Neuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering

Molecular Aspects of Medicine, Год журнала: 2023, Номер 92, С. 101193 - 101193

Опубликована: Июнь 16, 2023

Glaucoma is a common, complex, multifactorial neurodegenerative disease characterized by progressive dysfunction and then loss of retinal ganglion cells, the output neurons retina. most common cause irreversible blindness affects ∼80 million people worldwide with many more undiagnosed. The major risk factors for glaucoma are genetics, age, elevated intraocular pressure. Current strategies only target pressure management do not directly processes occurring at level cell. Despite to manage pressure, as 40% patients progress in least one eye during their lifetime. As such, neuroprotective that cell these great therapeutic need. This review will cover recent advances from basic biology on-going clinical trials neuroprotection covering degenerative mechanisms, metabolism, insulin signaling, mTOR, axon transport, apoptosis, autophagy, neuroinflammation. With an increased understanding both mechanisms disease, we closer than ever strategy glaucoma.

Язык: Английский

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Retinal ganglion cells adapt to ionic stress in experimental glaucoma

Frontiers in Neuroscience, Год журнала: 2023, Номер 17

Опубликована: Март 27, 2023

Identification of early adaptive and maladaptive neuronal stress responses is an important step in developing targeted neuroprotective therapies for degenerative disease. In glaucoma, retinal ganglion cells (RGCs) their axons undergo progressive degeneration resulting from driven by sensitivity to intraocular pressure (IOP). Despite that can effectively manage IOP many patients progress vision loss, necessitating development neuronal-based therapies. Evidence experimental models glaucoma indicates the disease RGCs experience altered excitability are challenged with dysregulated potassium (K+) homeostasis. Previously we demonstrated certain RGC types have distinct profiles thresholds depolarization block, which associated extracellular K+. Here, used our inducible mouse model investigate how K+ changes exposure elevated IOP. controls, conditions increased enhanced membrane depolarization, reduced action potential generation, widened potentials. Consistent previous work, 4 weeks elevation diminished light-and current-evoked responses. Compared found effects on block threshold, IOP-exposed maintaining greater excitability. Finally, did not alter axon initial segment dimensions, suggesting structural plasticity alone cannot explain decreased sensitivity. Thus, response prolonged process reduces while diminishing These experiments give insight into lay groundwork mechanistic investigation targets therapy.

Язык: Английский

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Prophylactic nicotinamide treatment protects from rotenone-induced neurodegeneration by increasing mitochondrial content and volume

Acta Neuropathologica Communications, Год журнала: 2024, Номер 12(1)

Опубликована: Март 1, 2024

Leber's hereditary optic neuropathy (LHON) is driven by mtDNA mutations affecting Complex I presenting as progressive retinal ganglion cell dysfunction usually in the absence of extra-ophthalmic symptoms. There are no long-term neuroprotective agents for LHON. Oral nicotinamide provides a robust effect against mitochondrial and metabolic other injuries. We explored potential to protect mitochondria LHON modelling disease mice through intravitreal injection inhibitor rotenone. Using MitoV expressing mitochondrial-tagged YFP cells we assessed morphology super-resolution imaging digital reconstruction. Rotenone induced inhibition resulted wide loss fragmentation. This was prevented oral treatment. Mitochondrial ultrastructure quantified transition electron microscopy, demonstrating cristae density following rotenone injection, which also These results demonstrate that protects during dysfunction. Nicotinamide has be useful treatment strategy limit degeneration.

Язык: Английский

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BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Сен. 26, 2023

Pro-apoptotic BAX is a central mediator of retinal ganglion cell (RGC) death after optic nerve damage. activation occurs in two stages including translocation latent to the mitochondrial outer membrane (MOM) and then permeabilization MOM facilitate release apoptotic signaling molecules. As critical component RGC death, an attractive target for neuroprotective therapies understanding kinetics mechanisms controlling this process RGCs potentially valuable informing development strategy.

Язык: Английский

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Protective effect of resveratrol on retinal damage in glaucoma: a systematic review and meta-analysis of preclinical studies

Frontiers in Pharmacology, Год журнала: 2025, Номер 15

Опубликована: Янв. 15, 2025

Resveratrol, a polyphenolic compound commonly found in natural plants and fruits, exhibits potential preventing optic nerve damage glaucoma, as indicated by several animal studies. However, there is presently dearth of relevant evidence available for comprehensive summarization. In this study, we conducted an extensive search across 7 electronic databases, encompassing all pertinent studies systematic review meta-analysis. Methodological quality was evaluated using SYRCLE's bias risk tool, with statistical analysis performed Stata 17.0. The primary outcome measures included the survival retinal ganglion cells thickness. 30 revealed that resveratrol can enhance expression Sirtuin 1(SIRT1) protein tissue (SMD: 3.00, 95% CI: 2.46, 3.53, P = 0.095), boost rate 4.33, 3.28, 5.38, < 0.05), decelerate thinning thickness 4.26, 2.77, 5.75, visual function. Its mechanism action may involve suppression pro-inflammatory cytokine levels cell apoptosis. Resveratrol emerges promising agent mitigating glaucoma-related damage. given research models utilized study not fully reflect intricate scenarios multiple coexisting diseases clinical settings, administration methods differ from those practice, future should aim to provide higher facilitate translation these findings. identifier [CRD42024535673].

Язык: Английский

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Ocular stress enhances contralateral transfer of lenadogene nolparvovec gene therapy through astrocyte networks

Molecular Therapy, Год журнала: 2023, Номер 31(7), С. 2005 - 2013

Опубликована: Апрель 4, 2023

Lenadogene nolparvovec (GS010) was developed to treat a point mutation in mitochondrial ND4 that causes Leber hereditary optic neuropathy. GS010 delivers human cDNA encoding wild-type packaged into an rAAV2/2 vector transduces retinal ganglion cells, induce allotopic expression of hybrid ND4. clinical trials improved best-corrected visual acuity (BCVA) up 5 years after treatment. Interestingly, unilateral treatment BCVA bilaterally. Subsequent studies revealed DNA tissues contralateral the injected eye, suggesting migration. Here we tested whether intraocular pressure (IOP) elevation could influence transfer viral RNA delivery IOP-elevated eye and probed potential mechanism mediating translocation mice. We found IOP enhanced transcripts tissues, including retinas. Using conditional transgenic mice, depleted astrocytic gap junction connexin 43 (Cx43), required for distant redistribution metabolic resources between astrocytes during stress. After injection, Cx43 knockdown eradicated transcript detection while still detectable nerves. Overall, our study indicates long-range migration product is by Cx43-linked astrocyte networks.

Язык: Английский

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Neutral sphingomyelinase inhibition promotes local and network degeneration in vitro and in vivo

Cell Communication and Signaling, Год журнала: 2023, Номер 21(1)

Опубликована: Окт. 30, 2023

Abstract Background Cell-to-cell communication is vital for tissues to respond, adapt, and thrive in the prevailing milieu. Several mechanisms mediate intercellular signaling, including tunneling nanotubes, gap junctions, extracellular vesicles (EV). Depending on local systemic conditions, EVs may contain cargoes that promote survival, neuroprotection, or pathology. Our understanding of pathologic signaling has been bolstered by disease models using neurons derived from human pluripotent stems cells (hPSC). Methods Here, we used hPSC-derived retinal ganglion (hRGC) mouse visual system investigate influence modulating EV generation trafficking cell survival. We probed impact modulation survival decreasing catabolism sphingomyelin into ceramide through inhibition neutral sphingomyelinase (nSMase), GW4869. assayed vitro probing annexin A5, phosphatidylserine, viable mitochondria, mitochondrial reactive oxygen species. In vivo, performed intraocular injections GW4869 measured RGC superior colliculus neuron density anterograde axon transport. Results Following twenty-four hours dosing hRGCs with GW4869, found nSMase decreased enhanced GM1 ganglioside accumulation. This also reduced small EVs, increased large enriched pro-apoptotic protein, A5. Reducing activity hRGC apoptosis initiation due uptake apoptotic particles, as identified A5 binding phospholipid, phosphatidylserine. mitochondria developing a coculture GW4869-treated naïve hRGCs. treated cells, number while driving species not only treated, but naive added coculture. mice, 20 days following single intravitreal injection significant loss RGCs their axonal recipient colliculus. followed more dramatic reduction transport Conclusion Overall, our data suggest perturbing physiologic inhibiting reorganizes plasma membrane associated sphingolipids, alters profile neuron-generated promotes neurodegeneration vivo shifting balance pro-survival versus -degenerative EVs.

Язык: Английский

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Glial cells as a promising therapeutic target of glaucoma: beyond the IOP

Frontiers in Ophthalmology, Год журнала: 2024, Номер 3

Опубликована: Янв. 8, 2024

Glial cells, a type of non-neuronal cell found in the central nervous system (CNS), play critical role maintaining homeostasis and regulating CNS functions. Recent advancements technology have paved way for new therapeutic strategies fight against glaucoma. While intraocular pressure (IOP) is most well-known modifiable risk factor, significant number glaucoma patients normal IOP levels. Because complex, multifactorial disease influenced by various factors that contribute to its onset progression, it imperative we consider beyond effectively prevent or slow down disease’s advancement. In realm neurodegenerative diseases, glial cells emerged as key players due their pivotal roles initiating hastening progression. The inhibition dysregulated function holds potential protect neurons restore brain function. Consequently, represent an enticing candidate glaucoma, even though majority research has historically concentrated solely on retinal ganglion (RGCs). addition neuroprotection RGCs, proper regulation can also facilitate structural functional recovery retina. this review, offer overview recent understanding non-cell-autonomous mechanisms underlying pathogenesis Furthermore, state-of-the-art technologies opened up possibilities regenerating optic nerve, which was previously believed be incapable regeneration. We will delve into regeneration nerve restoration visual

Язык: Английский

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Ucf-101 alleviates Ischaemia/Reperfusion induced retinal inflammation and injury via suppressing oxidative damage

Journal of Molecular Histology, Год журнала: 2024, Номер 55(4), С. 455 - 464

Опубликована: Июнь 15, 2024

Язык: Английский

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Intraocular Delivery of a Collagen Mimetic Peptide Repairs Retinal Ganglion Cell Axons in Chronic and Acute Injury Models

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(6), С. 2911 - 2911

Опубликована: Март 8, 2022

Vision loss through the degeneration of retinal ganglion cell (RGC) axons occurs in both chronic and acute conditions that target optic nerve. These include glaucoma, which sensitivity to intraocular pressure (IOP) causes early RGC axonal dysfunction, nerve trauma, rapid axon from site injury. In each case, is irreversible, necessitating new therapeutics protect, repair, regenerate axons. Recently, we demonstrated reparative capacity using collagen mimetic peptides (CMPs) heal fragmented neuronal extracellular milieu. This was an important step development neuronal-based therapies since neurodegeneration involves matrix metalloproteinase (MMP)-mediated remodeling collagen-rich environment neurons their exist. We found delivery a CMP comprising single-strand fractions triple helix human type I prevented dysfunction inducible glaucoma model. Additionally, CMPs also promoted neurite outgrowth dorsal root ganglia, challenged vitro by partial digestion collagen. Here, compared ability sequence protect crush. A three-week +40% elevation IOP caused 67% degradation anterograde transport superior colliculus, primary projection rodents. single intravitreal injection during period significantly reduced this degradation. The same delivered shortly after crush significant recovery two-week following Together, these findings support novel protective role for use affecting survival brain.

Язык: Английский

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