920 - 103920

Published: Feb. 17, 2024

Language: Английский

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