Progressive Loss Of Retinal Ganglion Cells Research Articles

Sirt6 protects retinal ganglion cells and optic nerve from degeneration during aging and glaucoma

Glaucoma is characterized by the progressive degeneration of retinal ganglion cells (RGCs) and their axons, and its risk increases with aging. Yet comprehensive insights into the complex mechanisms are largely unknown. Here, we found that anti-aging molecule Sirt6 was highly expressed in RGCs. Deleting Sirt6 globally or specifically in RGCs led to progressive RGC loss and optic nerve degeneration during aging, despite normal intraocular pressure (IOP), resembling a phenotype of normal tension glaucoma. These detrimental effects were potentially mediated by accelerated RGC senescence through Caveolin-1 upregulation and by the induction of mitochondrial dysfunction. In mouse models of high tension glaucoma, Sirt6 level was decreased after IOP elevation. Genetic overexpression of Sirt6 globally or specifically in RGCs significantly attenuated high tension-induced degeneration of RGCs and their axons, whereas partial or RGC-specific Sirt6 deletion accelerated RGC loss. Importantly, therapeutically targeting Sirt6 with pharmacological activator or AAV2-mediated gene delivery ameliorated high IOP-induced RGC degeneration. Together, our studies reveal a critical role of Sirt6 in preventing RGC and optic nerve degeneration during aging and glaucoma, setting the stage for further exploration of Sirt6 activation as a potential therapy for glaucoma.

Th1 cells contribute to retinal ganglion cell loss in glaucoma in a VCAM-1-dependent manner.

Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease.

Microglial involvement in ocular hypertension

Glaucoma, a chronic and multifactorial neurodegenerative disease, is the leading cause of irreversible blindness. It is characterized by the degeneration of retinal ganglion cells (RGCs), loss of their axons, and damage to the lamina cribrosa. To study glaucomatous optic neuropathy, experimental rodent models are commonly used due to their low cost, ease of handling, and similarities to the human retina. The ideal model must reproduce tissue changes observed in human glaucoma, such as alterations of the optic nerve head, thinning of the retinal nerve fibre layer, activation of glial cells, and progressive degeneration of RGCs.The DBA/2J transgenic mouse model is the most commonly used genetic model, characterized by a gradual increase in intraocular pressure (IOP) with age, leading to rapid and progressive loss of RGCs and optic nerve degeneration. However, limitations such as iris atrophy and peripheral anterior synechiae can alter the anterior segment and influence IOP measurement. Induced models of ocular hypertension (OHT) have a predictable IOP increase following experimental procedures, but this increase is usually rapid and sustained for a relatively short time, which may not represent the slow and sustained IOP elevation observed in primary open‐angle glaucoma. Nonetheless, induced models produce similar pathophysiological mechanisms to genetic models. Other models include the injection of hypertonic saline into episcleral veins to cause scarring of the trabecular meshwork and elevate IOP, and the intracameral injection of polystyrene or magnetic microbeads to obstruct normal drainage flow of aqueous humour, resulting in an IOP increase. A new model employs an intracameral injection of a cross‐linking polymer that produces a viscosity increase, impeding normal drainage of the aqueous humour and resulting in an IOP increase and loss of RGCs.In this SIS, we review the different glaucoma models, their methods, and the retinal tissue changes, with a focus on microglial cell changes.

Immunomodulatory and Antioxidant Drugs in Glaucoma Treatment.

Glaucoma, a group of diseases characterized by progressive retinal ganglion cell loss, cupping of the optic disc, and a typical pattern of visual field defects, is a leading cause of severe visual impairment and blindness worldwide. Elevated intraocular pressure (IOP) is the leading risk factor for glaucoma development. However, glaucoma can also develop at normal pressure levels. An increased susceptibility of retinal ganglion cells to IOP, systemic vascular dysregulation, endothelial dysfunction, and autoimmune imbalances have been suggested as playing a role in the pathophysiology of normal-tension glaucoma. Since inflammation and oxidative stress play a role in all forms of glaucoma, the goal of this review article is to present an overview of the inflammatory and pro-oxidant mechanisms in the pathophysiology of glaucoma and to discuss immunomodulatory and antioxidant treatment approaches.

DNA and RNA oxidative damage in the retina is associated with ganglion cell mitochondria

This study examines retinas from a rat glaucoma model for oxidized nucleosides 8OHdG and 8OHG, biomarkers for oxidative damage of DNA and RNA, respectively. Immunohistochemical data indicate a predominant localization of 8OHdG/8OHG in retinal ganglion cells (RGCs). The levels for these oxidized DNA/RNA products were 3.2 and 2.8 fold higher at 1 and 2 weeks after intraocular pressure elevation compared to control retinas, respectively. 8OHdG/8OHG were almost exclusively associated with mitochondrial DNA/RNA: ~ 65% of 8OHdG/8OHG were associated with RNA isolated from mitochondrial fraction and ~ 35% with DNA. Furthermore, we analyzed retinas of the rd10 mouse, a model for retinitis pigmentosa, with severe degeneration of photoreceptors to determine whether high levels of 8OHdG/8OHG staining intensity in RGCs of control animals is related to the high level of mitochondrial oxidative phosphorylation necessary to support light-evoked RGC activity. No significant difference in 8OHdG/8OHG staining intensity between control and rd10 mouse retinas was observed. The results of this study suggest that high levels of 8OHdG/8OHG in RGCs of wild-type animals may lead to cell damage and progressive loss of RGCs observed during normal aging, whereas ocular hypertension-induced increase in the level of oxidatively damaged mitochondrial DNA/RNA could contribute to glaucomatous neurodegeneration.

The Retinal Renin-Angiotensin-Aldosterone System: Implications for Glaucoma.

Aldosterone is one of the main effectors of the renin-angiotensin-aldosterone system (RAAS) along with having roles in hypertension, and cardiovascular and renal diseases. Recent evidence has also shown the presence of an active local RAAS within the human eye. It has been shown that at 12 h after a retinal ischemia-reperfusion injury, there is an upregulation of the protein levels of angiotensin II type 1 receptor (AT1-R) in the retina. Furthermore, at 12 h after reperfusion, there is an increase in reactive oxygen species (ROS) production in the retina that is mediated via an NADPH oxidase pathway. This ischemia-reperfusion injury-induced increase of retinal ROS levels and NADPH oxidase expression can be prevented by the administration of an AT1-R antagonist. This suggests that one of the main retinal ischemic injury pathways is via the local RAAS. It has also been reported that progressive retinal ganglion cell loss and glaucomatous optic nerve degeneration without elevated intraocular pressure occur after administration of local or systemic aldosterone. Elucidation of glaucoma pathogenesis, especially normal-tension glaucoma (NTG) subtype by our current animal model can be used for identifying potential therapeutic targets. Based on these results, we are further evaluating NTG prevalence among primary aldosteronism patients.

Effects of Hydrostatic Pressure on Electrical Retinal Activity in a Multielectrode Array-Based ex vivo Glaucoma Acute Model.

Glaucoma is a heterogeneous eye disease causing atrophy of the optic nerve head (ONH). The optic nerve is formed by the axons of the retinal ganglion cells (RGCs) that transmit visual input to the brain. The progressive RGC loss during glaucoma leads to irreversible vision loss. An elevated intraocular pressure (IOP) is described as main risk factor in glaucoma. In this study, a multielectrode array (MEA)-based ex vivo glaucoma acute model was established and the effects of hydrostatic pressure (10, 30, 60, and 90 mmHg) on the functionality and survival of adult male and female wild-type mouse (C57BL/6) retinae were investigated. Spontaneous activity, response rate to electrical and light stimulation, and bursting behavior of RGCs was analyzed prior, during, and after pressure stress. No pressure related effects on spontaneous firing and on the response rate of the RGCs were observed. Even a high pressure level (90 mmHg for 2 h) did not disturb the RGC functionality. However, the cells’ bursting behavior significantly changed under 90 mmHg. The number of spikes in bursts doubled during pressure application and stayed on a high level after pressure stress. Addition of the amino sulfonic acid taurine (1 mM) showed a counteracting effect. OFF ganglion cells did not reveal an increase in bursts under pressure stress. Live/dead staining after pressure application showed no significant changes in RGC survival. The findings of our ex vivo model suggest that RGCs are tolerant toward high, short-time pressure stress.

In situ-crosslinked hydrogel-induced experimental glaucoma model with persistent ocular hypertension and neurodegeneration.

A reliable animal model providing chronic and persistent ocular hypertension and characteristic neurodegeneration is essential to recapitulate human glaucoma and understand the underlying pathophysiological mechanisms behind this disease. Many approaches have been tried to establish persistently elevated intraocular pressure (IOP), while no efficient model and no systematic evaluation has been widely accepted yet. Herein, we developed a novel approach to reliably induce persistent IOP elevation using an injectable hydrogel formulated by hyperbranched macromolecular poly(ethylene glycol) (HB-PEG) and thiolated hyaluronic acid (HA-SH) under physiological conditions and established a systematic system for model evaluation. By formulation screening, an appropriate hydrogel with proper mechanical property, non-swelling profile and cytocompatibility was selected for further experiment. By intracameral injection, a persistent IOP elevation over 50% above baseline was obtained and it led to progressive retinal ganglion cell loss and ganglion cell complex thickness reduction. The evaluation of the efficacy of the model was thoroughly analyzed by whole-mounts retina immunostaining, optical coherence tomography, and hematoxylin-eosin staining for histological changes and by electroretinography for visual function changes. The N35-P50 amplitude of the pattern electroretinography and the N2-P2 amplitude of the flash visual-evoked potential were decreased, while the scotopic electroretinography showed no statistically significant changes. The in situ-forming HB-PEG/HA-SH hydrogel system could be an appropriate strategy for developing a reliable experimental glaucoma model without any confounding factors. We expect this model would be conducive to the development of neuroprotective and neuro-regenerative therapies.

Interleukin-4 promotes microglial polarization toward a neuroprotective phenotype after retinal ischemia/reperfusion injury.

Glaucoma results from irreversible loss of retinal ganglion cells (RGCs) through an unclear mechanism. Microglial polarization and neuroinflammation play an important role in retinal degeneration. Our study aimed to explore the function of microglial polarization during glaucoma progression and identify a strategy to alleviate retinal neuroinflammation. Retinal ischemia/reperfusion injury was induced in C57BL/6 mice. In a separate cohort of animals, interleukin (IL)-4 (50 ng/mL, 2 μL per injection) or vehicle was intravitreally injected after retinal ischemia/reperfusion injury. RGC loss was assessed by counting cells that were positive for the RGC marker RNA binding protein, mRNA processing factor in retinal flat mounts. The expression of classically activated (M1) and alternatively activated (M2) microglial markers were assessed by quantitative reverse transcription-polymerase chain reaction, immunofluorescence, and western blotting. The results showed that progressive RGC loss was accompanied by a continuous decrease in M2 microglia during the late phase of the 28-day period after retinal ischemia/reperfusion injury. IL-4 was undetectable in the retina at all time points, and intravitreal IL-4 administration markedly improved M2 microglial marker expression and ameliorated RGC loss in the late phase post-retinal ischemia/reperfusion injury. In summary, we observed that IL-4 treatment maintained a high number of M2 microglia after RIR and promoted RGC survival.

Inhibition of the cysteinyl leukotriene pathways increases survival of RGCs and reduces microglial activation in ocular hypertension

Glaucoma is the second leading cause of blindness worldwide. This multifactorial, neurodegenerative group of diseases is characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons, leading to irreversible visual impairment and blindness. There is a huge unmet and urging need for the development of new and translatable strategies and treatment options to prevent this progressive loss of RGC. Accumulating evidence points towards a critical role of neuroinflammation, in particular microglial cells, in the pathogenesis of glaucoma. Leukotrienes are mediators of neuroinflammation and are involved in many neurodegenerative diseases. Therefore, we tested the leukotriene receptors CysLT1R/GPR17-selective antagonist Montelukast (MTK) for its efficacy to modulate the reactive state of microglia in order to ameliorate RGCs loss in experimental glaucoma. Ocular hypertension (OHT) was induced unilaterally by injection of 8 μm magnetic microbead (MB) into the anterior chamber of female Brown Norway rats. The contralateral, untreated eye served as control. Successful induction of OHT was verified by daily IOP measurement using a TonoLab rebound tonometer. Simultaneously to OHT induction, one group received daily MTK treatment and the control group vehicle solution by oral gavage. Animals were sacrificed 13–15 days after MB injection. Retina and optic nerves (ON) of OHT and contralateral eyes were analyzed by immunofluorescence with specific markers for RGCs (Brn3a), microglial cells/macrophages (Iba1 and CD68), and cysteinyl leukotriene pathway receptors (CysLT1R and GPR17). Protein labeling was documented by confocal microscopy and analyzed with ImageJ plugins. Further, mRNA expression of genes of the inflammatory and leukotriene pathway was analyzed in retinal tissue. MTK treatment resulted in a short-term IOP reduction at day 2, which dissipated by day 5 of OHT induction in MTK treated animals. Furthermore, MTK treatment resulted in a decreased activation of Iba1+ microglial cells in the retina and ON, and in a significantly increased RGC survival in OHT eyes. Within the retina, GPR17 and CysLT1R expression was demonstrated in single RCGs and in microglial cells respectively. Further, increased mRNA expression of pro-inflammatory genes was detected in OHT induced retinas. In the ON, OHT induction increased the number of GPR17+ cells, showing a trend of reduction following MTK treatment. This study shows for the first time a significantly increased RGC survival in an acute OHT model following treatment with the leukotriene receptor antagonist MTK. These results strongly suggest a neuroprotective effect of MTK and a potential new therapeutic strategy for glaucoma treatment.

New solutions for old challenges in glaucoma treatment: is taurine an option to consider?

Glaucoma is a range of progressive optic neuropathies characterized by progressive retinal ganglion cell loss and visual field defects. It is recognized as a leading cause of irreversible blindness affecting more than 70 million people worldwide. Currently, reduction of intraocular pressure, a widely recognized risk factor for glaucoma development, is the only pharmacological strategy for slowing down retinal ganglion cell loss and disease progression. However, retinal ganglion cell death and visual field loss have been observed in normotensive glaucoma, suggesting that the disease process is partially independent of intraocular pressure. Taurine is one of the agents that have attracted attention of researchers recently. Taurine has been shown to be involved in multiple cellular functions, including a central role as a neurotransmitter, as a trophic factor in the central nervous system development, as an osmolyte, as a neuromodulator, and as a neuroprotectant. It also plays a role in the maintenance of the structural integrity of the membranes and in the regulation of calcium transport and homeostasis. Taurine is known to prevent N-methyl-D-aspartic acid-induced excitotoxic injury to retinal ganglion cells. A recently published study clearly demonstrated that taurine prevents retinal neuronal apoptosis both in vivo and in vitro. Protective effect of taurine may be attributed to direct inhibition of apoptosis, an activation of brain derived neurotrophic factor-related neuroprotective mechanisms and reduction of retinal oxidative and nitrosative stresses. Further studies are needed to fully explore the potential of taurine as a neuroprotective agent, so that it can be applied in clinical practice, particularly for the treatment of glaucoma. The objective of current review was to summarize recent evidence on neuroprotective properties of taurine in glaucoma.

EAAT1 variants associated with glaucoma

Glaucoma is one of the leading causes of blindness characterized by progressive loss of retinal ganglion cells (RGCs) and their axons. We reported that glutamate/aspartate transporter (GLAST) knockout mice showed progressive RGC loss and optic nerve degeneration that are similar to glaucoma. To explore the possibility that rare variants in the EAAT1 gene (the human homolog of GLAST) cause susceptibility to glaucoma, we performed targeted sequencing of EAAT1 in 440 patients with glaucoma and 450 control subjects. We identified 8 rare variants in 20 out of 440 patients, including 4 synonymous and 4 missense variants located at protein coding regions. One of these rare variants (rs117295512) showed significant association with the risk of glaucoma (OR = 10.44, P = 0.005). Furthermore, the allele frequency for loss-of-function EAAT1 variants, pAla169Gly and pAla329Thr, was 5.5 folds higher in the glaucoma (1.1%) compared with the control cohort (0.2%). These findings suggest that these rare variants may contribute to the pathogenesis of glaucoma and that loss-of-function variants in EAAT1 are present in a small number of patients with glaucoma.

Review of notices about critical values in outpatients

Glaucoma is one of the leading causes of blindness characterized by progressive loss of retinal ganglion cells (RGCs) and their axons. We reported that glutamate/aspartate transporter (GLAST) knockout mice showed progressive RGC loss and optic nerve degeneration that are similar to glaucoma. To explore the possibility that rare variants in the EAAT1 gene (the human homolog of GLAST) cause susceptibility to glaucoma, we performed targeted sequencing of EAAT1 in 440 patients with glaucoma and 450 control subjects. We identified 8 rare variants in 20 out of 440 patients, including 4 synonymous and 4 missense variants located at protein coding regions. One of these rare variants (rs117295512) showed significant association with the risk of glaucoma (OR = 10.44, P = 0.005). Furthermore, the allele frequency for loss-of-function EAAT1 variants, pAla169Gly and pAla329Thr, was 5.5 folds higher in the glaucoma (1.1%) compared with the control cohort (0.2%). These findings suggest that these rare variants may contribute to the pathogenesis of glaucoma and that loss-of-function variants in EAAT1 are present in a small number of patients with glaucoma.

Optical Coherence Tomography Angiography in Mice: Quantitative Analysis After Experimental Models of Retinal Damage.

We implemented optical coherence tomography angiography (OCT-A) in mice to: (1) develop quantitative parameters from OCT-A images, (2) measure the reproducibility of the parameters, and (3) determine the impact of experimental models of inner and outer retinal damage on OCT-A findings. OCT-A images were acquired with a customized system (Spectralis Multiline OCT2). To assess reproducibility, imaging was performed five times over 1 month. Inner retinal damage was induced with optic nerve transection, crush, or intravitreal N-methyl-d-aspartic acid injection in transgenic mice with fluorescently labeled retinal ganglion cells (RGCs). Light-induced retinal damage was induced in albino mice. Mice were imaged at baseline and serially post injury. Perfusion density, vessel length, and branch points were computed from OCT-A images of the superficial, intermediate, and deep vascular plexuses. The range of relative differences measured between sessions across the vascular plexuses were: perfusion density (2.8%-7.0%), vessel length (1.9%-4.1%), and branch points (1.9%-5.0%). In mice with progressive RGC loss, imaged serially and culminating in around 70% loss in the fluorescence signal and 18% loss in inner retinal thickness, there were no measurable changes in any OCT-A parameter up to 4 months post injury that exceeded measurement variability. However, light-induced retinal damage elicited a progressive loss of the deep vascular plexus signal, starting as early as 3 days post injury. Vessel length and branch points were generally the most reproducible among the parameters. Injury causing RGC loss in mice did not elicit an early change in the OCT-A signal.

Is primary open-angle glaucoma an ocular manifestation of systemic disease?

Primary open-angle glaucoma is currently characterized by a pattern of progressive retinal ganglion cell loss that stems from a complex underlying pathophysiology that remains poorly elucidated. The roles of blood flow and intraocular pressure (IOP) in glaucoma pathogenesis have been extensively studied. Further, it has been established that lowering IOP can slow the progression of glaucoma. In addition, a number of influential factors have emerged and gained momentum over the years. Increasing evidence implicates the contributions of low cerebrospinal fluid pressure, autoimmunity, neurodegeneration, and impaired autoregulation towards glaucoma pathophysiology. We aggregate and explore these different camps of thought that have garnered attention over the last few decades, and, in doing so, aim to challenge the long-standing view of glaucoma as a primary disease of the eye. A shift in our perspective towards understanding glaucoma as an ocular manifestation of systemic dysregulation may lead ultimately to better clinical management of the disease.

Time-Dependent Nerve Growth Factor Signaling Changes in the Rat Retina During Optic Nerve Crush-Induced Degeneration of Retinal Ganglion Cells.

Nerve growth factor (NGF) is suggested to be neuroprotective after nerve injury; however, retinal ganglion cells (RGC) degenerate following optic-nerve crush (ONC), even in the presence of increased levels of endogenous NGF. To further investigate this apparently paradoxical condition, a time-course study was performed to evaluate the effects of unilateral ONC on NGF expression and signaling in the adult retina. Visually evoked potential and immunofluorescence staining were used to assess axonal damage and RGC loss. The levels of NGF, proNGF, p75NTR, TrkA and GFAP and the activation of several intracellular pathways were analyzed at 1, 3, 7 and 14 days after crush (dac) by ELISA/Western Blot and PathScan intracellular signaling array. The progressive RGC loss and nerve impairment featured an early and sustained activation of apoptotic pathways; and GFAP and p75NTR enhancement. In contrast, ONC-induced reduction of TrkA, and increased proNGF were observed only at 7 and 14 dac. We propose that proNGF and p75NTR contribute to exacerbate retinal degeneration by further stimulating apoptosis during the second week after injury, and thus hamper the neuroprotective effect of the endogenous NGF. These findings might aid in identifying effective treatment windows for NGF-based strategies to counteract retinal and/or optic-nerve degeneration.

Transgenic TBK1 mice have features of normal tension glaucoma.

Duplication of the TBK1 gene is associated with 1-2% of normal tension glaucoma, a common cause of vision loss and blindness that occurs without grossly abnormal intraocular pressure. We generated a transgenic mouse that has one copy of the human TBK1 gene (native promoter and gene structure) incorporated into the mouse genome (Tg-TBK1). Expression of the TBK1 transgene in the retinae of these mice was demonstrated by real-time PCR. Using immunohistochemistry TBK1 protein was predominantly localized to the ganglion cell layer of the retina, the cell type most affected by glaucoma. More intense TBK1 labelling was detected in the retinal ganglion cells (RGCs) of Tg-TBK1 mice than in wild-type littermates. Tg-TBK1 mice exhibit the cardinal sign of glaucoma, a progressive loss of RGCs. Hemizygous Tg-TBK1 mice (with one TBK1 transgene per genome) had a 13% loss of RGCs by 18 months of age (P = 1.5 × 10-8). Homozygous Tg-TBK1 mice had 7.6% fewer RGCs than hemizygous Tg-TBK1 mice and 20% fewer RGCs than wild-type mice (P = 1.9 × 10-5) at 6 months of age. No difference in intraocular pressures was detected between Tg-TBK1 mice and wild-type littermates as they aged (P > 0.05). Tg-TBK1 mice with extra doses of the TBK1 gene recapitulate the phenotype of normal tension glaucoma in human patients with a TBK1 gene duplication. Together, these studies confirm the pathogenicity of the TBK1 gene duplication in human glaucoma and suggest that excess production of TBK1 kinase may have a role in the pathology of glaucoma.

SU‐F‐I‐18: Altered Visual Cortex Responses by Wide‐View FMRI in Primary Open Angle Glaucoma Patients

Purpose:Primary open‐angle glaucoma (POAG) is a common ocular disorder with progressive retinal ganglion cell loss. This study explored the application of wide view fMRI to evaluate neural activity of the whole visual cortex and its relation with visual field functions in POAG patients.Methods:Nine subjects with diagnosed POAG (age: 59.9±10.9 y.o., 4 males) and nine age‐matched healthy volunteers (age: 58.0±4.6 y.o., 6 males) were scanned on a 3T Siemens scanner. For each subject, wide view (110°) visual stimulation of a rotating wedge was performed during fMRI acquisition. T1‐MPRAGE was used to acquire anatomical images as a reference. fMRI signal percent change was calculated for quadrant areas of the visual field for each subject. Group comparison was performed using non‐parametric Mann‐Whitney test with Bonferroni correction. In POAG patients, indices of visual field score and retina layer thickness from each quadrant were correlated with the corresponding fMRI percent changes by Spearman's method. P<0.05 was the threshold for statistical significance.Results:The fMRI signal percent changes of moderate (0.65±0.10, N=9) and advanced (0.44±0.05, N=2) POAG quadrant visual cortex showed significant decrease (moderate: P<0.05; severe: P<0.01) compared with normal (1.02±0.05, N=36). Slightly reduced fMRI signal in early POAG (0.97±0.07, N=25) was observed but not statistically significant. For POAG patients, the fMRI responses per quadrant activation were positively correlated with the clinical visual field scores (ρ=0.48, P<0.005); no correlation was found between fMRI response and retinal nerve layer thickness (ρ=0.01, P>0.05).Conclusion:fMRI revealed a functional decrease of the neural activity in the visual cortex in moderate and advanced POAG. The correlation of fMRI signal with visual field test results indicate fMRI could be used as an objective tool to quantify visual field defects for glaucoma patients.

Decorin treatment for reversing trabecular meshwork fibrosis in open-angle glaucoma.

Decorin treatment for reversing trabecular meshwork fibrosis in open-angle glaucoma.

Caspase-7: a critical mediator of optic nerve injury-induced retinal ganglion cell death.

BackgroundAxonal injury of the optic nerve (ON) is involved in various ocular diseases, such as glaucoma and traumatic optic neuropathy, which leads to apoptotic death of retinal ganglion cells (RGCs) and loss of vision. Caspases have been implicated in RGC pathogenesis. However, the role of caspase-7, a functionally unique caspase, in ON injury and RGC apoptosis has not been reported previously. The purpose of this study is to evaluate the role of caspase-7 in ON injury-induced RGC apoptosis.ResultsC57BL/6 (wildtype, WT) and caspase-7 knockout (Casp7−/−) mice were used. We show that ON crush activated caspase-7 and calpain-1, an upstream activator of caspase-7, in mouse RGCs, as well as hydrolysis of kinectin and co-chaperone P23, specific substrates of caspase-7. ON crush caused a progressive loss of RGCs to 28 days after injury. Knockout of caspase-7 partially and significantly protected against the ON injury-induced RGC loss; RGC density at 28 days post ON crush in Casp7−/− mice was approximately twice of that in WT ON injured retinas. Consistent with changes in RGC counts, spectral-domain optical coherence tomography analysis revealed that ON crush significantly reduced the in vivo thickness of the ganglion cell complex layer (including ganglion cell layer, nerve fiber layer, and inner plexiform layer) in the retina. The ON crush-induced thinning of retinal layer was significantly ameliorated in Casp7−/− mice when compared to WT mice. Moreover, electroretinography analysis demonstrated a decline in the positive component of scotopic threshold response amplitude in ON crushed eyes of the WT mice, whereas this RGC functional response was significantly higher in Casp7−/− mice at 28 days post injury.ConclusionAltogether, our findings indicate that caspase-7 plays a critical role in ON injury-induced RGC death, and inhibition of caspase-7 activity may be a novel therapeutic strategy for glaucoma and other neurodegenerative diseases of the retina.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0039-2) contains supplementary material, which is available to authorized users.