Müller Glial‐Derived Small Extracellular Vesicles Mitigate RGC Degeneration by Suppressing Microglial Activation via Cx3cl1‐Cx3cr1 Signaling

Advanced Healthcare Materials, Journal Year: 2025, Volume and Issue: unknown

Published: March 25, 2025

Retinal ganglion cell (RGC) degeneration leads to irreversible blindness. Müller glia (MG) play pivotal roles in retinal homeostasis and disease through paracrine signaling. Small extracellular vesicles (sEVs) are bioactive nanomaterials derived from all types of live cells recognized as a potential strategy for neuroprotective therapy. The aim this study is investigate the MG-derived sEVs (MG-sEVs) mouse model optic nerve injury (ONC). It found that MG-sEVs treatment effectively mitigates RGC suppresses microglial activation, thereby improves visual function ONC mice. transcriptomic analysis reveals strong correlation between C-x3-c motif chemokine ligand 1 (Cx3cl1)-mediated glial activation inflammation. Subsequently, it confirmed expression levels Cx3cl1 proinflammatory cytokines significantly decreased retinas treated with MG-sEVs. components cargo identifies miR-125b-5p miR-16-5p target gene regulate its expression. also observed colocalizes on microglia transgenic receptor (Cx3Cr1)-GFP In conclusion, mitigate by suppressing via Cx3cl1-Cx3cr1 This research provides additional opportunities degeneration.

Language: Английский

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Targeting Connexin 43 in Retinal Astrocytes Promotes Neuronal Survival in Glaucomatous Injury

Glia, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

ABSTRACT Astrocytes in the retina and optic nerve head play an important role pathogenesis of glaucoma. extensively express connexin 43 (Cx43), a protein that forms gap junction (GJ) channels transmembrane unopposed hemichannels. While it is well documented Cx43 expression augmented retinal injuries, astrocytic glaucomatous injury not fully understood. Here, we used mouse model ocular hypertension caused by intracameral microbead injections more severe model, crush (ONC) injury, assessed changes GJ channel function. The effect astrocyte‐specific deletion (Cx43KO) on ganglion cell (RGC) loss visual function was also assessed. We show increased astrocytes at early time points remained elevated even after sustained elevation intraocular pressure (IOP) (~8 weeks), which paralleled increase coupling. Deletion markedly improved survival RGCs ~93% preserved as ERG reduced numbers activated microglial/macrophages retina. substantially ONC absence this RGC ~48%. These results reveal deleterious for glaucoma progression. Intravitreal Gap19, peptide reportedly inhibits hemichannels but channels, Further studies are required to assess whether targeting might be useful treatment.

Language: Английский

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Microglia remodeling in the visual thalamus of the DBA/2J mouse model of glaucoma

PLoS ONE, Journal Year: 2025, Volume and Issue: 20(5), P. e0323513 - e0323513

Published: May 15, 2025

Microglia are the resident immune cells of central nervous system and mediate a broad array adaptations during disease, injury, development. Typically, microglia morphology is understood to provide window into their function have capacity adopt spectrum functional phenotypes characterized by numerous morphologies gene expression profiles. Glaucoma, which leads blindness from retinal ganglion cell (RGC) degeneration, commonly associated with elevated intraocular pressure (IOP) triggers responses within layers, at optic nerve head, in projection targets brain. The goal this study was determine relationship loss RGC output synapses dorsolateral geniculate nucleus (dLGN), target thalamus that conveys information primary visual cortex. We accomplished analyzing dLGN sections DBA/2J mice, develop form inherited glaucoma, 4, 9, 12 months age, representing distinct time points disease progression. analyzed using skeletonized Iba1 fluorescence images fractal analyses individually reconstructed cells. found older mice adopted simplified morphologies, fewer endpoints less total process length per cell. There an age-dependent shift tissue control (DBA/2J Gpnmb+ ) accelerated mice. Measurements correlated cumulative IOP, immunofluorescence labeling for complement component C1q, vGluT2-labeled axon terminal density. Additionally, analysis revealed clear distinction between glaucomatous dLGN, ocular hypertensive showing elongated rod-like morphology. RNA-sequencing showed upregulation system-related genes. These results suggest alter physiology respond degeneration potentially contributing CNS neurodegenerative vision loss.

Language: Английский

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Melatonin in Glaucoma: Integrative Mechanisms of Intraocular Pressure Control and Neuroprotection

Biomedicines, Journal Year: 2025, Volume and Issue: 13(5), P. 1213 - 1213

Published: May 16, 2025

Background: Glaucoma is a leading cause of irreversible visual loss worldwide, characterized by progressive retinal ganglion cell (RGC) degeneration and optic nerve damage. Current therapies mainly focus on lowering intraocular pressure (IOP), yet fail to address pressure-independent neurodegenerative mechanisms. Melatonin, an endogenously produced indoleamine, has gained attention for its potential in modulating both IOP neurodegeneration through diverse cellular pathways. This review evaluates the therapeutic relevance melatonin glaucoma examining mechanistic actions emerging delivery approaches. Methods: A comprehensive literature search was conducted via PubMed Medline identify studies published between 2000 2025 melatonin’s roles glaucoma. Included articles discussed effects regulation, RGC survival, oxidative stress, mitochondrial integrity, inflammation. Results: Evidence supports involvement reduction MT receptor activation synergism with adrenergic enzymatic regulators. Moreover, it protects RGCs mitigating preventing dysfunction, inhibiting apoptotic inflammatory cascades. Recent advances ocular drug systems enhance bioavailability potential. Conclusions: Melatonin represents multi-target candidate treatment. Further clinical are necessary establish optimal dosing strategies, methods, long-term safety patients.

Language: Английский

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Insulin Signaling as a Therapeutic Target in Glaucomatous Neurodegeneration

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(9), P. 4672 - 4672

Published: April 28, 2021

Glaucoma is a multifactorial disease that conventionally managed with treatments to lower intraocular pressure (IOP). Despite these efforts, many patients continue lose their vision. The degeneration of retinal ganglion cells (RGCs) and axons in the optic tract characterizes glaucoma similar neurodegeneration other age-related disorders central nervous system (CNS). Identifying different molecular signaling pathways contribute early neuronal dysfunction can be utilized for neuroprotective strategies prevent degeneration. discovery insulin its receptor CNS retina led exploration role CNS. Historically, was considered peripherally secreted hormone regulated glucose homeostasis, no obvious roles However, growing number pre-clinical clinical studies have demonstrated potential modulating treatment neurodegenerative diseases. This review will highlight plays RGC neurodegeneration. We focus on how this pathway therapeutically targeted promote axon survival preserve

Language: Английский

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