The retina is a highly metabolically active tissue that is particularly sensitive to hypoxic stress, yet how its metabolic homeostasis is maintained under hypobaric hypoxia and modified by inflammation remains unclear. Here, we investigated retinal lactate dynamics and their functional role under hypoxia alone and combined hypoxic-inflammatory stress using a murine model of simulated high-altitude hypobaric hypoxia (7 km). Retinal lactate levels remained stable during acute hypoxic exposure (3-24 h), in contrast to transient brain lactate elevation and a gradual decline in blood lactate. However, when inflammation was induced by lipopolysaccharide (LPS), hypoxia combined with inflammation led to a marked reduction in retinal lactate, accompanied by microglial activation, oxidative stress, and blood-retinal barrier disruption. Neither hypoxia nor inflammation alone caused significant retinal injury or altered lactate homeostasis. Mechanistically, hypoxia with or without LPS increased hypoxia-inducible factor-1α (HIF-1α) expression, whereas key glycolytic enzymes and adenosine triphosphate (ATP) levels remained unchanged, indicating dissociation between hypoxic signaling and downstream glycolytic output. Although systemic glucose and lactate were reduced under inflammatory conditions, retinal lactate dynamics were only partially dependent on systemic metabolism, suggesting tissue-specific regulation. Importantly, exogenous lactate supplementation restored retinal lactate levels and attenuated oxidative stress and barrier leakage without affecting systemic lactate. In conclusion, lactate depletion-not energy failure-is a key determinant of retinal injury under inflammatory hypoxia. Lactate homeostasis thus represents a central mechanism of retinal resilience and a potential therapeutic target in hypoxia-related retinal disorders.
To investigate the changes in the neurovascular unit (NVU) of the retina in rats following optic nerve (ON) injury, and to explore the translational implications for traumatic optic neuropathy (TON). The ON transverse quantitative traction (ONTQT) was performed to establish the model of ON and retinal injury. The rats were divided into the sham operation group (SG) and the model group (MG). At 14th day post-modeling, flash visual evoked potential (FVEP) test was performed to evaluate the visual function. Transmission electron microscopy (TEM) was used to observe the microstructure of retinal NVU. RNA binding protein with multiple splicing (RBPMS) immunofluorescence was applied to detect the survival retinal ganglion cell (RGC). The activity of astrocytes and Müller cells in retina was detected by glial fibrillary acidic protein (GFAP) immunofluorescence. The expression of tight junction proteins (Claudin-1, Claudin-5) and glial end feet markers aquaporin-4 (AQP4) and inwardly rectifying potassium channel subtype 4.1 (Kir4.1) in retinal tissue were test by western blot and Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). At 14th day following ONTQT, the FVEP results exhibited the prolonged peak latency of P2 and the reduced amplitudes of N1-P1 and N2-P2. TEM showed structural changes of the basement membranes in NVU and ultrastructural abnormalities of tight junctions (TJs) after ONTQT. Besides, the expression of RBPMS in ganglion cell layer (GCL) was down-regulated and GFAP was over-expression in the injured retinal sections. The relative expressions of claudin-1and claudin-5 declined and the mRNA levels of AQP4 increased in the retina at 14 days following ONTQT. The mRNA levels of Kir4.1 was downregulated in the retina of MG. ONTQT can be applied in the model of ON and retina injury. The dysfunction of retinal NVU may promotes the optic degeneration in rats following ONTQT, contributing to the RGC loss and impaired visual function. These findings provide a mechanistic basis for NVU-targeted neuroprotection and identify potential clinical biomarkers for the diagnosis and treatment of TON.
Micro/nanoplastics (MNPs), as emerging environmental contaminants, present a growing concern for human health. This study aims to investigate the effects of polystyrene nanoplastics (PS-NPs) exposure on retinal pathology and underlying mechanisms. Retinal detachment (RD) model was established on adult mice following PS-NPs exposure (10 and 50 mg/L) through drinking water for two months. In vitro, oxygen glucose deprivation (OGD) model was established on BV2 microglia-661W photoreceptor co-culture system following PS-NPs exposure (100 mg/L) for 24 h. SPP1 neutralizing antibody and recombinant protein were administrated by subretinal injection. DNase I and Cl-amidine were utilized to achieve neutrophil extracellular traps (NETs) inhibition. Electroretinogram was used to assess retinal function. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), immunofluorescent staining, western blot analysis and enzyme activity assays were used to analyze photoreceptor apoptosis, microglial responses and oxidative stress. Microglia were purified with CD11b MicroBeads. Transcriptomic profiles of PS-NPs-exposed microglia and human retinas of proliferative vitreoretinopathy (PVR) were analyzed. PS-NPs were able to breach the blood-retina barrier, disrupt phototransduction, aggravate oxidative stress and apoptosis in RD-induced photoreceptor degeneration model dose-dependently. Mechanistically, PS-NPs exposure triggered retinal inflammation, microglial activation and microglial SPP1-mediated peripheral neutrophil recruitment. SPP1 neutralization mitigated PS-NPs-aggravated chemokine secretion, neutrophil infiltration and NETs formation. Recombinant SPP1 protein treatment heightened neutrophil-driven retinal damage, while this could be partially reversed by chemokine receptor inhibition. NETs inhibition alleviated PS-NPs-exacerbated microglial proinflammatory activation and photoreceptor degeneration. Furthermore, transcriptomic profiling showed parallels between PS-NPs-exposed microglia and human PVR specimens in SPP1 signaling and stress/stimulus response pathways. Our findings demonstrated that PS-NPs exposure aggravated retinal inflammation and photoreceptor degeneration by microglial SPP1 signaling activation and NETs formation, underscoring new insights into the effects and potential targets of MNPs exposure on retinal disorders.
To describe a novel postoperative optical coherence tomography (OCT) finding following rhegmatogenous retinal detachment (RRD) repair and explore its relationship with retinal displacement. Retrospective consecutive case series. Patients with primary RRD with partial macular involvement who underwent successful repair. Patients after RRD repair who demonstrated a marginal outer retinal ridge (MORR) on postoperative OCT were included. MORR was defined as a linear outer retinal hyperreflective ridge adjacent and parallel to the RRD margin. Clinical characteristics, surgical variables, multimodal imaging findings, and evidence of retinal displacement were assessed. Twelve eyes were included. MORRs were predominantly located along the inferior RRD margin (11/12) and were detectable as early as postoperative day 1. In 4/12 eyes (33%), MORRs occurred in regions that were attached at presentation. MORRs resolved spontaneously within months in all cases. In two cases, MORR involved the fovea. Retinal displacement was more pronounced superior to a MORR, supporting retinal redundancy as the mechanism of formation. MORR represents a novel OCT biomarker of retinal displacement and reflects postoperative retinal redundancy. Recognition of MORR provides new insight into the biomechanics of retinal reattachment and may have implications for surgical technique, postoperative imaging, and functional outcomes.
This multicenter, retrospective real-world study evaluated the efficacy and safety of aflibercept 2 mg biosimilar SB15 (Afilivu®) across multiple retinal diseases. A total of 1083 eyes from 984 patients received 2762 injections between March 2023 and February 2025 at three South Korean tertiary centers, comprising 188 treatment-naïve (17.4%) and 895 switching eyes (82.6%). Diagnoses included neovascular age-related macular degeneration (nAMD, n = 611), retinal vein occlusion (RVO, n = 182), diabetic macular edema (DME, n = 173), and other conditions (n = 117). Over a mean follow-up of 5.17 ± 2.76 months with 2.55 ± 1.09 injections, central foveal thickness decreased significantly by - 47.5 µm (95% CI - 55.2 to - 39.8; P < 0.001), while best-corrected visual acuity remained stable (mean change - 0.003 LogMAR; P = 0.572). Treatment-naïve eyes demonstrated greater anatomical improvement than switching eyes (- 93.9 vs. - 37.9 µm; P < 0.001). Retinal fluid resolved significantly across diagnostic groups: in nAMD, subretinal fluid decreased from 51.2 to 29.6% (P < 0.001); in RVO, intraretinal fluid reduced from 92.9 to 76.4% (P < 0.001); and in DME, intraretinal fluid decreased from 90.8 to 84.4% (P = 0.002). One case (0.09%) of rhegmatogenous retinal detachment occurred; no intraocular inflammation or other serious adverse events were observed. These findings support the real-world effectiveness and safety of SB15 (Afilivu®) in both treatment-naïve and switching populations across diverse retinal diseases.
Per- and polyfluoroalkyl substances (PFAS) have raised increasing concerns due to their potential neurotoxicity; however, their effects on retina, a highly specialized neural tissue, remain unclear. This study aimed to investigate the retinal toxicity of PFAS in adolescents and to elucidate underlying molecular mechanisms and therapeutic targets. A cross-sectional study involving 1,686 Chinese adolescents was conducted to evaluate associations between serum PFAS concentrations and retinal structural characteristics. In parallel, toxicogenomic analyses were performed to identify key genes associated with PFAS exposure and retinal diseases. Correspondingly, in vitro experiments were conducted to reveal the potential molecular mechanisms underlying the cytotoxic effects of PFAS on retinal ganglion cells (RGCs). Higher serum levels of PFOA (β = -0.05, P = 0.01), PFOS (β = -0.06, P = 0.04) and PFHxS (β = -0.11, P = 0.03), were negatively associated with global retinal nerve fiber layer (RNFL) thickness. Applying toxicogenomic screening, nine hub genes related to PFAS (e.g., CCL2, TNF-α, and TLR4) were identified to be enriched in inflammatory pathways. Mechanistically, apoptotic cell death in R28 and RGCs were promoted by PFAS exposure, characterized by elevated cleaved PARP and cleaved Caspase-3. This study provides evidence that PFAS exposures are correlated with retinal neurotoxicity in adolescents through inflammatory activation and apoptosis. The identified gene signatures highlight potential targets for prevention and therapeutic intervention.
X-linked retinoschisis is a recessive disease characterized by progressive macular degeneration and vision loss due to pathogenic variation in RS1. We administered a single subretinal injection of an AAV8 vector containing human RS1 complementary DNA (scAAV8-hRS1) into one eye of patients 5 to 18 years of age who had X-linked retinoschisis. The primary end point was safety during the 52-week period after injection. Secondary end points included the change from baseline to week 52 in the best corrected visual acuity (BCVA), retinal structure (assessed with swept-source optical coherence tomography; SS-OCT), the function of photoreceptor and bipolar cells (assessed with full-field electroretinography), and macular sensitivity to light (assessed with microperimetry). A total of 12 patients were enrolled. The dose-escalation phase included two cohorts of 3 patients each who received scAAV8-hRS1 at a dose of 7.5×1010 or 1×1011 vector genomes. In the dose-expansion phase, 3 additional patients were enrolled in each cohort. Overall, 56 adverse events were reported during the 52 weeks after surgery. No patient was reported to have an adverse event of grade 3 or higher or ocular inflammation. A macular hole in the treated eye was observed at week 1 in 1 patient. The mean increase at week 52 in the BCVA was 10.8 letters among the treated eyes and 2.4 letters among the untreated eyes. SS-OCT imaging showed closure of the macular schisis cavity by week 13 in the treated eye in all 12 patients. The mean change at week 52 in central retinal thickness was -437.7 μm among the treated eyes and -17.2 μm among the untreated eyes; the outer retinal layers in the treated eyes of 9 patients were continuous at week 52. No clinically meaningful changes in the function of photoreceptor and bipolar cells or macular retinal sensitivity were observed in the treated eyes. In this study of subretinal gene therapy with scAAV8-hRS1 in 12 patients with X-linked retinoschisis, there were no reports of adverse events of grade 3 or higher or ocular inflammation. Further clinical testing of scAAV8-hRS1 is warranted. (Funded by the National Natural Science Foundation of China and others; Chinese Clinical Trial Registry number, ChiCTR2300076682.).
Multiple sclerosis (MS) is a chronic neurological disease characterized by inflammatory demyelination and progressive neuroaxonal damage. Retinal layer thickness in the macular and optic disc regions, measurable using optical coherence tomography (OCT), might be considered as a promising non-invasive biomarker for detecting MS-related neurodegeneration. In this study, we present a novel AI framework leveraging macular ganglion cell-inner plexiform layer (GCL-IPL) and Retinal Nerve Fiber Layer (RNFL) thickness across sectors (covering [Formula: see text]) and peripapillary biomarkers from both macula and optic disc regions of retina. These biomarkers were collected from bilateral scans of 74 MS and 44 controls subjects. The retinal features were then fed into machine learning (ML) model for the detection of MS patients. Feature engineering and hyperparameter tuned patient level model was proposed as the final model for MS detection. SHAP and PCA biplot analysis improved the explainability of the ML models. The proposed ML model developed from patient-level GCL sectors achieved highest F1-score of 94.29%. RNFL biomarkers extracted from the peripapillary region yielded slightly lower performance, with F1-score of 87.84%. After integrating both GCL and RNFL sector markers, the proposed ML model achieved the best performance with F1-score of 95.71% and precision of 97.10%, outperforming other existing benchmark results. Statistical analysis (one-way ANOVA) revealed significant enlargement of multiple peripapillary regions (i.e., vertical and average cup-disc-ratio) in MS patients. On the other hand disc area, cup area, and cup volume were thinned in MS patients, though the results were not statistically significant. Notably, all the sectors of GCL and RNFL layers were found thinning for MS patients compared to the controls (p < 0.001). The proposed AI-based framework shows promising results for the detection of MS using OCT-derived retinal biomarkers, particularly GCL-IPL sectors, RNFL quadrants thickness, and peripapillary regions. Moreover, the explainable nature of the proposed framework supports clinical adoption and serve as a proof-of-concept for AI-enabled diagnosis of MS using retinal biomarkers.
Gestational diabetes mellitus (GDM) may induce subtle retinal microvascular alterations even in the absence of clinical diabetic retinopathy. This study represents the first systematic review and meta-analysis to comprehensively evaluate retinal and choroidal structural and microvascular alterations in women with GDM. A systematic search of PubMed, Embase, Scopus, and Web of Science up to September 2025 identified cross-sectional studies comparing OCT or OCTA parameters between women with GDM and healthy pregnant (HP) or healthy non-pregnant (HNP) controls. Pooled standardized mean differences (SMDs) were calculated using random-effects models with Knapp-Hartung adjustment. Twelve studies encompassing 2,798 eyes from 1,997 women were included. Compared with HP controls, eyes with GDM exhibited a small but statistically significant reduction in mean and parafoveal superficial capillary plexus vessel density (SMD = -0.07 and - 0.13, respectively; both p < 0.05) and thinning of the inferior peripapillary retinal nerve fiber layer (SMD = -0.25; p = 0.003), all with zero heterogeneity (I² = 0%). No significant differences were observed in central macular thickness, foveal avascular zone area, deep plexus density, or subfoveal choroidal thickness. This systematic synthesis demonstrates that GDM is associated with early, subclinical neurovascular alterations, particularly reduced superficial capillary density and inferior retinal nerve fiber layer thinning, while overall retinal and choroidal structures remain preserved. These findings introduce OCTA as a potential sensitive biomarker for detecting early microvascular compromise in GDM and emphasize the need for longitudinal studies to determine their reversibility postpartum.
To evaluate the association between continuous glucose monitoring (CGM)-derived glycaemic variability indicators and early microvascular changes of the retina and choroid in nondiabetic individuals. Community-based individuals at high risk for type 2 diabetes (T2DM) underwent detailed assessments including oral glucose tolerance tests (OGTT), CGM and ophthalmic imaging including optical coherence tomography angiography (OCTA). Based on the mean amplitude of glycaemic excursions (MAGE), 338 OGTT-confirmed nondiabetic participants were categorized as having normal glucose fluctuation (NGF) or abnormal glucose fluctuation (AGF). Between-group differences in foveal avascular zone (FAZ), blood flow density and thickness in retina and choroid were analysed. Multiple linear regression analysis was used to analyse the correlation between CGM metrics and blood flow density in retina and choroid. Compared with the NGF group (265 eyes from 265 participants), the AGF group (73 eyes from 73 participants) showed lower retinal blood flow density in the central (p = 0.007) and parafoveal temporal (p = 0.003) regions of the superficial layer and in the parafoveal temporal (p = 0.014) and parafoveal superior (p = 0.005) regions of the deep layer. In the choroid, the volume area ratio of large vessels (CVV/a) was reduced, whereas the choroidal vascular index (CVI) was increased in the AGF group. Choroidal thickness was decreased among individuals with AGF. CGM metrics such as MAGE and coefficient of variation (CV) were negatively correlated with the retinal and choroidal blood flow density. Increased glycaemic variability even in nondiabetic adults is associated with reduced blood flow density and decreased choroidal thickness. ClinicalTrials.gov NCT03811470.
Differentiation of vitreoretinal interface disorders on optical coherence tomography (OCT) relies on expert interpretation and can be challenging in borderline cases. Automated machine learning (AutoML) platforms may enable clinician-driven artificial intelligence development without coding expertise. This study evaluated the performance of a code-free AutoML approach for OCT-based classification. In this cross-sectional image classification study, 434 OCT B-scans from publicly available datasets were manually labeled into four categories: epiretinal membrane (ERM), lamellar macular hole (LMH), full-thickness macular hole (MH), and normal retina. Images were uploaded to a cloud-based AutoML platform (Google Cloud Vertex AI), which automatically performed data splitting (80% training, 10% validation, 10% test), model training, and optimization. Performance was assessed using precision, recall, average precision, and confusion matrix analysis. The model achieved an overall average precision of 0.988, with precision and recall of 97.6%. MH and normal retina were classified with perfect precision and recall (100%). ERM showed high precision (100%) with slightly reduced recall (92.9%), while LMH demonstrated complete recall (100%) with lower precision (83.3%). Misclassifications were limited to anatomically related entities. Code-free AutoML enables accurate OCT-based classification of vitreoretinal interface disorders using a clinician-driven workflow. This approach may facilitate broader adoption of artificial intelligence in ophthalmology and support rapid clinical research prototyping.
Retinal layer thinning is associated with disability progression and treatment failure in relapsing multiple sclerosis (RMS). However, the systematic integration of optical coherence tomography (OCT)-derived metrics into a composite measure of treatment response has not yet been evaluated. We analyzed two observational cohorts of patients with RMS who newly initiated DMT, received an MRI and OCT at baseline and 12 months, and had ≥ 24 months of clinical follow-up. No evidence of disease activity (NEDA-3/NEDA-3 + OCT) status was assigned at 12 months after DMT. Retinal thinning was defined as a reduction of ≥ 1.0 µm/year peripapillary retinal nerve fiber layer or ≥ 0.5 µm/year ganglion-cell/inner plexiform layer. The primary endpoint was confirmed disability progression occurring after the 12 month NEDA assessment. Both low-efficacy DMT and high-efficacy were included and analyzed jointly, with treatment class entered as a covariate in all models. Overall, 124 individuals (72% female, mean age 33.1 [SD ± 7.7] years, median EDSS of 2.0 [IQR 0.0-2.5]) were included. Over a median follow-up period of 3.4 years, disability progression was observed in 28 (23%) individuals. Time to and risk of disability progression did not significantly differ between EDA-3 and NEDA-3 (restricted mean survival time [RMST]: 43.4 [SE ± 2.8] vs. 48.1 [SE ± 1.3] months, p = 0.067; adjusted hazard ratio [aHR] 1.52, 95% LL-CI 0.64, p = 0.173). When retinal layer thinning was incorporated, EDA-3 + OCT was associated with a higher risk of future progression (aHR 6.59, 95% LL-CI 2.38, p = 0.005) and shorter time to progression (RMST: 41.9 [SE ± 2.1] vs. 51.9 [SE ± 0.9] months, p < 0.001). Incorporating retinal layer thinning into the NEDA-3 framework substantially improves prediction of subsequent disability progression compared with conventional NEDA-3 alone, identifying a subgroup of patients in whom ongoing neurodegeneration appears to drive disability accumulation despite suppressed inflammatory activity.
Autonomous artificial intelligence (AI) systems for retinal image interpretation are being deployed in routine clinical practice, fundamentally altering the training environment of retinal specialists. We map available evidence on how AI integration affects medical retina specialist training, addressing educational opportunities, developmental risks, and curricular responses. Following the PRISMA extension for scoping reviews and Joanna Briggs Institute methodology, we searched PubMed/MEDLINE, Embase, Web of Science, the Cochrane Library, and gray literature from major ophthalmological and medical education organizations from inception to March 2026. Six thematic domains emerged: deployment context, artificial intelligence as educational tool, explainability and pedagogy, risks to trainee development, large language models and assessment validity, and institutional responses. AI creates genuine opportunities for personalized case allocation, synthetic dataset generation, explainable visual feedback, and knowledge scaffolding in medical retina training, while simultaneously posing documented risks including deskilling, never-skilling, automation bias, and disruption of established assessment frameworks. The professional identity formation of trainees in environments where AI routinely matches or exceeds first-year resident performance remains an underexplored concern. Institutional and accreditation responses lag substantially behind clinical deployment, ophthalmology-specific competency frameworks validated for residency training are largely absent, and targeted research and coordinated curriculum reform are urgently needed.
Photoreceptors (PR) are responsible for absorbing and converting light into electrical signals necessary to create vision. To accomplish that, they are in an intimate relationship and attached to the underlying retinal pigment epithelium (RPE). Separation of the PR from the underlying RPE is seen in many retina disorders and leads to PR cell death and subsequent vision loss. Separation of PR from the RPE (detachment) interferes with the normal phagocytosis and recycling of PR outer segments by the RPE, and disrupts nutrient and metabolite delivery, including glucose. All these factors contribute to cell dysfunction and eventual cell death. In this work, we sought to understand the importance of different factors in PR cell loss after detachment using mathematical modeling. We used known information of photoreceptor interactions in the healthy retina from the literature, and datasets for rod and cone degeneration after detachment. We also included three additional published datasets of PR cell death kinetics. A mathematical sensitivity analysis examined the impact of the parameters on the system over a detachment of 150 days and found that the parameters that significantly impact the rod and the cone population at the stages where "early intervention" happens (3-7 days after detachment) are not always the same ones that significantly impact the populations at 150 days. Additionally, some of the parameters negatively affected one population while having the opposite effect on the other. An increase in nutrient availability and efficiency of rod energy uptake were the only parameters that did not have a negative effect on either population. Similar results were obtained for reattachment. The interplay between these variables indicates that effective photoreceptor neuroprotection in retinal detachment may require multiple strategies. The prediction of these impactful parameters over time can be further assessed in experimental models and may provide guidance on the most effective ways to improve PR survival after their separation from RPE.
Autism Spectrum Disorder (ASD) affects around 1% of the population, and its diagnosis is primarily clinical. Therefore, the study of biological markers is essential. The retina and optic nerve have been studied in many ocular and non-ocular diseases using non-invasive techniques such as Optical Coherence Tomography (OCT) and OCT Angiography (OCT-A). A systematic literature search was performed using the Covidence® platform across promimnent databases including PubMed, PsycINFO and Embase up to February 2023. The analysis of the included studies revealed differences in retinal parameters between individuals with ASD and neurotypical controls (NT). These variations encompassed changes in macular thickness and volume, RNFL thickness and volume, and in vascular perfusion and vessel density. Furthermore, certain changes were found to be correlated with clinical measures of ASD features. Current evidence reported diverse changes in neuroretinal parameters in ASD individuals. OCT and OCT-A have shown promising results in evaluating neuroretinal alterations in individuals with ASD. These techniques hold potential as biomarkers for early detection and monitoring of ASD. However, further research is necessary to fully explore the diagnostic and therapeutic potential of OCT and OCT-A in ASD population.
Disruption of sleep and circadian rhythms is one of the earliest symptoms of Alzheimer's disease (AD). Circadian entrainment and modulation of alertness are non-visual responses to light driven by intrinsically photosensitive retinal ganglion cells (ipRGCs). To explore structural and functional changes of ipRGCs and ipRGC circuits in AD, we analyzed the retinas and brains of 13 elderly patients ranging from normal cognition to AD and performed ex vivo extracellular electrophysiological recordings on freshly harvested retinas. While no impairment of rods and cones was observed, there was a severe loss of ipRGCs in AD donors. Importantly, the remaining ipRGCs exhibited morphological alterations, hyperexcitability, and were not able to sustain high levels of activation. These changes may be ipRGC subtype-specific and vary across donors with pathological severity. Altered ipRGC circuits and function could contribute to the disruption of sleep and circadian rhythms reported in AD patients. Measuring ipRGC-dependent responses to light could be a promising way to predict or monitor pathological changes in the brain.
Glaucoma is one of the leading causes of irreversible blindness, and lowering intraocular pressure alone is insufficient to rescue lost retinal ganglion cells (RGCs) or restore visual function. In this study, we intravitreally injected a liquid chitosan gel loaded with nerve growth factor (NGF), previously developed by our group, into the vitreous body of rats with ocular hypertension-induced glaucoma. Using a combination of techniques--including multiplex immunofluorescence staining, TUNEL staining, CTB tracing, Western blotting, visual electrophysiology, and behavioral assessments--we demonstrated that, compared with the lesion control (LC) group, the NGF-chitosan hydrogel significantly enhanced RGC survival following glaucomatous injury (by approximately 27%), preserved dendritic architecture and long-distance axonal projections, and promoted recovery of visual function. Mechanistically, treatment with the NGF-chitosan hydrogel upregulated the expression of NGF and its high-affinity receptor, tropomyosin receptor kinase A (TrkA), in the retina. In addition, it suppressed retinal glial activation and enhanced mammalian target of rapamycin (mTOR) signaling, collectively contributing to RGC protection and repair. Notably, we further observed activation of Nestin+ neural stem cells in the ciliary body region, along with their differentiation into BrdU+/Brn3a+ neuron-like cells; the precise mechanisms underlying this phenomenon warrant further investigation. In conclusion, intravitreal delivery of NGF-chitosan hydrogel provides novel mechanistic insights and represents a promising therapeutic strategy for the treatment of glaucoma.
Progranulin (PGRN) is a secreted protein composed of 7.5 granulin domains. The protein is implicated in various functions, including cell survival, inflammation, lysosomal homeostasis, tumorigenesis, and aging. Haploinsufficiency and complete loss of PGRN function cause the neurodegenerative disorders frontotemporal lobar degeneration and neuronal ceroid lipofuscinosis type 11, respectively. In the nervous system, administration of exogenous PGRN has been shown to promote the survival of various nerve cell types under different pathological conditions and to stimulate neurite outgrowth in vitro and axonal regeneration in vivo. In the retina, PGRN dysfunction results in photoreceptor and retinal ganglion cell (RGC) loss, whereas PGRN administration promotes photoreceptor cell survival. In the present study, we analyzed whether a sustained intravitreal administration of PGRN promotes the survival of axotomized RGCs and the regrowth of the lesioned axons. To this end, we generated a PGRN-overexpressing clonal neural stem cell line and injected the cells into the vitreous cavity of a mouse optic nerve crush model. The progression of the lesion-induced degeneration of RGCs was studied at different time points after the nerve crush. The regeneration of the injured RGC axons into the distal optic nerve stump was analyzed one month after nerve lesioning. We found that the intravitreally administered PGRN slowed the degeneration of the injured RGCs for up to four months, the latest post-lesion interval analyzed. Furthermore, PGRN stimulated the regeneration of some RGC axons over long distances into the distal optic nerve stumps. Taken together, our results identify PGRN as a novel neurotrophic factor for retinal ganglion cells.
To develop and validate a novel set of ocular-centric diagnostic criteria for Behçet's uveitis (BU). A case-control study was designed to develop the BU-specific diagnostic criteria (BU-SDC). The International Criteria for Behçet's Disease were adopted as the reference standard for diagnostic performance evaluation. The ocular findings of BU-SDC were weighted as two points for vitreous cells or haze and retinal vasculitis identified by fluorescein fundus angiography, respectively, and one point for anterior cell-flare dissociation, sterile hypopyon, diffuse retinal atrophy, optic nerve atrophy, superficial retinal infiltrates, retinal haemorrhages, retinal vascular sheathing and retinal ghost vessels, respectively. The systemic features, including recurrent oral ulceration, multiform skin lesions and genital ulceration were weighted as 4 points, 3 points and 2 points, respectively. Primary assessment was based on ocular features alone. An ocular score ≥5 supported a BU diagnosis in patients without signs of granulomatous uveitis or evidence of sarcoidosis or syphilis. For patients with ocular score <5 but high clinical suspicion (the presence of one or more characteristic ocular signs, including vitreous cells or haze, retinal vasculitis identified by fluorescein fundus angiography, superficial retinal infiltrates or retinal vascular sheathing), a secondary assessment incorporating systemic variables was applied, and a combined score ≥5 supported diagnosis. Validation in the independent cohort showed that the area under the receiver operating characteristic curve for BU-SDC (0.954) significantly outperformed the International Study Group criteria (0.911; p<0.01) and the Standardization of Uveitis Nomenclature (0.881; p<0.01) criteria. The BU-SDC provides a validated ocular-centric diagnostic framework for BU, prioritising ocular signs while retaining flexibility through selective systemic integration.
Visual system damage and dysfunction caused by exposure to a blast wave has been described in both clinical studies and in pre-clinical models. Within the retina, retinal ganglion cells (RGC) exhibit sensitivity to mild blast-mediated traumatic brain injury (bTBI), which can result in progressive neurodegeneration. The purpose of this study was to determine if repetitive hypoxic preconditioning (HPC) can prevent bTBI-mediated RGC damage and death. This study utilized clinically relevant outcomes of RGC structure and function, supported by histological analysis of the surviving RGCs. Mice were exposed to six sessions of HPC over a two-week period at an 11% oxygen concentration, and subsequently subjected to bTBI using a shock tube. Four-weeks following exposure to bTBI or sham, functional and structural analysis of RGCs was performed using the pattern electroretinogram (PERG) and optical coherence tomography (OCT). BRN3A antibody labeling was subsequently used to quantify the number of RGCs surviving at the termination of the study. Analysis of RGC outcomes showed significantly decreased PERG amplitude and RGC Complex + retinal nerve fiber layer (RNFL) thickness in mice with bTBI compared to sham. There was no significant difference in RGC outcomes between sham mice and HPC+ bTBI mice. Taken together, these results show that HPC can provide at least partial neuroprotection to RGCs prior to blast exposure.