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Optical coherence tomography and electroretinography studies have revealed structural and functional retinal alterations in individuals with schizophrenia spectrum disorders (SSDs). However, it remains unclear which specific retinal layers are affected; how the retina, brain, and clinical symptomatology are connected; and how alterations of the visual system are related to genetic disease risk. Optical coherence tomography, electroretinography, and brain magnetic resonance imaging were applied to comprehensively investigate the visual system in a cohort of 103 patients with SSDs and 130 healthy control individuals. The sparse partial least squares algorithm was used to identify multivariate associations between clinical disease phenotype and biological alterations of the visual system. The association of the revealed patterns with individual polygenic disease risk for schizophrenia was explored in a post hoc analysis. In addition, covariate-adjusted case-control comparisons were performed for each individual optical coherence tomography and electroretinography parameter. The sparse partial least squares analysis yielded a phenotype-eye-brain signature of SSDs in which greater disease severity, longer duration of illness, and impaired cognition were associated with electrophysiological alterations and microstructural thinning of most retinal layers. Higher individual loading onto this disease-relevant signature of the visual system was significantly associated with elevated polygenic risk for schizophrenia. In case-control comparisons, patients with SSDs had lower macular thickness, thinner retinal nerve fiber and inner plexiform layers, less negative a-wave amplitude, and lower b-wave amplitude. This study demonstrates multimodal microstructural and electrophysiological retinal alterations in individuals with SSDs that are associated with disease severity and individual polygenic burden. [ABSTRACT FROM AUTHOR]

Photoreception is essential for the development of the visual system, shaping vision's first synapse to cortical development. Here, we find that the lighting environment controls developmental rod apoptosis via Opn4-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). Using genetics, sensory environment manipulations, and computational approaches, we establish a pathway where light-dependent glutamate released from ipRGCs is detected via a transiently expressed glutamate receptor (Grik3) on rod precursors within the inner retina. Communication between these cells is mediated by hybrid neurites on ipRGCs that sense light before eye opening. These structures span the ipRGC-rod precursor distance over development and contain the machinery for photoreception (Opn4) and neurotransmitter release (Vglut2 & Syp). Assessment of the human gestational retina identifies conserved hallmarks of an ipRGC-to-rod axis, including displaced rod precursors, transient GRIK3 expression, and ipRGCs with deep-projecting neurites. This analysis defines an adaptive retrograde pathway linking the sensory environment to rod precursors via ipRGCs prior to eye opening. [Display omitted] • Light controls developing rod apoptosis through interactions with Opn4-expressing RGCs • ipRGCs project hybrid neurites into the developing inner retina, close to rods • Rods transiently express Grik3, allowing for signaling between ipRGCs and rods • Hallmarks of this retinal pathway are conserved between developing mice and humans Photoreception is crucial for the development of the visual system. D'Souza et al. identified a developmental light-dependent pathway that induces rod apoptosis through transient excitatory hybrid neurites on ipRGC photoreceptors, which appears conserved across mouse and human development. [ABSTRACT FROM AUTHOR]

Leber’s Hereditary Optic Neuropathy (LHON) is a rare, maternally inherited eye disease, predominantly due to the degeneration of retinal ganglion cells (RGCs). It is associated with a mitochondrial DNA (mtDNA) point mutation. Our previous study identified that the m.15927G > A homoplasmic mutation damaged the highly conserved base pairing (28C42G) in anticodon stem of tRNAThr, caused deficient t6 A modification and significantly decreased efficiency in aminoacylation and steady-state levels of tRNAThr, and led to mitochondrial dysfunction. Meanwhile, mechanisms underlying mtDNA mutations regulate intracellular signaling related to mitochondrial and cellular integrity are less explored. Here, we manifested that defective nucleotide modification induced by the m.15927G > A mutation interfered with the expression of nuclear genes involved in cytoplasmic proteins essential for oxidative phosphorylation system (OXPHOS), thereby impacting the assemble and integrity of OXPHOS complexes. As a result of these mitochondrial dysfunctions, there was an imbalance in mitochondrial dynamics, particularly distinguished by an increased occurrence of mitochondrial fission. Excessive fission compromised the autophagy process, including the initiation phase, formation, and maturation of autophagosomes. Both Parkin-mediated mitophagy and receptor-dependent mitophagy were significantly impaired in cybrids haboring the m.15927G > A mutation. These changes facilitated intrinsic apoptosis, as indicated by increased cytochrome c release and elevated levels of apoptosis-associated proteins (e.g., BAK, BAX, cleaved caspase 9, cleaved caspase 3, and cleaved PARP) in the mutant cybrids. This study demonstrates that the m.15927G > A mutation contributes to LHON by dysregulating OXPHOS biogenesis, aberrant quality control, increased autophagy, inhibited mitophagy, and abnormal apoptosis. [ABSTRACT FROM AUTHOR]

Retinal diseases are the leading cause of blindness, resulting in irreversible degeneration and death of retinal neurons. One such cell type, the retinal ganglion cell (RGC), is responsible for connecting the retina to the rest of the brain through its axons that make up the optic nerve and is the primary cell lost in glaucoma and traumatic optic neuropathy. To date, different therapeutic strategies have been investigated to protect RGCs from death and preserve vision, yet currently available strategies are restricted to treating neuron loss by reducing intraocular pressure. A major barrier identified by these studies is drug delivery to RGCs, which is in large part due to drug stability, short duration time at target, low delivery efficiency, and undesired off-target effects. Therefore, a delivery system to deal with these problems is needed to ensure maximum benefit from the candidate therapeutic material. Extracellular vesicles (EV), nanocarriers released by all cells, are lipid membranes encapsulating RNAs, proteins, and lipids. As they naturally shuttle these encapsulated compounds between cells for communicative purposes, they may be exploitable and offer opportunities to overcome hurdles in retinal drug delivery, including drug stability, drug molecular weight, barriers in the retina, and drug adverse effects. Here, we summarize the potential of an EV drug delivery system, discussing their superiorities and potential application to target RGCs. [Display omitted] [ABSTRACT FROM AUTHOR]

• Armcx1 is involved in the regulation of mitochondrial transport after traumatic brain injury. • Neuroprotective effect of Armcx1 after traumatic brain injury is associated with Miro1. • Inhibition of Armcx1 expression promotes neuronal apoptosis and behavioral deficits in mice after TBI. Armcx1 is a member of the ARMadillo repeat-Containing protein on the X chromosome (ARMCX) family, which is recognized to have evolutionary conserved roles in regulating mitochondrial transport and dynamics. Previous research has shown that Armcx1 is expressed at higher levels in mice after axotomy and in adult retinal ganglion cells after crush injury, and this protein increases neuronal survival and axonal regeneration. However, its role in traumatic brain injury (TBI) is unclear. Therefore, the aim of this study was to assess the expression of Armcx1 after TBI and to explore possible related mechanisms by which Armcx1 is involved in TBI. We used C57BL/6 male mice to model TBI and evaluated the role of Armcx1 in TBI by transfecting mice with Armcx1 small interfering RNA (siRNA) to inhibit Armcx1 expression 24 h before TBI modeling. Western blotting, immunofluorescence, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, Nissl staining, transmission electron microscopy, adenosine triphosphate (ATP) level measurement, neuronal apoptosis analysis, neurological function scoring and the Morris water maze were performed. The results demonstrated that Armcx1 protein expression was elevated after TBI and that the Armcx1 protein was localized in neurons and astroglial cells in cortical tissue surrounding the injury site. In addition, inhibition of Armcx1 expression further led to impaired mitochondrial transport, abnormal morphology, reduced ATP levels, aggravation of neuronal apoptosis and neurological dysfunction, and decrease Miro1 expression. In conclusion, our findings indicate that Armcx1 may exert neuroprotective effects by ameliorating neurological injury after TBI through a mitochondrial transport pathway involving Miro1. [ABSTRACT FROM AUTHOR]

The molecular mechanism of how reduced mobile zinc (Zn2+) affected retinal ganglion cell (RGC) survival and optic nerve regeneration after optic nerve crush (ONC) injury remains unclear. Here, we used conditionally knocked out ZnT-3 in the amacrine cells (ACs) of mice (CKO) in order to explore the role of reactive oxygen species (ROS), nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) and autophagy in the protection of RGCs and axon regeneration after ONC injury. We found that reduced Zn2+ can promote RGC survival and axonal regeneration by decreasing ROS, activating Nrf2, and inhibiting autophagy. Additionally, autophagy after ONC is regulated by ROS and Nrf2. Visual function in mice after ONC injury was partially recovered through the reduction of Zn2+, achieved by using a Zn2+ specific chelator N,N,Nʹ,Nʹ-tetrakis-(2-Pyridylmethyl) ethylenediamine (TPEN) or through CKO mice. Overall, our data reveal the crosstalk between Zn2+, ROS, Nrf2 and autophagy following ONC injury. This study verified that TPEN or knocking out ZnT-3 in ACs is a promising therapeutic option for the treatment of optic nerve damage and elucidated the postsynaptic molecular mechanism of Zn2+-triggered damage to RGCs after ONC injury. Schematic summary of results and potential signaling pathway. (A) Transsynaptic process of Zn2+ from ACs to RGCs in retinas after ONC injury. (B) Overload Zn2+ damaged mitochondrial and increased ROS level after ONC injury. Zn2+ inhibited Nrf2 and its downstream of NQO1 and HO-1, which also resulted in the higher production of ROS. Changes in ROS and Nrf2 promoted the formation of autophagosomes after ONC injury. [Display omitted] • Elimination of Zn2+, by its specific chelator (TPEN) or ZnT-3 deletion in ACs (CKO), promoted RGCs survival and axon regeneration after ONC injury by reducing ROS. • Reduced Zn2+ promoted RGCs survival and axon regeneration after ONC injury by increasing the expression of Nrf2 pathway. • Reduced Zn2+ promoted RGCs survival and axon regeneration after ONC injury through inhibiting autophagy. • Autophagy after ONC injury was regulated by ROS and Nrf2. [ABSTRACT FROM AUTHOR]

Glaucoma is a leading cause of blindness; despite efficacious lowering of intraocular pressure, the disease progresses because neurodegeneration of retinal ganglion cells (RGCs)represents the primary neurodegenerative event. Recently, the identification of a programmed axonal degeneration program triggered by NAD shortage opened new vistas on the possibility of developing efficacious neuroprotective strategies to counteract glaucoma progression, and proof-of-concept clinical trials with NAD supplements have already provided positive results in patients with glaucoma. Here, I provide a critical reappraisal on how the pathogenesis of RGC death should instruct drug development programs for neuroprotection in glaucoma. Clinical evidence shows that intraocular hypertension is not the primary pathogenetic event of glaucoma, whereas early neurodegeneration of retinal ganglion cells (RGCs) represents a key therapeutic target. Unfortunately, failure of clinical trials with neuroprotective agents, in particular those testing the anti-excitotoxic drug memantine, generated widespread skepticism regarding the possibility of counteracting neurodegeneration during glaucoma. New avenues for neuroprotective approaches to counteract glaucoma evolution have been opened by the identification of a programmed axonal degeneration (PAD) program triggered by increased nicotinamide mononucleotide (NMN)/NAD concentration ratio. Positive results of proof-of-concept clinical studies based on sustaining axonal NAD homeostasis facilitated the design of Phase 2/3 trials. Here, I share my opinion on how neurodegeneration in glaucoma should be put into context, together with an appraisal of the pharmacological rationale of NAD-supporting therapies for use during glaucoma progression. [ABSTRACT FROM AUTHOR]

Lysosomes in photoreceptors (PRs), the retinal pigmented epithelium (RPE), and retinal ganglion cells (RGCs) are essential for maintaining retinal homeostasis. Phagocytosis of PR outer segments and autophagy in RPE are crucial for maintaining retinal health. Lysosomal impairments are involved in various retinal diseases: dysfunction in the RPE contributes to the biogenesis of drusen, a hallmark of early age-related macular degeneration (AMD); lysosomal dysfunction in PRs characterizes early stages of retinitis pigmentosa (RP), a constellation of blinding diseases caused by numerous genetic mutations; and development of glaucoma is linked to lysosomal abnormalities. Lysosomes interact with other organelles such as mitochondria. This coordination is vital to the cytoprotective responses of retinal cells and, when dysfunctional, contributes to the pathogenesis of blinding retinal diseases. Lysosomes play crucial roles in various cellular processes – including endocytosis, phagocytosis, and autophagy – which are vital for maintaining retinal health. Moreover, these organelles serve as environmental sensors and act as central hubs for multiple signaling pathways. Through communication with other cellular components, such as mitochondria, lysosomes orchestrate the cytoprotective response essential for preserving cellular homeostasis. This coordination is particularly critical in the retina, given its high metabolic rate and susceptibility to photo-oxidative stress. Consequently, impaired lysosomal function and dysregulated communication between lysosomes and other organelles contribute significantly to the pathobiology of major retinal degenerative diseases. This review explores the pivotal role of lysosomes in retinal cells and their involvement in retinal degenerative diseases. [ABSTRACT FROM AUTHOR]

To assess the prevalence of nonglaucomatous optic nerve atrophy (NGOA) in highly myopic individuals. Population-based study. The Ural Eye and Medical Study included 5899 (80.5%) of 7328 eligible individuals (80.5%). Nonglaucomatous optic nerve atrophy, graded into 5 arbitrary stages, was characterized by decreased visibility of the retinal nerve fiber layer (RNFL) on photographs, neuroretinal rim pallor, abnormally thin retinal arteriole diameter, and abnormally thin peripapillary RNFL as measured by OCT. Nonglaucomatous optic nerve atrophy prevalence and degree. Of 5709 participants (96.9%) with axial length measurements, 130 individuals (2.3%) were highly myopic, of whom 116 individuals (89.2%; age, 57.8 ± 11.1 years; axial length, 27.0 ± 1.2 mm) had available fundus photographs and OCT images and were included into the study. Nonglaucomatous optic nerve atrophy prevalence was 34/116 individuals (29.3%; 95% confidence interval [CI], 21.0–38.0), and mean NGOA degree in eyes with NGOA was 1.7 ± 1.0 arbitrary units. Higher NGOA degree correlated (multivariable analysis; regression coefficient, r 2 = 0.59) with longer axial length (β, 0.22; P = 0.007), wider temporal parapapillary γ zone width (β, 0.50; P < 0.001), higher prevalence of diabetes (β, 0.20; P = 0.005), and higher systolic blood pressure (β, 0.15; P = 0.03). Higher NGOA prevalence was associated with longer axial length (odds ratio [OR], 7.45; 95% CI, 2.15–25.7), wider temporal parapapillary γ zone (OR, 6.98; 95% CI, 2.61–18.7), and higher systolic blood pressure (OR, 1.05; 95% CI, 1.01–1.10). In this ethnically mixed population from Russia with an age of 40 years or more, high axial myopia showed a relatively high prevalence of NGOA, increasing with longer axial length and wider temporal parapapillary γ zone. For each 1 mm of axial elongation and γ zone widening, the odds for NGOA increased 7.45-fold and 6.98-fold, respectively. The axial elongation–associated and γ zone–related increase in the distance between the retinal ganglion cells and the optic disc may lead to a lengthening and stretching of the retinal ganglion cell axons and may be of importance pathogenetically. In highly myopic eyes, NGOA may be a reason for visual field and central visual acuity loss, unexplainable by myopic macular pathologic features. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Optic neuropathy is the leading cause of irreversible blindness and is characterized by progressive degeneration of retinal ganglion cells (RGCs). Several studies have demonstrated that transplantation of Schwann cells (SCs) is a promising candidate therapy for optic neuropathy and that intravitreally transplanted cells exert their effect via paracrine actions. Extracellular vesicle (EV)-based therapies are increasingly recognized as a potential strategy for cell replacement therapy. In this study, we aimed to investigate the neuroprotective and regenerative effects of SC-EVs following optic nerve injury. We found that SC-EVs were internalized by RGCs in vitro and in vivo without any transfection reagents. Intriguingly, SC-EVs significantly enhanced the survival and axonal growth of primary RGCs in a coculture system. In a rat optic nerve crush model, SC-EVs mitigated RGC degeneration, prevented RGC loss, and preserved the thickness of the ganglion cell complex, as demonstrated by the statistically significant improvement in RGC counts and thickness measurements. Mechanistically, SC-EVs activated the cAMP-response element binding protein (CREB) signaling pathway and regulated reactive gliosis in ONC rats, which is crucial for RGC protection and axonal regeneration. These findings provide novel insights into the neuroprotective and regenerative properties of SC-EVs, suggesting their potential as a cell-free therapeutic strategy and natural biomaterials for neurodegenerative diseases of the central nervous system. [Display omitted] [ABSTRACT FROM AUTHOR]

This study quantified age-related changes to retinal autophagy using the CAG-RFP-EGFP-LC3 autophagy reporter mice and considered how aging impacts autophagic responses to acute intraocular pressure (IOP) stress. IOP was elevated to 50 mm Hg for 30 minutes in 3-month-old and 12-month-old CAG-RFP-EGFP-LC3 (n = 7 per age group) and Thy1-YFPh transgenic mice (n = 3 per age group). Compared with younger eyes, older eyes showed diminished basal autophagy in the outer retina, while the inner retina was unaffected. Autophagic flux (red:yellow puncta ratio) was elevated in the inner plexiform layer. Three days following IOP elevation, older eyes showed poorer functional recovery, most notably in ganglion cell responses compared to younger eyes (12 months old: −33.4 ± 5.3% vs. 3 months mice: −13.4 ± 4.5%). This paralleled a reduced capacity to upregulate autophagic puncta volume in the inner retina in older eyes, a response that was seen in younger eyes. Age-related decline in basal and stress-induced autophagy in the retina is associated with greater retinal ganglion cells' susceptibility to IOP elevation. [ABSTRACT FROM AUTHOR]

Effective eye drop delivery systems for treating diseases of the posterior segment have yet to be clinically validated. Further, adherence to eye drop regimens is often problematic due to the difficulty and inconvenience of repetitive dosing. Here, we describe a strategy for topically dosing a peptide-drug conjugate to achieve effective and sustained therapeutic sunitinib concentrations to protect retinal ganglion cells (RGCs) in a rat model of optic nerve injury. We combined two promising delivery technologies, namely, a hypotonic gel-forming eye drop delivery system, and an engineered melanin binding and cell-penetrating peptide that sustains intraocular drug residence time. We found that once daily topical dosing of HR97-SunitiGel provided up to 2 weeks of neuroprotection after the last dose, effectively doubling the therapeutic window observed with SunitiGel. For chronic ocular diseases affecting the posterior segment, the convenience of an eye drop combined with intermittent dosing frequency could result in greater patient adherence, and thus, improved disease management. [Display omitted] • A hypotonic gel-forming eye drop was used to increase drug delivery to posterior segment to protect retinal ganglion cells. • Conjugation of sunitinib to the engineered melanin binding and cell-penetrating peptide increased intraocular residence time. • The peptide-drug conjugate in the hypotonic gel-forming eye drop (HR97-SunitiGel) provided sustained ocular drug delivery. • HR97-SunitiGel has potential for improving disease management in chronic ocular diseases affecting the posterior segment. [ABSTRACT FROM AUTHOR]

Glaucoma is the third leading cause of blindness worldwide and is primarily characterized by elevated intraocular pressure (IOP). Common risk factors such as age, myopia, ocular trauma, and hypertension all increase the risk of elevated IOP. Prolonged high IOP not only causes physiological discomfort like headaches, but also directly damages retinal cells and leads to retinal ischemia, oxidative imbalance, and accumulation of reactive oxygen species (ROS) in the retina. This oxidative stress causes the oxidation of proteins and unsaturated lipids, leading to peroxide formation and exacerbating retinal damage. While current clinical treatments primarily target reducing IOP through medication or surgery, there are currently no effective methods to mitigate the retinal cell damage associated with glaucoma. To address this gap, we developed a novel nanoemulsion to co-delivery latanoprost and α-tocopherol (referred to as LA@VNE later) that prolongs ocular retention and enhances retinal permeability through localized administration. By encapsulating latanoprost, an IOP-lowering drug, and α-tocopherol, a potent antioxidant, we effectively reduced ROS accumulation (>1.5-fold in vitro and 2.5-fold in vivo), retinal ganglion cell (RGC) apoptosis (>9 fold), and inflammatory cell infiltration (>1.6 fold). Our approach showed strong biocompatibility and significant potential for clinical translation, providing a promising platform for the treatment of glaucoma. [Display omitted] • We not only focused on IOP in glaucoma, but also emphasized retinal ganglion cells protection strategies. • Our nanoemulsions offer a safer strategy to treat glaucoma because the safer excipient ingredients were chosen. • LA@VNE reach fundus non-invasively, reduce oxidative stress and damage better than clinical approaches in glaucoma animals [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects of 7,8-dihydroxyflavone (7,8-DHF) in protecting retinal ganglion cells (RGCs) and promoting axonal regeneration, and to explore its potential molecular mechanisms. We used three-dimensional retinal culture system and optic nerve crush (ONC) rat models in this study. The pro-axonal regenerative effect of 7,8-DHF was determined with light microscopy observation and immunofluorescence staining of Thy1.1 and GAP43. The RGC protective function of 7,8-DHF was detected by RBPMS immunofluorescent staining and TUNEL staining. The inhibition effect of 7,8-DHF on astrocyte activation was measured using GFAP immunofluorescence and Western blotting. The protein levels of p-TrkB, p-AKT and p-ERK was examined by Western blotting and immunohistochemistry. Our results revealed that 7,8-DHF significantly promoted the average density and length of regenerated neurites and suppressed the apoptosis of GCL cells in three-dimensional culture system and significantly increased the number of RBPMS-positive cells and inhibited the GFAP expression and apoptosis of GCL cells in ONC rats. Our results also revealed that 7,8-DHF activates TrkB, AKT and ERK proteins in vivo, however, these activations can be inhibited byANA-12. In conclusion, 7,8-DHF protects RGCs and promotes axonal regeneration through the TrkB signaling pathway followed by AKT and ERK activation. • 7,8-Dihydroxiflavone (7,8-DHF) promotes neurite regeneration in vitro. • 7,8-DHF ameliorates the death of RGCs in vivo. • 7,8-DHF provides neuroprotection via TrkB signaling followed by AKT and ERK activation. [ABSTRACT FROM AUTHOR]

Light is a known factor affecting mood and the circadian system. Light deficit is linked to deteriorated transduction of photic information to the brain, and reduced amplitude of the perceived circadian light signaling. Retinal ganglion cells (RGCs) loss due to advanced glaucoma can be a factor compromising light perception, with consequences for circadian rhythms, sleep and mood. This study aimed to estimate associations of RGCs loss with a depression score by multiple regression, accounting for other features of glaucoma. One hundred and fifteen patients diagnosed with primary open-angle glaucoma completed the Beck Depression Inventory II questionnaire. The damage to their RGCs was assessed by high-definition optical coherence tomography (HD-OCT) and their function by pattern electroretinogram (PERG). On fifteen of these patients, 24-h salivary melatonin patterns were determined under light-controlled laboratory conditions, and analysis of eight clock related gene polymorphisms was performed. Backward stepwise multiple regression revealed that the BDI score was the strongest factor that was most closely associated with the HD-OCT-based percentage of global RGCs loss (standardized coefficient, b* = 0.784, p < 0.001), surpassing other related factors, including age, intraocular pressure, visual field loss, and PERG amplitude. A high BDI score was associated with the GNβ3 825C > T polymorphism (dbSNP rs5443). This study did not specifically address damage to intrinsically photoreceptive RGCs. The gene study is based on a limited number of volunteers. Depression scores are strongly associated with RGCs loss, increasing abruptly above a threshold of 15 %, supporting the hypothesis that RGCs loss in advanced glaucoma may affect non-visual photic transduction and lead to mood disturbances. • The BDI score strongly correlates with Retinal Ganglion Cells' (RGCs) loss in glaucoma. • RGCs loss correlates more strongly with the BDI score than with other features of glaucoma progression. • The abrupt increase in depression score occurs above threshold of 15% RGCs loss and relates to circadian alterations. • GNβ3 825C>T polymorphism (dbSNP rs5443) associates with a high BDI score. [ABSTRACT FROM AUTHOR]

Retinal ganglion cell (RGC) neurodegeneration in glaucoma is not prevented by controlling the elevated intraocular pressure alone. Neuroprotective gene therapy approaches could be an essential part of a combination treatment. Five cell adhesion peptide (CAP)-gemini surfactants (18-7N(p 1 – 5)-18) were synthesized as building blocks for brain-derived neurotrophic factor (BDNF) gene carrier nanoparticles (CAP-NPXs). The composition of CAP-NPXs was optimized, physicochemically characterized and evaluated for in vitro transfection efficiency (TE) in A7 astrocytes, 3D retinal neurospheres and for gene expression in vivo in CD1 mice using RFP reporter gene and BDNF levels after intravitreal (IVT) injection. The IgSF-binding 18-7N(p FASNKL)-18 pNPXs treated cells demonstrated 1.4-fold higher TE compared to integrin-binding 18-7N(p RGD)-18 pNPXs and parent 18-7NH-18 NPXs with overall viability between 86 and 95%. The 18-7N(p FASNKL)-18 pNPXs selectively transfected RGCs in 3D MiEye8 neurospheres. In the in vivo CD1 mouse model 18-7N(p FASNKL)-18 pNPXs administered by IVT injection delivered tdTomato/BDNF plasmid to retinal cells and produced higher gene expression than the 18-7N(p RGD)-18 pNPXs, the parent 18-7NH-18 NPXs and Lipofectamine® 3000 as demonstrated by confocal microscopy of whole mount retinas. The BDNF gene expression, assessed by ELISA, showed significantly high levels of BDNF with 18-7N(p FASNKL)-18 (422.60 ± 42.60 pg/eye), followed by 18-7N(p RGD)-18 pNPXs (230.62 ± 24.47 pg/eye), 18-7NH-18 NPXs (245.90 ± 39.72 pg/eye), Lipofectamine® 3000 (199.99 ± 29.90 pg/eye) and untreated controls (131.33 ± 20.30 pg/eye). In summary, the 18-7N(p FASNKL)-18 pNPXs induced 3.4-fold higher BDNF level compared to controls and 2-fold higher than 18-7N(p RGD)-18 pNPXs. The in vivo efficacy of 18-7N(p FASNKL)-18 NPXs to produce BDNF at pharmacologically relevant levels supports further studies. [Display omitted] [ABSTRACT FROM AUTHOR]

Human visual performance typically declines with eccentricity; the neural bases of this effect exist at multiple stages of the visual system. Visual performance also varies with polar angle: it is better along the horizontal than vertical meridian, and along the lower than upper vertical meridian. Polar angle asymmetries exist at multiple stages of the visual system: in the density of photoreceptors and midget retinal ganglion cells, and in the distribution of tissue representing the visual field in visual cortex. Each subsequent stage explains more of the perceptual variability. Polar angle asymmetries are rooted in the asymmetric distribution of tissue in visual cortex, but asymmetric differences in neural tuning properties (spatial frequency tuning, orientation tuning, and receptive field size) likely play a key role in the perceptual asymmetries. Human visual performance changes with visual field location. It is best at the center of gaze and declines with eccentricity, and also varies markedly with polar angle. These perceptual polar angle asymmetries are linked to asymmetries in the organization of the visual system. We review and integrate research quantifying how performance changes with visual field location and how this relates to neural organization at multiple stages of the visual system. We first briefly review how performance varies with eccentricity and the neural foundations of this effect. We then focus on perceptual polar angle asymmetries and their neural foundations. Characterizing perceptual and neural variations across and around the visual field contributes to our understanding of how the brain translates visual signals into neural representations which form the basis of visual perception. [ABSTRACT FROM AUTHOR]

The responses of astrocytes in the optic nerve head (ONH) to mechanical and biochemical stimuli are important to understanding the degeneration of retinal ganglion cell axons in glaucoma. The ONH in glaucoma is vulnerable to stress produced by the intraocular pressure (IOP). Notably, after three days of elevated IOP in a mouse model, the junctions between the astrocytic processes and the peripapillary sclera were altered and the structural compliance of the ONH increased. In order to simulate this aspect of glaucomatous remodeling, explanted mouse eyes were treated with TrypLE, a recombinant trypsin enzyme. Treatment with TrypLE caused the periphery of the astrocytic lamina to contract radially by 0.044 ± 0.038. Transmission electron microscopy showed that TrypLE caused a separation of the end-feet of the astrocyte processes from the basement membrane at the junction with the sclera. Inflation testing after treatment with TrypLE caused an increased strain response in the astrocytic lamina compared to the strain response before treatment. The greatest increase was in the radial Green-Lagrange strain, E rr = 0.028 ± 0.009, which increased by 340%. The alterations in the microstructure and in the strain response of the astrocytic lamina reported in mouse experimental glaucoma were partially reproduced by experimental treatment of mouse eyes with TrypLE. The results herein suggest that separation of junctions between the astrocyte processes and the sclera may be instrumental in increasing the structural compliance of the ONH after a period of elevated IOP. Astrocytes of the optic nerve of the eye spread out from edge to edge across the optic nerve in a region referred to as the astrocytic lamina. In an experimental model of glaucoma caused by elevated eye-pressure, there is disruption of the connections between astrocytes and the edge of the astrocytic lamina. We caused a similar event in the lamina by incubating explanted mouse eyes with an enzyme. Disruption of the astrocyte connections to the edge of their tissue caused the tissue to stretch more when we increased the eye-pressure, compared to the control tissue. This work is the first on the tissue of the optic nerve to demonstrate the importance of cell connections in preventing the over-stretching of the astrocytic lamina. [Display omitted] [ABSTRACT FROM AUTHOR]

• We analyzed the functional and structural changes in retinal ganglion cells (RGCs) and their axons in patients affected by Leber's hereditary optic neuropathy (LHON) using photopic negative response (PhNR) and spectral domain optical coherence tomography (SD-OCT). • The functional and structural changes in RGCs and their axons in LHON asymptomatic carriers have also been evaluated. • In addition, affected individuals were divided into subacute, dynamic and chronic phases based on disease duration in order to evaluate the decay in RGCs function and structure. To analyze the functional and structural changes in retinal ganglion cells (RGCs) and their axons that occur during Leber's hereditary optic neuropathy (LHON) using photopic negative response (PhNR) and spectral domain optical coherence tomography (SD-OCT). Individuals diagnosed with LHON and their family members were invited to participate in this cross-sectional study. PhNR and OCT were used. The PhNR amplitude and peripapillary retinal nerve fiber layer (pRNFL) thicknesses were compared among the three groups. In addition, affected individuals were divided into subacute, dynamic and chronic phases based on disease duration in order to evaluate the decay in RGCs function and structure. 73 affected and 30 carriers with a m.11778G > A mutation were included. PhNR amplitude and the thickness of pRNFL significantly decreased in affected individuals and carriers compared to that of the controls (P＜0.001). However, there was no difference between the carriers and the controls (P＞0.05). There was no difference in the PhNR amplitude of different phases (P = 0.464). In the subacute phase, only temporal pRNFL thickness decreased significantly (P＜0.001). PRNFL thickness decreased significantly in dynamic phase (P＜0.001). Temporal pRNFL thickness continued to decrease in the chronic phase (P = 0.042). In the subacute phase, the function of RGCs was severely impaired. Thickness of pRNFL decreased significantly in four quadrants during disease progression. In the chronic phase, pRNFL thickness decreased slightly. Carriers have shown RGCs dysfunction before pathological changes occur, suggesting subclinical abnormalities. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cell (MSCs)-derived extracellular vesicles (EVs) are emerging therapeutic tools. Hypoxic pre-conditioning (HPC) of MSCs altered the production of microRNAs (miRNAs) in EVs, and enhanced the cytoprotective, anti-inflammatory, and neuroprotective properties of their derivative EVs in retinal cells. EV miRNAs were identified as the primary contributors of these EV functions. Through miRNA seq analyses, miRNA-424 was identified as a candidate for the retina to overexpress in EVs for enhancing cytoprotection and anti-inflammatory effects. FEEs (functionally engineered EVs) overexpressing miR424 (FEE424) significantly enhanced neuroprotection and anti-inflammatory activities in vitro in retinal cells. FEE424 functioned by reducing inflammatory cytokine production in retinal microglia, and attenuating oxygen free radicals in retinal Muller cells and microvascular endothelial cells, providing a multi-pronged approach to enhancing recovery after retinal ischemic insult. In an in vivo model of retinal ischemia, native, HPC, and FEE424 MSC EVs robustly and similarly restored function to close to baseline, and prevented loss of retinal ganglion cells, but HPC EVs provided the most effective attenuation of apoptosis-related and inflammatory cytokine gene expression. These results indicate the potential for EV engineering to produce ameliorative effects for retinal diseases with a significant inflammatory component. We show that functionally engineered extracellular vesicles (FEEs) from mesenchymal stem cells (MSCs) provide cytoprotection in rat retina subjected to ischemia. FEEs overexpressing microRNA 424 (FEE424) function by reducing inflammatory cytokine production in retinal microglia, and attenuating oxygen free radicals in Muller cells and microvascular endothelial cells, providing a multi-pronged approach to enhancing recovery. In an in vivo model of retinal ischemia in rats, native, hypoxic-preconditioned (HPC), and FEE424 MSC EVs robustly and similarly restored function, and prevented loss of retinal ganglion cells, but HPC EVs provided the most effective attenuation of apoptosis-related and inflammatory cytokine gene expression. The results indicate the potential for EV engineering to produce ameliorative effects for retinal diseases with a significant inflammatory component. [Display omitted] [ABSTRACT FROM AUTHOR]

• Changes of retinal function after treatment with PNU-282987. • PNU-282987 affects ERG activity after blast trauma. • Retinal ganglion cells extend axons into optic nerve after PNU-282987 treatment. • PNU-282987 induces changes of retinal neurons after blast exposure. • PNU-282987 prevents amplitude decrease in ERG waveforms after blast. Currently, there is a lack of treatments for retinal neurotrauma. To address this issue, this study uses an alpha7 nAChR agonist, PNU-282987, to determine it effects on functional activity in the retina shortly after a traumatic blast exposure. The objectives of this research include: (1) examination of the cellular and functional damage associated with ocular blast exposure, and (2) evaluation of structural and functional changes that occur post PNU-282987 treatment. Significant ocular blast damage was induced in adult mice after exposure to a single blast of 35 psi to the left eye. Blast-exposed transgenic mice expressing tdTomato Müller glia were treated daily with eyedrops containing PNU-282987 for 4 weeks following the blast exposure. Antibody staining studies in these transgenic mice was conducted to examine lineage tracing and electroretinograms (ERGs) were obtained to examine functional changes. Blast exposure caused a significant loss of cells in all retinal layers after 4 weeks. Immunohistochemical analysis demonstrated tdTomato-positive labeled photoreceptors and retinal ganglion cells in blast-exposed mice treated with PNU-282987. ERG recordings were taken from control animals, from blast-damaged animals and from animals exposed to blast followed by 4 weeks of PNU-282987 treatment. Scotopic ERG recordings from blast-exposed mice had significantly decreased amplitudes of a-wave, b-wave, oscillatory potentials and flicker frequencies, which were prevented after PNU-282987 treatment. In photopic experiments, the PhNR response was reduced significantly after blast exposure but the decrease was prevented after treatment with PNU-282987. These are the first experiments that demonstrate preservation of retinal function after blast exposure using an alpha7 nAChR agonist. [ABSTRACT FROM AUTHOR]

Hereditary optic neuropathies result from defects in the human genome, both nuclear and mitochondrial. The two main and most recognised phenotypes are dominant optic atrophy and Leber hereditary optic neuropathy. Advances in modern molecular diagnosis have expanded our knowledge of genotypes and phenotypes of inherited disorders that affect the optic nerve, either alone or in combination, with various forms of neurological and systemic degeneration. A unifying feature in the pathophysiology of these disorders appears to involve mitochondrial dysfunction, suggesting that the retinal ganglion cells and their axons are especially susceptible to perturbations in mitochondrial homoeostasis. As we better understand the pathogenesis behind these genetic diseases, aetiologically targeted therapies are emerging and entering into clinical trials, including treatments aimed at halting the cascade of neurodegeneration, replacing or editing the defective genes or their protein products, and potentially regenerating damaged optic nerves, as well as preventing generational disease transmission. [ABSTRACT FROM AUTHOR]

[Display omitted] • Single-plasmid approach with multiple expression modules (including self-excising piggyBac transposase). • Allows simultaneous loss- (shRNA, CRISPR/Cas9) and gain-of-function (protein overexpression) experiments. • Applicable across diverse (non-transgenic) species including mouse, rat, ferret and Xenopus tropicalis. • Cell-type specific and temporal (CreERT2) control. Advances in single cell sequencing have enabled the identification of a large number of genes, expressed in many different cell types, and across a variety of model organisms. In particular, the nervous system harbors an immense number of interacting cell types, which are poorly characterized. Future loss- and gain-of-function experiments will be essential in determining how novel genes play critical roles in diverse cellular, as well as evolutionarily adapted, contexts. However, functional analysis across species is often hampered by technical limitations, in non-genetic animal systems. Here, we describe a new single plasmid system, misPiggy. The system is based around the hyperactive piggyBac transposon system, which combines stable genomic integration of transgenes (for long-term expression) with large cargo capacity. Taking full advantage of these characteristics, we engineered novel expression modules into misPiggy that allow for cell-type specific loss- and gain-of-gene function. These modules work widely across species from frog to ferret. As a proof of principle, we present a loss-of-function analysis of the neuronal receptor Deleted in Colorectal Cancer (DCC) in retinal ganglion cells (RGCs) of Xenopus tropicalis tadpoles. Single axon tracings of mosaic knock-out cells reveal a specific cell-intrinsic requirement of DCC, specifically in axonal arborization within the frog tectum, rather than retina-to-brain axon guidance. Furthermore, we report additional technical advances that enable temporal control of knock-down or gain-of-function analysis. We applied this to visualize and manipulate labeled neurons, astrocytes and other glial cells in the central nervous system (CNS) of mouse, rat and ferret. We propose that misPiggy will be a valuable tool for rapid, flexible and cost-effective screening of gene function across a variety of animal models. [ABSTRACT FROM AUTHOR]

• Temporally regulated gene modules are expressed at distinct phases of postmitotic RGC differentiation in mice. • Transcription factors and recognition molecules are selectively expressed by subsets of 45 developing or adult RGC types. • Three models of visual deprivation showed that vision is dispensable for RGC type specification. • Visual deprivation does, however, affect molecular aspects of RGC maturation and maintenance. The development and connectivity of retinal ganglion cells (RGCs), the retina's sole output neurons, are patterned by activity-independent transcriptional programs and activity-dependent remodeling. To inventory the molecular correlates of these influences, we applied high-throughput single-cell RNA sequencing (scRNA-seq) to mouse RGCs at six embryonic and postnatal ages. We identified temporally regulated modules of genes that correlate with, and likely regulate, multiple phases of RGC development, ranging from differentiation and axon guidance to synaptic recognition and refinement. Some of these genes are expressed broadly while others, including key transcription factors and recognition molecules, are selectively expressed by one or a few of the 45 transcriptomically distinct types defined previously in adult mice. Next, we used these results as a foundation to analyze the transcriptomes of RGCs in mice lacking visual experience due to dark rearing from birth or to mutations that ablate either bipolar or photoreceptor cells. 98.5% of visually deprived (VD) RGCs could be unequivocally assigned to a single RGC type based on their transcriptional profiles, demonstrating that visual activity is dispensable for acquisition and maintenance of RGC type identity. However, visual deprivation significantly reduced the transcriptomic distinctions among RGC types, implying that activity is required for complete RGC maturation or maintenance. Consistent with this notion, transcriptomic alternations in VD RGCs significantly overlapped with gene modules found in developing RGCs. Our results provide a resource for mechanistic analyses of RGC differentiation and maturation, and for investigating the role of activity in these processes. [ABSTRACT FROM AUTHOR]

Epidemiological studies have shown that patients with glaucoma are more prone to depression, but the mechanism of comorbid depression in patients with glaucoma remains unknown. Excessive neuroinflammation has been shown to participate in glaucoma-induced retinal degeneration and hippocampal neural apoptosis in depression. However, little research has been conducted to determine whether neuroinflammation contributes to glaucoma-induced depression. Since the degeneration of retinal ganglion cells is a hallmark of glaucoma, we investigated the role of microglia-induced neuroinflammation in retinal degeneration-induced depression and its potential mechanism. An N-methyl-D-aspartate (NMDA)-induced retinal degeneration model was established, and behavioral tests were conducted at 3, 7, 14, and 21 days after retinal degeneration. After tissue collection, we used immunohistochemistry to assess the activation of microglia and real-time polymerase chain reaction to measure the levels of pro-inflammatory cytokines and the NOD-, LRR-, and pyrin-domain containing protein 3 (NLRP3) inflammasome. The mice exhibited depressive-like behaviors 14 and 21 days after retinal degeneration, based on the open field test, tail suspension test, and forced swimming test. Mice also displayed a lower body weight gain than the control group. In addition, microglial activation was observed in the hippocampus. Microglial proliferation was first observed in the dentate gyrus on day 3, while the number of microglia in cornu ammonis 1 grew the most. Moreover, not only was the expression of pro-inflammatory cytokines, including interleukin-1β, interleukin-18, and interleukin-6 promoted, but the messenger ribonucleic acid levels of the NLRP3 inflammasome were also increased. In conclusion, our research shows that NMDA-induced retinal degeneration can induce depressive-like behaviors, which may be attributed to hippocampal neuroinflammation. • NMDA-induced retinal degeneration leads to depressive-like behaviors. • Microglia-mediated neuroinflammation contributes to depressive-like behaviors. • The NLRP3/IL-1β pathway participates in depressive-like behaviors. [ABSTRACT FROM AUTHOR]

The intrinsically photosensitive retinal ganglion cells (ipRGCs) regulate pupil size and circadian rhythms. Stimulation of the ipRGCs using short-wavelength blue light causes a sustained pupil constriction known as the post-illumination pupil response (PIPR). Here we examined the effects of ipRGC stimulation on axial length changes to imposed optical defocus in young adults. Nearly emmetropic young participants were given either myopic (+3 D, n = 16) or hyperopic (-3 D, n = 17) defocus in their right eye for 2 h. Before and after defocus, a series of axial length measurements for up to 180 s were performed in the right eye using the IOL Master following exposure to 5 s red (625 nm, 3.74 × 1014 photons/cm2/s) and blue (470 nm, 3.29 × 1014 photons/cm2/s) stimuli. The pupil measurements were collected from the left eye to track the ipRGC activity. The 6 s and 30 s PIPR, early and late area under the curve (AUC), and time to return to baseline were calculated. The PIPR with blue light was significantly stronger after 2 h of hyperopic defocus as indicated by a lower 6 and 30 s PIPR and a larger early and late AUC (all p <0.05). Short-wavelength ipRGC stimulation also significantly exaggerated the ocular response to hyperopic defocus, causing a significantly greater increase in axial length than that resulting from the hyperopic defocus alone (p = 0.017). Neither wavelength had any effect on axial length with myopic defocus. These findings suggest an interaction between myopiagenic hyperopic defocus and ipRGC signaling. [ABSTRACT FROM AUTHOR]

Glaucoma is a degenerative optic neuropathy in which the degeneration of optic nerve and blindness occur. The main cause is a malfunction of ciliary processes (protrusions of the ciliary bodies) resulting in increased intraocular pressure (IOP). Ocular hypertension (OHT) causes ischemic events leading to retinal ganglion cell (RGC) depletion and blindness. Histaminergic and nitrergic systems are involved in the regulation of IOP. Therefore, we developed novel hybrid compounds that target histamine H 3 receptor (H 3 R) with nitric oxide (NO) releasing features (ST-1989 and ST-2130). After H 3 R binding was proven in vitro , we investigated their effects in two OHT models in New Zealand White rabbits. Compound ST-1989 showed the highest NO elevation, together with antioxidative and anti-inflammatory features partly superior to the co-administered H 3 R antagonist (ciproxifan) and NO donor (molsidomine). This hybrid compound demonstrated IOP reduction in both OHT models induced by intravitreal injection of hypertonic saline and carbomer into the anterior chamber of the eye, respectively. Ocular perfusion and photoreceptor neuroprotection were evaluated in a model of ischemia/reperfusion (I/R) of the ophthalmic artery induced by repeated sub-tenon injections of endothelin-1 (ET-1), twice a week for six weeks. Compound ST-1989 counteracts retinal degeneration reducing ophthalmic artery resistance index and increasing photoreceptor responses, thus rescuing RGCs. Our results indicate that compound ST-1989 is a promising molecule with long-lasting hypotensive effects and good effectiveness in reducing inflammation, oxidative stress, and RGCs apoptosis. In conclusion, these hybrid compounds could be a novel strategy to combat glaucomatous blindness and RGC depletion for ocular diseases involving retinal damage. [Display omitted] • H 3 R-NO hybrid compound reduces intraocular pressure in acute and chronic OHT models. • H 3 R-NO hybrid compound decreases oxidative stress, inflammation and apoptotic process. • ST-1989 improves hemodynamic profile and reduces IOP in ocular ischemic injury model. • ST-1989 preserves retinal ganglion cell layer preventing retinal degeneration. [ABSTRACT FROM AUTHOR]

• The earliest sign of glaucoma is a diffuse loss of visual sensitivity. • The synaptic mechanisms underlying such sensitivity loss are largely unknown. • AIIAC circuitry mediates H-IOP induced sensitivity loss in sONαGCs and sOFFαGCs. • H-IOP affects AIIAC circuitry via pressure-sensitive BK channels in A17ACs. • H-IOP induced ganglion cell sensitivity loss is circuitry-specific. • Our results help to design effective early glaucoma detection and treatment. Glaucoma is a leading cause of blindness worldwide and glaucoma patients exhibit an early diffuse loss of retinal sensitivity followed by focal loss of RGCs. Combining some previous published results and some new data, this paper provides our current view on how high IOP (H-IOP) affects the light response sensitivity of a subset of RGCs, the alpha-ganglion cells (αGCs), as well as their presynaptic bipolar cells (DBCs and HBCs) and A2 amacrine cells (AIIACs) in dark-adapted mouse retinas. Our data demonstrate that H-IOP in experimental glaucoma mice significantly decreases light-evoked spike response sensitivity of sONαGCs and sOFFαGCs (i.e., raises thresholds by 1.5–2.5 log units), but not that of the tONαGCs and tOFFαGCs. The sensitivity loss in sONαGCs and sOFFαGCs is mediated by a H-IOP induced suppression of AIIAC response which is caused by a decrease of transmission efficacy of the DBC R →AIIAC synapse. We also provide evidence supporting the hypothesis that BK channels in the A17AC→DBC R feedback synapse are the H-IOP sensor that regulates the DBC R →AIIAC synaptic efficacy, as BK channel blocker IBTX mimics the action of H-IOP. Our results provide useful information for designing strategies for early detection and possible treatments of glaucoma as physiological changes occur before irreversible structural damage. [ABSTRACT FROM AUTHOR]

[Display omitted] • Citrus treatment regulated gene expression profile after optic nerve crush injury. • Citrus treatment regulated inflammation and apoptosis related pathways. • Four genes were found to be associated with the neuroprotective effect of Citrus. • Citrus exerted neuroprotective effect by regulating P53/BCL-2/BAX pathway. Optic nerve injury induces the loss of retinal ganglion cells and optic nerve atrophy. Our previous study demonstrated the neuroprotective effects of Citrus in the optic nerve crush (ONC) injury model. To explore the underlying neuroprotective mechanism, we focus on the changes in gene expression profile pre- and post-Citrus treatment in the ONC injury model. The results suggested that the Citrus regulated the chemokine signaling pathway and P53 signaling pathway, etc. Four genes were identified as potential target genes (Melk , Mki67 , Ccnb1 , and Cenpf). Subsequent qRT-PCR and western blot confirmed that Citrus regulated cell apoptosis and inflammation-related gene expression, and inhibited P53 activation-induced cell death. The present study demonstrated that the neuroprotective effect of Citrus was achieved through the regulation of the P53/BCL-2/BAX pathway and the expression regulation of four critical genes, which provide novel therapeutic targets for the therapy of optic nerve injury. [ABSTRACT FROM AUTHOR]

• A ROS-responsive hydrogel hybrid system (EL-Gel) loaded with exosomes and Liproxsrain-1 that has anti-apoptotic-, anti-ferroptosis-, and anti-oxidative stress properties. • The exosomes released by EL-Gel can be taken up by R28 cells and retinal cells and retained for a long time. Liproxsrain-1 was detected in the retina at 7 d and 28 d after intravitreal injections of EL-Gel in mice, proving that EL-Gel achieved a slow and long-lasting release. • EL-Gel has a long-lasting and effective protective effect on the RGC and optic nerve in glaucoma. Retinal ischemia–reperfusion is a major cause of vision loss in a variety of ocular diseases, including glaucoma, age-related macular degeneration, diabetic retinopathy, and central retinal artery occlusion. Previous studies have reported the protective effects of injectable hydrogels in optic nerve injury, but reports of multifunctional hydrogels loaded with drugs and bioactive substances that synergistically promote neuroprotection are rare. Here, we designed an injectable, drug-loaded, and reactive oxygen species responsive multifunctional hydrogel. Upon intravitreal injection into a retinal ischemia–reperfusion injury model in mice, the hydrogel released exosomes and liproxstatin-1 over an extended period exceeding a month, leading to a significant recovery of visual function and reduction of retinal ganglion cell loss. The effect was superior to that of the common drug and exosome combination. The results of this study suggest that this multifunctional hydrogel is expected to advance retinal tissue engineering and provide an innovative strategy for acute neuroprotection in retinal ischemia–reperfusion injury. [ABSTRACT FROM AUTHOR]

Glaucoma is a degenerative disease characterized by retinal ganglion cell (RGC) death and visual impairment caused by elevated intraocular pressure (IOP). Elevated IOP can activate microglia, which participate in ganglion cell injury. Based on the study of caveolin-1 (Cav-1) in glaucoma, we aimed to explore the effect and mechanism of Cav-1 on RGC apoptosis in mice with acute ocular hypertension (AOH). AOH mice were established, and Cav-1 was intravitreally injected. Retinal microglia and RGCs were isolated from neonatal mice. TUNEL staining, hematoxylin-eosin staining, immunohistochemistry, flow cytometry, PCR and western blotting were used to observe the effect of Cav-1 on RGCs and mouse retinas. The thickness of the whole retina and the inner retinal sublayer decreased significantly, retinal cell apoptosis increased after AOH injury, and Cav-1 treatment reversed the effect of AOH injury. In addition, Cav-1 treatment promoted the conversion of proinflammatory M1 microglia to anti-inflammatory M2 microglia. Microglia and RGCs were isolated from neonatal mice. Cav-1 protects RGCs from OGD/R-induced injury by changing the polarization status of retinal microglia in vitro. Further studies revealed that Cav-1 activated the Akt/PTEN signaling pathway and inhibited TLR4. Our study provides evidence that Cav-1 may be a promising therapeutic target for glaucoma. [ABSTRACT FROM AUTHOR]

Force sensing is a fundamental ability that allows cells and organisms to interact with their physical environment. The eye is constantly subjected to mechanical forces such as blinking and eye movements. Furthermore, elevated intraocular pressure (IOP) can cause mechanical strain at the optic nerve head, resulting in retinal ganglion cell death (RGC) in glaucoma. How mechanical stimuli are sensed and affect cellular physiology in the eye is unclear. Recent studies have shown that mechanosensitive ion channels are expressed in many ocular tissues relevant to glaucoma and may influence IOP regulation and RGC survival. Furthermore, variants in mechanosensitive ion channel genes may be associated with risk for primary open angle glaucoma. These findings suggest that mechanosensitive channels may be important mechanosensors mediating cellular responses to pressure signals in the eye. In this review, we focus on mechanosensitive ion channels from three major channel families—PIEZO, two-pore potassium and transient receptor potential channels. We review the key properties of these channels, their effects on cell function and physiology, and discuss their possible roles in glaucoma pathophysiology. [ABSTRACT FROM AUTHOR]

[Display omitted] • Transient reduction in arteriolar and venular caliber as early changes due to OHT. • Permanent retinal capillary dystrophy in response to OHT without fluorescein leakage. • OHT induced long-term increase in optic nerve cupping and aberrant choroidal vessels. • Late venular thinning and lack of vitreal infiltrating immune cells following LPC. • Progressive degeneration of RGCs despite the return to normal IOP values. Glaucoma, the leading cause of irreversible blindness worldwide, is a neurodegenerative disease characterized by chronic axonal damages and progressive loss of retinal ganglion cells, with increased intraocular pressure (IOP) as the primary risk factor. While current treatments focus solely on reducing IOP, understanding glaucoma through experimental models is essential for developing new therapeutic strategies and biomarkers for early diagnosis. Our research group developed an ocular hypertension rat model based on limbal plexus cautery, which provides significant glaucomatous neurodegeneration up to four weeks after injury. We evaluated long-term morphological, functional, and vascular alterations in this model. Our results showed that transient ocular hypertension, lasting approximately one week, can lead to progressive increase in optic nerve cupping and retinal ganglion cells loss. Remarkably, the pressure insult caused several vascular changes, such as arteriolar and venular thinning, and permanent choroidal vascular swelling. This study provides evidence of the longitudinal effects of a pressure insult on retinal structure and function using clinical modalities and techniques. The multifactorial changes reported in this model resemble the complex retinal ganglion cell degeneration found in glaucoma patients, and therefore may also provide a unique tool for the development of novel interventions to either halt or slow down disease progression. [ABSTRACT FROM AUTHOR]

Glaucoma, a leading cause of blindness worldwide, encompasses a group of pathological conditions affecting the optic nerve and is characterized by progressive retinal ganglion cell loss, cupping of the optic nerve head, and distinct visual field defects. While elevated intraocular pressure (IOP) is the main risk factor for glaucoma, many patients do not have elevated IOP. Consequently, other risk factors, such as ocular blood flow abnormalities and immunological factors, have been implicated in its pathophysiology. Traditional therapeutic strategies primarily aim to reduce IOP, but there is growing interest in developing novel treatment approaches to improve disease management and reduce the high rates of severe visual impairment. In this context, targeting the ocular renin-angiotensin-aldosterone system (RAAS) has been found as a potential curative strategy. The RAAS contributes to glaucoma development through key effectors such as prorenin, angiotensin II, and aldosterone. Recent evidence has highlighted the potential of using RAAS modulators to combat glaucoma, yielding encouraging results. Our study aims to explore the molecular pathways linking the ocular RAAS and glaucoma, summarizing recent advances that elucidate the role of the RAAS in triggering oxidative stress, inflammation, and remodelling in the pathogenesis of glaucoma. Additionally, we will present emerging therapeutic approaches that utilize RAAS modulators and antioxidants to slow the progression of glaucoma. [Display omitted] • Glaucoma is a major cause of blindness worldwide, creating a significant need for innovative medications. • The ocular renin-angiotensin-aldosterone system (RAAS) contributes to the pathogenesis of glaucoma. • An overactivated RAAS promotes inflammation, remodelling, and oxidative stress in glaucoma pathogenesis. • RAAS modulatorsmay slow disease progression, reducing damage in glaucomas. [ABSTRACT FROM AUTHOR]

• PBG-based scaffolds facilitate directional growth of neurites in hiPSC-derived RGCs. • PBG-based scaffolds facilitate functional maturation of hiPSC-derived RGCs. • These findings could be helpful for optic nerve regeneration. To culture human induced pluripotent stem cells(hiPSCs)- derived retinal ganglion cells (RGCs) with appropriate structure and functionality is critical for cell therapy of optic nerve degeneration. In this study, we aimed to assess the effectiveness of three biocompatible scaffolds -poly(γ-benzyl-L-glutamate) (PBG)-based three-dimensional fibrous scaffolds in promoting the structural and functional maturation of hiPSC-derived RGCs. The study investigated three scaffolds (1) PBG, (2) PBG with glutamic acid (PBGA20), and (3) PBGA20 with sodium salt (PBGA20-Na). The biocompatibility was evaluated in vivo with C57BL/6 mice. Neurite outgrowth was assessed using immunostaining for axon markers, while fluorescence-based Ca2+ imaging and patch-clamp technique were employed to measure neuronal calcium signaling and electrophysiological activity, respectively. All three PBG-based scaffolds exhibited excellent biocompatibility in vivo and effectively supported the directional outgrowth of neurites from hiPSC-derived RGCs while the PBGA20-Na group demonstrated the most favorable outcomes. The presence of glutamic acid in PBGA20 and PBGA20-Na scaffolds led to an increase in calcium signaling within hiPSC-derived RGCs. HiPSC-derived RGCs cultured on PBGA20 and PBGA20-Na scaffolds exhibited an earlier onset of electrophysiological activities with lower thresholds. These promising results provide a foundation for potential sheet transplantation of hiPSC-derived RGCs as cell therapy for optic nerve regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]

• Irisin exerts a protective effect against AOH-induced retinal neuroinflammation. • Microglia and microglia derived inflammatory factors promote AOH-induced RGC injury. • Irisin promotes the conversion of microglia from M1 to M2 phenotype. • Irisin activates microglia integrin αVβ5/AMPK pathway and further enhances autophagy. • Enhanced autophagy ameliorates AOH-induced RGC injury. Neuroinflammation, characterized by microglial activation and the release of multiple inflammatory mediators, is a key factor in acute glaucomatous injury leading to retinal ganglion cell (RGC) death and ultimately irreversible vision loss. Irisin, a novel exercise-induced myokine, has demonstrated anti-inflammatory activity in ischemia/reperfusion injuries across multiple organs and has displayed a significant neuroprotective role in experimental stroke disease models. This study examined the protective impact of irisin and investigated its potential mechanism involved in this process utilizing an acute ocular hypertension (AOH)-induced retinal injury model in mice and a microglia inflammation model induced by lipopolysaccharide (LPS). There was a transient downregulation of irisin in the retina after AOH injury, with parallel emergence of retinal neuroinflammation and RGC death. Irisin attenuated retinal and optic nerve damage and promotes the phenotypic conversion of microglia from M1 to M2. Mechanistically, irisin significantly upregulated the expression of integrin αVβ5, p-AMPK, and autophagy-related markers. Integrin αVβ5 was highly expressed on microglia but hardly expressed on RGC. The integrin αVβ5 inhibitor cilengitide, the AMPK inhibitor dorsomorphin, and the autophagy inhibitor 3-Methyladenine (3-MA) blocked the neuroprotective effects of irisin. Our results suggest irisin attenuates acute glaucoma-induced neuroinflammation and RGC death by activating integrin αVβ5/AMPK in microglia and promoting autophagy. It should be considered a potential neuroprotective therapy for acute glaucoma. [ABSTRACT FROM AUTHOR]

To investigate the possible roles of Interleukin 17A (IL-17A) and IL-17A neutralizing antibodies (IL-17Ab) in glaucoma and the potential mechanisms. The two glaucoma animal models, chronic ocular hypertension (COH) and N-methyl-D-aspartate (NMDA)-induced retinal ganglion cell (RGC) damage, were established and treated with intravitreal injection of IL-17A or IL-17Ab. Intraocular pressure (IOP) was measured by a rebound tonometer. The retina and RGC injury were evaluated by HE staining, TUNLE assay and Brn3a immunofluorescence staining. The frequency of IL-17A+CD4+T cells in peripheral blood was detected by flow cytometry. The expression of glial fibrillary acidic protein (GFAP) was detected by immunofluorescence staining, Western Blot and qPCR in retina. The RNA and protein expression of Act1/TRAF6/NF-κB were detected by Western Blot and qPCR in retina. The expression of IL-17A increased in glaucoma models. After intravitreal injection of IL-17A, in the retina, the number of RGCs decreased, the apoptosis of RGCs increased, the Müller cell gliosis was more obvious. In addition, peripheral inflammation aggravated. Whereas the intravitreal injection of IL-17Ab alleviated the relevant manifestations and peripheral inflammation, reduced the gliosis of Müller cells. In the COH model, IOP increased after the injection of IL-17A, while the intravitreal injection of IL-17Ab led to a decrease in IOP. Furthermore, IL-17A promotes the apoptosis of RGCs by binding to IL-17A receptor, activating Act1/TRAF6/NF-κB pathways. IL-17A plays a role in and aggravates RGC damage in glaucoma. IL-17Ab can neutralize the pro-inflammatory effect of IL-17A and have a protective function in glaucoma. These findings reveal the importance of IL-17A in the pathogenesis of glaucoma, which will shed light on a novel direction for the prevention and treatment of glaucoma, and also provide a reference for further research on other retinal diseases. • IL-17A can aggravate glaucoma-related manifestations. • IL-17A neutralizing antibody can reduce the intraocular pressure in the chronic ocular hypertension (COH) model. • IL-17A can activate Act1/TRAF6/NF-κB signaling pathway and promote RGC apoptosis. [ABSTRACT FROM AUTHOR]

The blood supply in the retina ensures photoreceptor function and maintains regular vision. Leber's hereditary optic neuropathy (LHON), caused by the mitochondrial DNA mutations that deteriorate complex I activity, is characterized by progressive vision loss. Although some reports indicated retinal vasculature abnormalities as one of the comorbidities in LHON, the paracrine influence of LHON-affected retinal ganglion cells (RGCs) on vascular endothelial cell physiology remains unclear. To address this, we established an in vitro model of mitochondrial complex I deficiency using induced pluripotent stem cell-derived RGCs (iPSC-RGCs) treated with a mitochondrial complex I inhibitor rotenone (Rot) to recapitulate LHON pathologies. The secretomes from Rot-treated iPSC-RGCs (Rot-iPSC-RGCs) were collected, and their treatment effect on human umbilical vein endothelial cells (HUVECs) was studied. Rot induced LHON-like characteristics in iPSC-RGCs, including decreased mitochondrial complex I activity and membrane potential, and increased mitochondrial reactive oxygen species (ROS) and apoptosis, leading to mitochondrial dysfunction. When HUVECs were exposed to conditioned media (CM) from Rot-iPSC-RGCs, the angiogenesis of HUVECs was suppressed compared to those treated with CM from control iPSC-RGCs (Ctrl-iPSC-RGCs). Angiogenesis-related proteins were altered in the secretomes from Rot-iPSC-RGC-derived CM, particularly angiopoietin, MMP-9, uPA, collagen XVIII, and VEGF were reduced. Notably, GeneMANIA analysis indicated that VEGFA emerged as the pivotal angiogenesis-related protein among the identified proteins secreted by health iPSC-RGCs but reduced in the secretomes from Rot-iPSC-RGCs. Quantitative real-time PCR and western blots confirmed the reduction of VEGFA at both transcription and translation levels, respectively. Our study reveals that Rot-iPSC-RGCs establish a microenvironment to diminish the angiogenic potential of vascular cells nearby, shedding light on the paracrine regulation of LHON-affected RGCs on retinal vasculature. [ABSTRACT FROM AUTHOR]

• G661R mutation of ADAMTS10 causing glaucoma introduced in mice using CRISPR/Cas9. • ADAMTS10 is expressed along optic nerve axons and in retinal ganglion cells. • ADAMTS10 is not colocalized with fibrillin microfibrils in retina and optic nerve. • ADAMTS10 could function independent of fibrillin. • ADAMTS10 regulates transforming growth factor beta signaling in developing retina. Glaucoma is a neurodegenerative disease that causes irreversible blindness due to loss of retinal ganglion cells (RGCs) and their axons. We previously identified a G661R mutation of ADAMTS10 (A Disintegrin And Metalloproteinase with ThromboSpondin type 1 motif 10) as the disease-causing mutation in a beagle model of glaucoma. ADAMTS10 is a secreted matrix metalloproteinase that belongs to the ADAMTS family which is involved in extracellular matrix (ECM) turnover. Previous studies have shown that ADAMTS10 binds fibrillin microfibrils, promotes their formation, and influences their fibrillin isoform composition. Here, we established a mouse model carrying the G661R mutation of ADAMTS10 (ADAMTS10G661R/G661R) to investigate its ocular phenotypes related to glaucoma and to explore possible functions of ADAMTS10. We found that ADAMTS10 was expressed in the inner retina and along RGC axons in the optic nerve. However, ADAMTS10 was not colocalized with fibrillin microfibrils in these tissues, suggesting fibrillin-independent function for ADAMTS10. In electroretinogram experiments, we found that ADAMTS10G661R/G661R mice had reduced amplitude of retinal responses to dim light stimulus, indicating RGC dysfunction. The reduced RGC function coincided with RGC axon structural changes manifested as smaller optic nerves and fewer optic nerve axons, which may contribute to glaucoma. The reduced number of optic nerve axons found for ADAMTS10G661R/G661R mice occurred early, suggesting developmental deficits. Subsequent experiments found increased apoptosis in the retina of ADAMTS10G661R/G661R mice during postnatal development, which could result in fewer RGCs produced, accounting for fewer optic nerve axons in adulthood. Consistent with a protective effect of transforming growth factor β (TGFβ) signaling against apoptosis during retinal development as shown previously by others, we found increased apoptosis accompanied by decreased TGFβ signaling in the developing retina of ADAMTS10G661R/G661R mice, suggesting a novel role for ADAMTS10 in regulating TGFβ signaling which could involve direct interaction between ADAMTS10 and latent TGFβ. [ABSTRACT FROM AUTHOR]

Superior segmental optic nerve hypoplasia (SSONH) is a congenital condition characterized by developmental abnormalities of the superior optic disc and an underappreciated differential diagnosis for glaucoma. The reported prevalence is less than 1%, although likely underestimated due to the difficulties with diagnosis. The exact pathophysiology of SSONH remains elusive, but a mechanism involving developmental attrition of retinal ganglion cells has been proposed, and maternal diabetes is recognized as a major risk factor. SSONH often is observed incidentally, and the patients typically are then evaluated for an acquired optic atrophy, often glaucoma because of the presence of inferior visual field defects. There are 4 characteristic signs of SSONH: superior entrance of the central retinal artery, superior disc pallor, superior peripapillary halo, and thinning of the superior peripapillary nerve fiber layer; however, the presence of these signs is variable. Optical coherence tomography can be helpful in distinguishing SSONH by demonstrating superonasal retinal nerve fiber layer thinning, as compared to the inferotemporal thinning seen in glaucoma, and an aberrant extension of retinal pigment epithelium over Bruch membrane. Overall, the prognosis of SSONH is favorable, with a non-progressive course. It is essential that ophthalmologists recognize and differentiate SSONH from glaucoma to avoid misdiagnosis and unnecessary treatment. [ABSTRACT FROM AUTHOR]

Glaucoma is a progressive optic neuropathy characterized by the neurodegeneration of the retinal ganglion cells (RGCs) resulting in irreversible visual impairment and eventual blindness. RGCs are extremely susceptible to mitochondrial compromise due to their marked bioenergetic requirements and morphology. There is increasing interest in therapies targeting mitochondrial health as a method of preventing visual loss in managing glaucoma. The bioenergetic profile of Tenon's ocular fibroblasts from glaucoma patients and controls was investigated using the Seahorse XF24 analyser. Impaired mitochondrial cellular bioenergetics was detected in glaucomatous ocular fibroblasts including basal respiration, maximal respiration and spare capacity. Spare respiratory capacity levels reflect mitochondrial bio-energetic adaptability in response to pathophysiological stress. Basal oxidative stress was elevated in glaucomatous Tenon's ocular fibroblasts and hydrogen peroxide (H 2 O 2) induced reactive oxygen species (ROS) simulated the glaucomatous condition in normal Tenon's ocular fibroblasts. This work supports the role of therapeutic interventions to target oxidative stress or provide mitochondrial energetic support in glaucoma. [Display omitted] • Mitochondrial bioenergetics were altered in Tenon's ocular fibroblast cells from glaucoma patients. • Impaired mitochondrial cellular bioenergetics was detected in glaucomatous ocular fibroblasts. • Basal oxidative stress was elevated in glaucomatous Tenon's ocular fibroblasts. • This study provides further evidence for the potential of neuroprotective bioenergetic based therapies for glaucoma. [ABSTRACT FROM AUTHOR]

Glaucoma is a neurodegenerative disease leading to visual loss. Since glaucoma is associated with chronic renal diseases (RDs) their rate is higher in patients with RDs, and end-stage RDs (ESRDs) than in the general population and kidney transplant recipients. Objective To explore the molecular mechanism of diabetic internal environment in regulating the endoplasmic reticulum stress of the retinal ganglion cells (RGCs). Methods Thirty-six SPF grade type 2 diabetes models were divided into 3 groups: Diabetes mellitus (DM), DM + glaucoma and 4-phenylbutyric acid-DM (4-PBA-DM) + glaucoma group. C57BL6 mice of the same week age were taken as the negative control (NC) group. The morphology of RGCs and their axon in the 4 groups were labeled by fluorescent reactive dye Dil. The apoptosis situation of RGCs was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay. The protein expression values of RTN4IP1, Protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2A (eIF2a) and X-box-binding Protein 1 (XBP1) were determined by western blot. The relative mRNA levels of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), Caspase12 and Bax were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Results Glaucoma promotes the apoptosis of RGCs. The protein expression values of RTN4IP1, PERK and XBP1 in DM mouse models with glaucoma were much higher compared to only DM mouse models. Further injection of endoplasmic reticulum stress inhibitor 4-PBA decreased the expression values. The relative mRNA levels of CHOP, Cysteine aspartic acid specific protease12 (Caspase12) and BCL2-associated X protein (Bax) in DM + glaucoma were significantly higher compared to those in DM group. Further injection of endoplasmic reticulum stress inhibitor 4-PBA decreased the mRNA levels. Conclusion Endoplasmic reticulum stress (ERS) is the underlying cause of glaucoma, which could promote the apoptosis of RGCs in diabetic mice. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson's disease (PD)-associated inner retinal abnormalities, particularly the retinal ganglion cells (RGC) layer, on optical coherence tomography (OCT) have recently gained importance as a biomarker of non-motor involvement of the disease but functional RGC evaluation using photopic negative response (PhNR) has not yet been determined. This study aims to compare structural and functional findings of the retina and optic nerve in PD with healthy controls (CT) including PhNR and OCT.Methods: Forty-one eyes of 21 PD patients and 38 eyes of 19 CT underwent ophthalmic examination including visual contrast sensitivity test (CS), OCT, light-adapted full-field electroretinography (ffERG), and PhNR. OCT was used to measure the peripapillary retinal nerve fiber layer, the segmented macular layers, and the choroid. For functional parameters, CS, ffERG (oscillatory potentials, photopic response, 30 Hz-flicker), and PhNR waves were used. Measurements were compared using generalized estimating equation and significance was set at P ≤ 0.05.Results: The PD group presented a significantly lower mono- and binocular CS, oscillatory potentials amplitude, b-wave amplitude on ffERG (152.3[45.4] vs 187.1[32.7]μV; P = 0.002), and PhNR amplitude (135.0[35.0] vs 156.3[34.1]μV; P = 0.025). There was no statistically significant difference in OCT measurements between groups. No correlation was found between statistically significant measurements and clinical data.Conclusions: Functional abnormalities on CS, ffERG, and PhNR can be detected in PD even when structural damages are not observed on OCT. PhNR represents a new potential biomarker in PD. Our findings indicate dysfunction of bipolar, amacrine, and retinal ganglion cells in PD, probably with a cellular dysfunction overcoming morphological damage. [ABSTRACT FROM AUTHOR]

Glaucoma is an optic neuropathy disorder marked by progressive degeneration of the retinal ganglion cells (RGC). It is a leading cause of blindness worldwide, prevailing in around 2.2% of the global population. The hallmark of glaucoma, intraocular pressure (IOP), is governed by the aqueous humor dynamics which plays a crucial role in the pathophysiology of the diesease. Glaucomatous eye has an IOP of more than 22 mmHg as compared to normotensive pressure of 10-21 mmHg. Currently used treatments focus on reducing the elevated IOP through use of classes of drugs that either increase aqueous humor outflow and/or decrease its production. However, effective treatments should not only reduce IOP, but also offer neuroprotection and regeneration of RGCs. Hydrogen Sulfide (H 2 S), a gasotransmitter with several endogenous functions in mammalian tissues, is being investigated for its potential application in glaucoma. In addition to decreasing IOP by increasing aqueous humor outflow, it scavenges reactive oxygen species, upregulates the cellular antioxidant glutathione and protects RGCs from excitotoxicity. Despite the potential of H 2 S in glaucoma, its delivery to anterior and posterior regions of the eye is a challenge due to its unique physicochemical properties. Firstly, development of any delivery system should not require an aqueous environment since many H 2 S donors are susceptible to burst release of the gas in contact with water, causing potential toxicity and adverse effects owing to its inherent toxicity at higher concentrations. Secondly, the release of the gas from the donor needs to be sustained for a prolonged period of time to reduce dosing frequency as per the requirements of regulatory bodies. Lastly, the delivery system should provide adequate bioavailability throughout its period of application. Hence, an ideal delivery system should aim to tackle all the above challenges related to barriers of ocular delivery and physicochemical properties of H 2 S itself. This review discusses the therapeutic potential of H 2 S, its delivery challenges and strategies to overcome the associated chalenges. [Display omitted] • Hydrogen sulphide is an endogenous gasotransmitter with potential superior treatment to glaucoma. • It can offer IOP reduction in the anterior chamber and neuroprotection to retinal ganglionic cells. • An efficient and safe hydrogen sulphide delivery system is the main barrier to its clinical translation. • An ideal delivery system must provide hydrogen sulphide.at a slow and sustained rate for extended period of time. [ABSTRACT FROM AUTHOR]

Glaucoma, a progressive optic neuropathy characterized by retinal ganglion cell degeneration and visual field loss, is the leading cause of irreversible blindness worldwide. Intraocular pressure (IOP) is presently the only modifiable risk factor demonstrated to slow or halt disease progression; however, glaucomatous damage persists in almost 50% of patients despite significant IOP reduction. Many studies have investigated the non-IOP-related risk factors that contribute to glaucoma progression as well as interventions that can prevent or delay glaucomatous neurodegeneration and preserve vision throughout life, independently of IOP. A vast number of experimental studies have reported effective neuroprotection in glaucoma, and clinical studies are ongoing attempting to provide strong evidence of effectiveness of these interventions. We look into the current understanding of the pathophysiology of glaucoma and explore the recent advances in non‐IOP related strategies for neuroprotection and neuroregeneration in glaucoma. [ABSTRACT FROM AUTHOR]

Glaucoma is a chronic optic neuropathy that creates a significant burden on public health. Oxidative stress is hypothesized to play a role to glaucoma progression, and its reduction is being analyzed as a therapeutic target. Dietary antioxidants play a crucial role in helping provide insight into this hypothesis. We reviewed 71 trials, interventional, in-vivo and Iin vitro , including 11 randomized controlled trials, to determine if adjunctive nutritional supplementation could lead to a reduction in oxidative stress and prevent glaucomatous progression. Many laboratory findings show that vitamins and natural compounds contain an abundance of intrinsic antioxidative, neuroprotective and vasoprotective properties that show promise in the treatment and prevention of glaucoma. Although there is encouraging early evidence, most clinical findings are inconclusive. The group of B vitamins appear to have the greatest amount of evidence. Other compounds such as flavonoids, carotenoids, curcumin, saffron, CoQ10, gingko biloba, and resveratrol however warrant further investigation in glaucoma patients. Studies of these antioxidants and other nutrients could create adjunctive or alternative preventative and treatment modalities for glaucoma to those currently available. [ABSTRACT FROM AUTHOR]

Detecting the direction of motion underlies many visually guided behaviors, from reflexive eye movements to identifying and catching moving objects. A subset of motion sensitive cells are direction selective – responding strongly to motion in one direction and weakly to motion in other directions. In mammals, direction-selective cells are found throughout the visual system, including the retina, superior colliculus, and primary visual cortex. Direction selectivity maps are well characterized in the mouse retina, where the preferred directions of retinal direction-selective cells follow the projections of optic flow, generated by the movements animals make as they navigate their environment. Here, we synthesize recent findings implicating activity-dependent mechanisms in the development of retinal direction selectivity maps, with primary focus on studies in mice, and discuss the implications for the development of direction-selective responses in downstream visual areas. Direction selectivity is present in the mouse retina and is organized in a map that represents axes of optic flow. Visual experience plays a minimal role in the establishment of direction selectivity in the mouse retina and visual cortex. Transient retinal spontaneous activity, termed retinal waves, is present before eye opening in mice and is critical for the establishment of direction selectivity in the retina and superior colliculus. Although retinal waves seem poised to set up direction selectivity, the mechanism via which they do so is still unresolved. [ABSTRACT FROM AUTHOR]

Mechanistic target of rapamycin (mTOR) and mTOR complex 1 (mTORC1), linchpins of the nutrient sensing and protein synthesis pathways, are present at relatively high levels in the ganglion cell layer (GCL) and retinal ganglion cells (RGCs) of rodent and human retinas. However, the role of mTORCs in the control of protein synthesis in RGC is unknown. Here, we applied the SUrface SEnsing of Translation (SUnSET) method of nascent protein labeling to localize and quantify protein synthesis in the retinas of adult mice. We also used intravitreal injection of an adeno-associated virus 2 vector encoding Cre recombinase in the eyes of mtor- or rptor-floxed mice to conditionally knockout either both mTORCs or only mTORC1, respectively, in cells within the GCL. A novel vector encoding an inactive Cre mutant (CreΔC) served as control. We found that retinal protein synthesis was highest in the GCL, particularly in RGC. Negation of both complexes or only mTORC1 significantly reduced protein synthesis in RGC. In addition, loss of mTORC1 function caused a significant reduction in the pan- RGC marker, RNA-binding protein with multiple splicing, with little decrease of the total number of cells in the RGC layer, even at 25 weeks after adeno-associated virus-Cre injection. These findings reveal that mTORC1 signaling is necessary for maintaining the high rate of protein synthesis in RGCs of adult rodents, but it may not be essential to maintain RGC viability. These findings may also be relevant to understanding the pathophysiology of RGC disorders, including glaucoma, diabetic retinopathy, and optic neuropathies. [ABSTRACT FROM AUTHOR]

The center-surround receptive field of retinal ganglion cells represents a fundamental concept for how the retina processes and encodes visual information. Yet, traditional approaches of using the receptive field as a linear filter to integrate light intensity over space often do not capture the responses of a ganglion cell to complex visual stimuli. Thus, models with local nonlinearities in subunits of the receptive field or with local temporal dynamics are emerging to better reflect relevant aspects of retinal circuitry and capture stimulus encoding. Here, we review recent efforts to identify such receptive-field substructure and evaluate its role in visual stimulus encoding. The concomitant development of new computational tools may pave the way toward a model-based, functional approach to retinal circuit analysis. Visual stimulus encoding by the retina is not fully captured by the center-surround receptive fields of retinal ganglion cells. Mounting evidence of nonlinear spatial signal integration under natural stimuli and of specific visual functions solved by distinct ganglion cell types indicates the need to better understand receptive-field substructure. Nonlinear spatial integration can be captured by subdividing ganglion cell receptive fields into subunits, which are thought to correspond to presynaptic bipolar cells. Several statistical and model-based methods have recently been developed to identify the subunit layout from spiking responses of ganglion cells to visual stimuli. The subunits provide scaffolding for retinal computations, which may act through local adaptation and inhibition to shape responses to dynamic stimulation and to extract specific visual features. [ABSTRACT FROM AUTHOR]