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Science (New York, N.Y.) May 2020
Topics: Humans; Light; Retinal Ganglion Cells; Visual Perception
PubMed: 32355019
DOI: 10.1126/science.abb7529 -
Cells Jun 2021As part of the central nervous system, mammalian retinal ganglion cells (RGCs) lack significant regenerative capacity. Glaucoma causes progressive and irreversible... (Review)
Review
As part of the central nervous system, mammalian retinal ganglion cells (RGCs) lack significant regenerative capacity. Glaucoma causes progressive and irreversible vision loss by damaging RGCs and their axons, which compose the optic nerve. To functionally restore vision, lost RGCs must be replaced. Despite tremendous advancements in experimental models of optic neuropathy that have elucidated pathways to induce RGC neuroprotection and axon regeneration, obstacles to achieving functional visual recovery through RGC transplantation remain. Key challenges include poor graft survival, low donor neuron localization to the host retina, and inadequate dendritogenesis and synaptogenesis with afferent amacrine and bipolar cells. In this review, we summarize the current state of experimental RGC transplantation, and we propose a set of standard approaches to quantifying and reporting experimental outcomes in order to guide a collective effort to advance the field toward functional RGC replacement and optic nerve regeneration.
Topics: Animals; Humans; Nerve Regeneration; Neuroprotection; Regenerative Medicine; Retinal Ganglion Cells; Stem Cell Transplantation
PubMed: 34200991
DOI: 10.3390/cells10061426 -
Experimental Eye Research Apr 2017Within the field of glaucoma research, neuroprotection is defined as slowing the functional loss in glaucoma by a mechanism independent of lowering of intraocular... (Review)
Review
Within the field of glaucoma research, neuroprotection is defined as slowing the functional loss in glaucoma by a mechanism independent of lowering of intraocular pressure. There is currently a great potential for research surrounding neuroprotection as it relates to glaucoma. Anatomical targets for neuroprotection should focus on upstream rather than downstream factors, and could include any part of the retinal ganglion cell, the glia, especially astrocytes or Muller cells, and vasculature. The great number of anatomical targets is exceeded only by the number of possible biochemical pathways and potential treatments. Successful treatment may be accomplished through the targeting of one or even a combination of multiple pathways. Once a treatment is shown effective in vitro, it should be evaluated in vivo with carefully chosen animal models and studied in sufficient numbers to detect statistically and clinically significant effects. Such a drug should have few systemic side effects and its delivery should be optimized so as to encourage compliance. There are still a multitude of possible screens available to test the efficacy of a neuroprotective drug and a single gold standard is ideal for the accurate assessment and comparison of new drugs. Future studies in neuroprotection should investigate the genetic component of the disease, novel pharmaceutical agents for new or known pathways, modulations of scleral biomechanics, and relation to research of other complex disorders of the central nervous system.
Topics: Animals; Astrocytes; Axons; Glaucoma; Humans; Neuroprotection; Neuroprotective Agents; Optic Nerve Diseases; Retinal Ganglion Cells; Translational Research, Biomedical
PubMed: 27955999
DOI: 10.1016/j.exer.2016.12.005 -
Molecular Aspects of Medicine Dec 2023In the last years, neuroprotective therapies have attracted the researcher interests as modern and challenging approach for the treatment of neurodegenerative diseases,... (Review)
Review
In the last years, neuroprotective therapies have attracted the researcher interests as modern and challenging approach for the treatment of neurodegenerative diseases, aimed at protecting the nervous system from injuries. Glaucoma is a neurodegenerative disease characterized by progressive excavation of the optic nerve head, retinal axonal injury and corresponding vision loss that affects millions of people on a global scale. The molecular basis of the pathology is largely uncharacterized yet, and the therapeutic approaches available do not change the natural course of the disease. Therefore, in accordance with the therapeutic regimens proposed for other neurodegenerative diseases, a modern strategy to treat glaucoma includes prescription of drugs with neuroprotective activities. With respect to this, several preclinical and clinical investigations on a plethora of different drugs are currently ongoing. In this review, first, the conceptualization of the rationale for the adoption of neuroprotective strategies for retina is summarized. Second, the molecular aspects highlighting glaucoma as a neurodegenerative disease are reported. In conclusion, the molecular and pharmacological properties of most promising direct neuroprotective drugs used to delay glaucoma progression are examined, including: neurotrophic factors, NMDA receptor antagonists, the α2-adrenergic agonist, brimonidine, calcium channel blockers, antioxidant agents, nicotinamide and statins.
Topics: Humans; Neurodegenerative Diseases; Retinal Ganglion Cells; Glaucoma; Brimonidine Tartrate; Retina; Retinal Diseases
PubMed: 38000334
DOI: 10.1016/j.mam.2023.101225 -
Advanced Biology May 2024Glaucoma, a blind-leading disease largely since chronic pathological intraocular high pressure (ph-IOP). Hitherto, it is reckoned incurable for irreversible neural... (Review)
Review
Glaucoma, a blind-leading disease largely since chronic pathological intraocular high pressure (ph-IOP). Hitherto, it is reckoned incurable for irreversible neural damage and challenges in managing IOP. Thus, it is significant to develop neuroprotective strategies. Ferroptosis, initially identified as an iron-dependent regulated death that triggers Fenton reactions and culminates in lipid peroxidation (LPO), has emerged as a focal point in multiple tumors and neurodegenerative diseases. Researches show that iron homeostasis play critical roles in the optic nerve (ON) and retinal ganglion cells (RGCs), suggesting targeted treatments could be effective. In glaucoma, apart from neural lesions, disrupted metal balance and increased oxidative stress in trabecular meshwork (TM) are observed. These disturbances lead to extracellular matrix excretion disorders, known as sclerotic mechanisms, resulting in refractory blockages. Importantly, oxidative stress, a significant downstream effect of ferroptosis, is also a key factor in cell senescence. It plays a crucial role in both the etiology and risk of glaucoma. Moreover, ferroptosis also induces non-infectious inflammation, which exacerbate glaucomatous injury. Therefore, the relevance of ferroptosis in glaucoma is extensive and multifaceted. In this review, the study delves into the current understanding of ferroptosis mechanisms in glaucoma, aiming to provide clues to inform clinical therapeutic practices.
Topics: Humans; Ferroptosis; Glaucoma; Oxidative Stress; Animals; Iron; Lipid Peroxidation; Retinal Ganglion Cells
PubMed: 38411382
DOI: 10.1002/adbi.202300530 -
Current Eye Research Mar 2020Müller glia constitute the main glial cells of the retina. They are spatially distributed along this tissue, facilitating their close membrane interactions with all... (Review)
Review
Müller glia constitute the main glial cells of the retina. They are spatially distributed along this tissue, facilitating their close membrane interactions with all retinal neurons. Müller glia are characterized by their active metabolic functions, which are neuroprotective in nature. Although they can become reactive under pathological conditions, leading to their production of inflammatory and neurotoxic factors, their main metabolic functions confer neuroprotection to the retina, resulting in the promotion of neural cell repair and survival. In addition to their protective metabolic features, Müller glia release several neurotrophic factors and antioxidants into the retinal microenvironment, which are taken up by retinal neurons for their survival. This review summarizes the Müller glial neuroprotective mechanisms and describes advances made on the clinical application of these factors for the treatment of retinal degenerative diseases. It also discusses prospects for the use of these cells as a vehicle to deliver neuroprotective factors into the retina.
Topics: Animals; Nerve Growth Factors; Neuroglia; Neuroprotection; Retinal Ganglion Cells
PubMed: 31355675
DOI: 10.1080/02713683.2019.1648831 -
Annual Review of Neuroscience Jul 2015In the retina, photoreceptors pass visual information to interneurons, which process it and pass it to retinal ganglion cells (RGCs). Axons of RGCs then travel through... (Review)
Review
In the retina, photoreceptors pass visual information to interneurons, which process it and pass it to retinal ganglion cells (RGCs). Axons of RGCs then travel through the optic nerve, telling the rest of the brain all it will ever know about the visual world. Research over the past several decades has made clear that most RGCs are not merely light detectors, but rather feature detectors, which send a diverse set of parallel, highly processed images of the world on to higher centers. Here, we review progress in classification of RGCs by physiological, morphological, and molecular criteria, making a particular effort to distinguish those cell types that are definitive from those for which information is partial. We focus on the mouse, in which molecular and genetic methods are most advanced. We argue that there are around 30 RGC types and that we can now account for well over half of all RGCs. We also use RGCs to examine the general problem of neuronal classification, arguing that insights and methods from the retina can guide the classification enterprise in other brain regions.
Topics: Animals; Biological Evolution; Models, Neurological; Retinal Ganglion Cells
PubMed: 25897874
DOI: 10.1146/annurev-neuro-071714-034120 -
Biological Psychology Nov 2023Two recent studies of eye closure triggered by intense luminance increase suggest that this behavior reflects the melanopsin-based retinal activity known to underlie... (Review)
Review
Two recent studies of eye closure triggered by intense luminance increase suggest that this behavior reflects the melanopsin-based retinal activity known to underlie photophobia, the pathological aversion to light (Kardon, 2012; Kaiser et al., 2021). Early studies of the photic blink reflex (PBR) are reviewed to help guide future research on this possible objective index of photophobia. Electromyographic recordings of the lid-closure muscle, orbicularis oculi, reveal distinct bursts with typical onset latencies of 50 and 80 ms, R50 and R80, respectively. The latter component appears to be especially sensitive to visual signals from intrinsically photosensitive retinal ganglion cells (ipRGCs) and to prior trigeminal nociceptive stimuli. The authors argue that the R80's function, in addition to protecting the eyeballs from physical contact, is to shape the upper and lower eyelids into a narrow slit to restrict incoming light. This serves to prevent retinal bleaching or injury, while allowing continued visual function.
Topics: Humans; Photophobia; Photic Stimulation; Blinking; Retinal Ganglion Cells; Sensation; Reflex, Pupillary
PubMed: 37757999
DOI: 10.1016/j.biopsycho.2023.108695 -
Science (New York, N.Y.) Jun 2017Humans are highly visual. Retinal ganglion cells (RGCs), the neurons that connect the eyes to the brain, fail to regenerate after damage, eventually leading to... (Review)
Review
Humans are highly visual. Retinal ganglion cells (RGCs), the neurons that connect the eyes to the brain, fail to regenerate after damage, eventually leading to blindness. Here, we review research on regeneration and repair of the optic system. Intrinsic developmental growth programs can be reactivated in RGCs, neural activity can enhance RGC regeneration, and functional reformation of eye-to-brain connections is possible, even in the adult brain. Transplantation and gene therapy may serve to replace or resurrect dead or injured retinal neurons. Retinal prosthetics that can restore vision in animal models may too have practical power in the clinical setting. Functional restoration of sight in certain forms of blindness is likely to occur in human patients in the near future.
Topics: Animals; Axons; Blindness; Cicatrix; Humans; Inflammation; Myelin Proteins; Optic Nerve; Regeneration; Retinal Ganglion Cells; Stem Cell Transplantation
PubMed: 28596336
DOI: 10.1126/science.aal5060 -
Journal of Translational Medicine May 2024Retinal ischemia/reperfusion (RIR) is implicated in various forms of optic neuropathies, yet effective treatments are lacking. RIR leads to the death of retinal ganglion...
BACKGROUND
Retinal ischemia/reperfusion (RIR) is implicated in various forms of optic neuropathies, yet effective treatments are lacking. RIR leads to the death of retinal ganglion cells (RGCs) and subsequent vision loss, posing detrimental effects on both physical and mental health. Apigenin (API), derived from a wide range of sources, has been reported to exert protective effects against ischemia/reperfusion injuries in various organs, such as the brain, kidney, myocardium, and liver. In this study, we investigated the protective effect of API and its underlying mechanisms on RGC degeneration induced by retinal ischemia/reperfusion (RIR).
METHODS
An in vivo model was induced by anterior chamber perfusion following intravitreal injection of API one day prior to the procedure. Meanwhile, an in vitro model was established through 1% oxygen and glucose deprivation. The neuroprotective effects of API were evaluated using H&E staining, spectral-domain optical coherence tomography (SD-OCT), Fluoro-Gold retrograde labeling, and Photopic negative response (PhNR). Furthermore, transmission electron microscopy (TEM) was employed to observe mitochondrial crista morphology and integrity. To elucidate the underlying mechanisms of API, the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry assay, western blot, cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay, JC-1 kit assay, dichlorofluorescein-diacetate (DCFH-DA) assay, as well as TMRE and Mito-tracker staining were conducted.
RESULTS
API treatment protected retinal inner plexiform layer (IPL) and ganglion cell complex (GCC), and improved the function of retinal ganglion cells (RGCs). Additionally, API reduced RGC apoptosis and decreased lactate dehydrogenase (LDH) release by upregulating Bcl-2 and Bcl-xL expression, while downregulating Bax and cleaved caspase-3 expression. Furthermore, API increased mitochondrial membrane potential (MMP) and decreased extracellular reactive oxygen species (ROS) production. These effects were achieved by enhancing mitochondrial function, restoring mitochondrial cristae morphology and integrity, and regulating the expression of OPA1, MFN2, and DRP1, thereby regulating mitochondrial dynamics involving fusion and fission.
CONCLUSION
API protects RGCs against RIR injury by modulating mitochondrial dynamics, promoting mitochondrial fusion and fission.
Topics: Retinal Ganglion Cells; Apigenin; Animals; Reperfusion Injury; Neuroprotective Agents; Mitochondrial Dynamics; Male; Apoptosis; Mitochondria; Reactive Oxygen Species; Models, Biological; Mice, Inbred C57BL
PubMed: 38741132
DOI: 10.1186/s12967-024-05260-1