Altered F-actin distribution in retinal nerve fiber layer of a rat model of glaucoma

Glaucoma damages the retinal nerve fiber layer (RNFL). The purpose of this study was to investigate the distribution in RNFL of axonal F-actin, a cytoskeletal component, under the development of glaucoma. Intraocular hypertension was induced in a rat model by translimbal laser photocoagulation of the trabecular meshwork. The retinas of control and treated eyes were obtained after different exposures to elevated IOP. Nerve fiber bundles were identified by fluorescent phalloidin staining of F-actin. Nuclei of cell bodies were identified by DAPI fluorescent counterstain. F-actin distribution in whole-mounted retinas was examined by confocal microscopy. En face and cross-sectional images of RNFL were collected around the optic nerve head (ONH). F-actin in normal RNFL was intensely and uniformly stained. In glaucomatous retina, F-actin staining was not uniform within bundles and total loss of F-actin staining was found in severely damaged areas. Altered F-actin often occurred near the ONH in bundles that appeared normal more peripherally. Both alteration and total loss of F-actin were found most often in dorsal retina. In normal RNFL, F-actin is rich and approximately uniformly distributed within nerve fiber bundles. Elevated IOP changes F-actin distribution in RNFL. Topographic features of F-actin alteration suggest that F-actin near the ONH is more sensitive to glaucomatous damage. The alteration pattern also suggests an ONH location for the glaucomatous insult in this rat model.     

Retinal ganglion cell apoptosis in glaucoma is related to intraocular pressure and IOP-induced effects on extracellular matrix

PURPOSE: To investigate the effect of IOP on retinal ganglion cell (RGC) apoptosis and correlate the effects with IOP-induced changes in extracellular matrix (ECM) in the retina and optic nerve head (ONH) in glaucomatous rat eyes. METHODS: Thirty-seven Dark Agouti rats had elevated IOP induced in the left eye by hypertonic saline episcleral vein injections. Eyes were examined at 3 months histologically for RGC apoptosis and expression of specific ECM components. RESULTS: RGC apoptosis was significantly related to IOP exposure (integral DeltaIOP P <0.001; peak IOP P <0.01). In the RGC layer, elevated IOP correlated positively to a significant increase in MMP-9 activity (P <0.001), tissue inhibitor of matrix metalloproteinase (TIMP-1) (P <0.05), and collagen I (P <0.01), and negatively correlated to deposition of laminin (P <0.05) and TGF-beta2 (P <0.05). There was a significant correlation between MMP-9 activity and both RGC apoptosis (P <0.001) and loss of laminin (P <0.01). IOP exposure was also associated with increased deposition of TGF-beta2 and collagen I at the ONH (P <0.01). CONCLUSIONS: The results demonstrated that RGC apoptosis in glaucoma correlates strongly with elevated IOP and is significantly associated with IOP-induced changes in specific ECM components in the RGC layer. The study shows for the first time a link between MMP-9, laminin degradation, RGC apoptosis, and IOP exposure in glaucoma. The findings suggest that abnormal ECM remodeling in the glaucomatous retina may relate to RGC death and support the notion that the retina is a primary site of injury in glaucoma.     

Upregulation of EphB2 and ephrin-B2 at the optic nerve head of DBA/2J glaucomatous mice coincides with axon loss

PURPOSE: To identify genes with upregulated expression at the optic nerve head (ONH) that coincides with retinal ganglion cell (RGC) axon loss in glaucomatous DBA/2J mice. To further demonstrate that the proteins encoded by these genes bind to RGC axons and influence fundamental axon physiology. METHODS: In situ hybridization and cell-type-specific immunolabeling were performed on ONH sections from DBA/2J mice (3 to 11 months old) and C57Bl/6NCrl mice (10 months old). EphB2-Fc and ephrin-B2-Fc chimeric proteins were applied to adult RGC axons in vitro and in vivo at the ONH to demonstrate protein binding on axons. EphB2-Fc or control Fc protein was applied in a bath or locally to axons preloaded with the calcium indicator Fluo-4-AM, and changes in intra-axonal calcium were determined. RESULTS: EphB2 and ephrin-B2 were specifically upregulated at the ONH of DBA/2J mice starting at 9 months of age, but not in age-matched C57Bl/6NCrl mice or in DBA/2J animals that did not have axon loss. EphA4 was also present at the ONH, but no difference in expression was detected between unaffected and affected animals. EphB2 was expressed by F4/80(+), MOMA2(+), ED1(-) macrophage-like cells, ephrin-B2 was expressed by Iba-1(+) microglia and GFAP(+) astrocytes, whereas EphA4 was expressed by GFAP(+) astrocytes. EphB2-Fc and ephrin-B2-Fc protein bound to RGC axons in culture and to ONH RGC axons in vivo. Adult RGC axons in vitro elevated intra-axonal calcium in response to EphB2-Fc but not to control Fc protein. CONCLUSIONS: The expression of EphB2 and ephrin-B2 is upregulated at the ONH of glaucomatous DBA/2J mice coinciding with RGC axon loss. The direct binding of EphB2 and ephrin-B2 on adult RGC axons at the ONH and the ability of EphB2 to elevate intra-axonal calcium indicate that these proteins may affect RGC axon physiology in the setting of glaucoma and thus affect the development or progression of the disease.     

Cyclooxygenase-1 and Cyclooxygenase-2 in the Human Optic Nerve Head

To investigate the hypothesis that eicosanoids act as cellular mediators in the optic nerve head of normals and of patients with glaucoma, we have determined the presence of the two cyclooxygenase (COX) isoforms in human tissue. Histological sections of optic nerve heads were studied by immunohistochemistry. Age matched normal donors were compared with eyes from glaucoma patients with moderate to severe nerve damage. Polyclonal antibodies to human COX-1 and COX-2 were localized with immunoperoxidase staining. Specific antibodies for vascular endothelia and microglia were also co-localized. In normal and glaucomatous eyes, COX-1 was localized exclusively to the prelaminar and lamina cribrosa regions of the optic nerve head. No staining for COX-1 was observed in the nerve fiber layer or the myelinated optic nerve. COX-1 was associated with the astrocytes of the glial columns and the cribriform plates, but not with the endothelia lining the capillaries. In glaucoma, more astrocytes appeared to be stained with antibody to COX-1 than in normals and staining was intensely perinuclear. There was no staining for COX-2 in normal tissue. A few COX-2 positive cells were found in the prelaminar, lamina cribrosa and postlaminar regions of the glaucomatous optic nerves. Positive staining for COX-2 was not associated with microglia. COX-1 is constitutively present in astrocytes that are localized exclusively to the prelaminar and lamina cribrosa regions of the human optic nerve head. Eicosanoids, synthesized by COX-1 in this tissue, may have a homeostatic and a neuroprotective role related to the axons of the retinal ganglion cells. The sparse presence of COX-2 in glaucomatous tissue probably reflects the lack of inflammation associated with glaucomatous optic neuropathy.     

The pathogenic role of transforming growth factor-β2 in glaucomatous damage to the optic nerve head

In patients with primary open angle glaucoma (POAG), the optic nerve head (ONH) shows characteristic cupping correlated with visual field defects. The progressive optic neuropathy is characterized by irreversible loss of retinal ganglion cells (RGC). The critical risk factor for axonal damage at the ONH is an elevated intraocular pressure (IOP). The increase in IOP correlates with axonal loss in the ONH, which might be due to an impaired axoplasmatic flow leading to the loss of RGCs. Damage to the optic nerve is thought to occur in the lamina cribrosa (LC) region of the ONH, which is composed of characteristic sieve-like connective tissue cribriform plates through which RGC axons exit the eye. The cupping of the optic disc, and the compression and excavation of LC are characteristic signs of glaucomatous ONH remodelling. In ONH of POAG patients a disorganized distribution and deposition of elastic fibers and a typical pronounced thickening of the connective tissue septae surrounding the optic nerve fibers is found.Transforming growth factor (TGF)-β2 could be one of the pathogenic factors responsible for the structural alterations in POAG patients as the TGF-β2 levels in the ONH of glaucomatous eyes are elevated as well as in the aqueous homour. TGF-β2 leads to an increased synthesis of extracellular matrix (ECM) molecules mediated by connective tissue growth factor and to an impaired ECM degradation in cultured ONH astrocytes. Bone morphogenetic protein (BMP)-4 effectively antagonizes the effects of TGF-β2 on matrix deposition. The BMP antagonist gremlin blocks this inhibition, allowing TGF-β2 stimulation of ECM synthesis. Overall, the ECM in the ONH is kept in balance in the OHN by factors that augment or block the activity of TGF-β2.     

Optic nerve dynein motor protein distribution changes with intraocular pressure elevation in a rat model of glaucoma

Acute intraocular pressure (IOP) elevation causes accumulation of retrogradely-transported brain derived neurotrophic factor and its receptor at the optic nerve head (ONH) in rats and monkeys. Obstruction of axonal transport may therefore be involved in glaucoma pathogenesis, but it is unknown if obstruction is specific to certain transported factors or represents a generalized failure of retrograde axonal transport. The dynein motor complex mediates retrograde axonal transport in retinal ganglion cells (RGC). Our hypothesis was that elevated IOP interferes with dynein-mediated axonal transport. We studied the distribution of dynein subunits in the retina and optic nerve after acute and chronic experimental IOP elevation in the rat. IOP was elevated unilaterally in 54 rats. Dynein subunit distribution was compared in treated and control eyes by immunohistochemistry and Western blotting at 1 day (n=12), 3 days (n=4), 1 week (n=15), 2 weeks (n=12) and 4 weeks (n=11). For immunohistochemistry, sections through the ONH were probed with an anti-dynein heavy chain (HC) antibody and graded semi-quantitatively by masked observers. Other freshly enucleated eyes were microdissected for separate Western blot quantification of dynein intermediate complex (IC) in myelinated and unmyelinated optic nerve, ONH and retina. Immunohistochemistry showed accumulation of dynein HC at the ONH in IOP elevation eyes compared to controls (P<0.001, Wilcoxon paired sign-rank test, n=29). ONH dynein IC was elevated by 46.5% in chronic IOP elevation eyes compared to controls by Western blotting (P<0.001, 95% CI=25.9% to 67.8%, n=17). The maximum increase in ONH dynein IC was 78.7% after 1 week (P<0.05, n=5), but significant increases were also detected after 4 h and 4 weeks of IOP elevation (P<0.05, n=4 rats per group). Total retinal dynein IC was increased by 8.7% in chronic IOP elevation eyes compared to controls (P<0.03, 95% CI 1.4% to 16.1%, n=24). In the retina, IOP elevation particularly affected the 72 kD subunit of dynein IC, which was 100.7% higher in chronic IOP elevation eyes compared to controls (P<0.00001, 95% CI 71.0% to 130.4%, n=21). Dynein IC changes in myelinated and unmyelinated optic nerve were not significant (P>0.05). We conclude that dynein accumulates at the ONH with experimental IOP elevation in the rat, supporting the hypothesis that disrupted axonal transport in RGC may be involved in the pathogenesis of glaucoma. The effect of IOP elevation on other motor proteins deserves further investigation in the future.     

Complement component 1Q (C1Q) upregulation in retina of murine, primate, and human glaucomatous eyes

PURPOSE: Complement has been implicated in the pathogenesis of neurodegenerative diseases. The purpose of this study was to investigate whether complement activation is part of the pathogenesis of retinal ganglion cell (RGC) loss in glaucoma. METHODS: mRNA and protein was extracted from the retina and brain of DBA/2 and C57/BL6 mice and subjected to RT-PCR and immunoblot analysis, respectively. In addition, eyes from the same mouse strains were subjected to immunohistochemistry with antibodies specific to complement component 1q (C1q). Eyes from monkeys with unilateral experimental glaucoma were also subjected to immunohistochemical analysis, as were eyes from human subjects with or without glaucoma. RESULTS: C1q mRNA and C1q protein were found to be upregulated in the retina of glaucomatous DBA/2 mice. Upregulation of C1q preceded the time of extensive RGC death and increased with increasing age to 15 months in the retina, but not in the brain. No age-related C1q upregulation was detected in the reference mouse strain (C57BL/6), which develops significant nonglaucomatous RGC loss toward the end of the same time frame. C1q upregulation was also detected in laser-induced glaucomatous monkey eyes and in some (but not all) eyes of patients with glaucoma. C1q upregulation was localized to the Müller cells within the retina and in the area of the inner limiting membrane. CONCLUSIONS: Complement expression is upregulated in the retina of two commonly used glaucoma models (in the DBA/2 mouse and the monkey) and in some human glaucomatous eyes. The timing of this upregulation suggests that complement activation plays a significant role in the pathogenesis of glaucoma.     

Ceruloplasmin upregulation in retina of murine and human glaucomatous eyes

PURPOSE: Ceruloplasmin (Cp) expression is increased locally as a response to many neurodegenerative conditions. The purposes of this study were to confirm findings of Cp upregulation in glaucoma, detect the time course of this upregulation in a glaucoma model, and better localize its expression in the retina. METHODS: mRNA and protein were extracted from the retina and brain of DBA/2 and C57BL/6 mice and were subjected to analysis by RT-PCR and immunoblotting. In addition, eyes from the same mouse strains were subjected to immunohistochemistry using antibodies specific for Cp. Eyes from human subjects with or without glaucoma were also subjected to immunohistochemical analysis for Cp. RESULTS: Cp mRNA and Cp protein were upregulated in the retinas of glaucomatous DBA/2 mice. Upregulation of Cp occurred at approximately the time of extensive retinal ganglion cell (RGC) death and increased with increasing age to 15 months in the retinas but not in the brains of these animals. No age-related Cp upregulation was detected in the reference normal mouse strain (C57BL/6), which can develop significant nonglaucomatous RGC loss toward the end of the same time frame. Cp upregulation was also detected in most eyes from the patients with glaucoma. Cp upregulation was localized to the Müller cells within the retinas and in the area of the inner limiting membrane. CONCLUSIONS: Cp is upregulated in the retina of a commonly used glaucoma model (the DBA/2 mouse) and in most human glaucomatous eyes. The timing of this upregulation suggests that it may represent a reactive change of the retina in response to a noxious stimulus or to RGC death. Such Cp upregulation may represent a protective mechanism within the retina.     

Comparing glaucomatous optic neuropathy in primary open angle and chronic primary angle closure glaucoma eyes by optical coherence tomography

PURPOSE: To comparatively evaluate the optic nerve head (ONH) using Optical Coherence Tomography (OCT) in normal subjects, primary open angle glaucoma (POAG) and chronic primary angle closure glaucoma (CPACG) patients. METHODS: A total of 138 normal eyes (138 subjects) and 139 glaucomatous eyes (139 patients), were evaluated in this cross-sectional observational study. The ONH was imaged on OCT using the optic disc scan. Disc area, cup area, rim area, vertical integrated rim area (VIRA), rim volume (horizontal integrated rim volume), average cup/disc ratio, horizontal and vertical cup/disc ratios, and cup volume were evaluated. Additionally, cup depth and slope of the temporal ONH were also measured. These ONH parameters were compared between normal subjects and eyes with early POAG and CPACG. Correlation of mean deviation and corrected pattern standard deviation on full threshold 30-2 perimetry, with measured ONH parameters was carried out amongst the two groups. RESULTS: There was a significant difference in disc area (2.38 +/- 0.5, 2.77 +/- 0.4, 2.62 +/- 0.4 mm(2), p < 0.01), cup area (0.88 +/- 0.6, 1.99 +/- 0.7, 1.60 +/- 0.7 mm(2), p < 0.01), rim area (1.48 +/- 0.4, 0.86 +/- 0.4, 0.96 +/- 0.4 mm(2), p < 0.01), VIRA (1.64 +/- 0.3, 1.23 +/- 0.3, 1.22 +/- 0.4 mm(2), p < 0.01), rim volume (0.34 +/- 0.2, 0.1 +/- 0.1, 0.15 +/- 0.1 mm(3), p < 0.01) and cup/disc ratio (0.36 +/- 0.2, 0.69 +/- 0.1, 0.63 +/- 0.2, p < 0.01) in normal vs POAG vs CPACG eyes respectively. A comparison of ONH parameters between early POAG and early CPACG showed a significant difference in the disc area (2.85 +/- 0.3, 2.57 +/- 0.4 mm(2), p = 0.03), cup area (2 +/- 0.5, 1.34 +/- 0.5 mm(2), p < 0.01), rim area (0.96 +/- 0.4, 1.21 +/- 0.5 mm(2), p = 0.009), rim volume (0.12 +/- 0.1, 0.18 +/- 0.1 mm(3), p < 0.01) and cup/disc ratio (0.67 +/- 0.1, 0.53 +/- 0.2, p < 0.01). The parameters with the highest area under the receiver operator characteristic (AROC) curves for differentiating normal and early POAG eyes were rim volume, 0.89, VIRA, 0.84, and rim area, 0.76. The AROC values (normal vs early CPACG eyes) were 0.75 for rim volume, 0.72 for VIRA, and 0.66 for rim area. CONCLUSION: OCT may serve as a useful diagnostic modality in distinguishing a normal optic disc from a glaucomatous one, even in the early stages of glaucoma. Rim volume, VIRA and rim area can be used to differentiate normal from early glaucoma (both early POAG and CPACG), and most efficiently early POAG eyes. CPACG eyes have smaller discs, a smaller cup, smaller cup/disc ratio, and a larger rim area when compared with eyes with POAG.     

Vessel density in OCT angiography permits differentiation between normal and glaucomatous optic nerve heads

AIM: To evaluate whether optical coherence tomography angiography (OCTA) can detect altered vessel density (VD) at the optic nerve head (ONH) in glaucoma patients. Special attention is paid to the accuracy of the OCTA technique for distinguishing healthy from glaucomatous eyes. METHODS: A total of 171 eyes were examined by the OCTA system AngioVue? (Optovue): 97 eyes diagnosed with glaucoma and 74 healthy control eyes. The papillary and peripapillary VD was measured. Furthermore, the VD was correlated with different structural and functional measurements. In order to test the accuracy of differentiation between eyes with and without glaucoma, we calculated the receiver operating characteristic curve (ROC) and the area under the curve (AUC). RESULTS: The papillary and peripapillary VD in glaucomatous eyes was significantly lower than in healthy eyes (P<0.05). The VD of the nasal peripapillary sector was significantly lower than in the other sectors. The further the disease had progressed [measured by determining the thickness of the ganglion cell complex (GCC) and the retinal nerve fiber layer (RNFL)] the greater the VD reduction. The AUC discriminated well between glaucomatous and normal eyes (consensus classifier 94.2%). CONCLUSION: OCTA allows non-invasive quantification of the peripapillary and papillary VD, which is significantly reduced in glaucomatous eyes and accurately distinguishes between healthy and diseased eyes. OCTA expands the spectrum of procedures for detecting and monitoring glaucoma.     

Expression of ephrinB1 and its receptor in glaucomatous optic neuropathy

OBJECTIVE: To determine ephrinB1, ephrinB2 and EphB1 expression in the optic nerve head (ONH) and retina of monkeys with glaucoma and in human ONH astrocytes. METHODS: Using immunohistochemistry, the localisation of ephrinB1, ephrinB2 and EphB1 was determined in the ONH and retina bilaterally in monkeys with monocular laser-induced glaucoma. RT-PCR, western blot and immunocytochemistry were used to study ephrinB1, ephrinB2 and EphB1 expression in cultured human ONH astrocytes from donors with and without glaucoma. RESULTS: There was an increase in ephrinB1 and EphB1 expression in mild to moderate glaucoma. In the ONH, both ephrinB1 and EphB1 were localised to astrocytes and EphB1 was also localised to lamina cribrosa cells and perivascular cells. In the retina, ephrinB1 localised to Muller cells and astrocytes, and EphB1 was found in retinal ganglion cells. In ONH astrocytes in humans with glaucoma, ephrinB1 and EphB1 were up-regulated but barely present in donors without glaucoma. CONCLUSIONS: Ephrins are activated in early and moderate glaucoma in the ONH and retina. We postulate that the up-regulation of Eph/ephrin pathway may play a protective role by limiting axonal damage and inflammatory cell invasion. Loss of ephrin signalling in advanced glaucoma may explain macrophage activation.     

Changes in optic nerve head circulation in response to vasoactive agents: intereye comparison in monkeys with experimental unilateral glaucoma

Purpose. To investigate circulatory changes in the optic nerve head (ONH) in response to vasoactive agents including calcium antagonists, a substrate of nitric oxide (NO), and an inhibitor of NO synthase (NOS) in monkeys with unilateral experimental glaucoma. Methods. Argon laser cautery to the trabecular meshwork was used to create experimental unilateral glaucoma in nine monkeys. The effects of systemic lomerizine or nilvadipine (calcium-antagonists), L-arginine (a substrate of NO), and NG-nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor) on the ONH tissue blood velocity (NB(ONH)) was studied by the laser speckle METHOD: Results. Lomerizine and nilvadipine significantly increased NB(ONH) in the untreated normal eyes (P = 0.039 and 0.008, respectively), while significant, less increases were found in the laser-treated experimental glaucomatous eyes with significant intereye differences (P = 0.036 and 0.011, respectively). L-arginine significantly increased NB(ONH) in both eyes without intereye difference (P = 0.71). L-NAME had no significant effects on NB(ONH) in the experimental glaucoma eyes; however, it produced a significant decrease in the nonlaser treated eyes (P = 0.036). Conclusions. In experimental glaucomatous eyes, the reactivity of ONH vessels to calcium antagonists was preserved, but was significantly reduced. The response to a NOS inhibitor was lost; however, reactivity to a substrate of NO was normal. These data indicate that in experimental glaucoma, vasodilator reactivity in the peripheral vasculature of the ONH is preserved, but functional alterations are likely to affect reactivity to the NO system. Japanese Abstract.     

正常眼与原发性开角型青光眼的OCT视盘参数分析的对比研究

目的使用OCT评估正常眼与原发性开角型青光眼(primary open angle glaucoma,POAG)视盘(opticnerve head,ONH)的差异。方法选择具有青光眼性视神经损害或RNFL缺损、相应的视野缺损的开角型青光眼60例(60只眼),另选择正常眼60例(60只眼)作为正常对照组。对二组患者进行详细的眼科检查,并使用光学相干断层扫描仪(optical coherence tomography,OCT)测定视盘形态。OCT检查采用视盘扫描模式,评估数据包括视盘面积、视杯面积、盘沿面积、垂直盘沿面积(vertical integrated rim area,VIRA)、水平盘沿容积、平均杯盘比、水平和垂直杯盘比以及视杯容积。比较二组视盘参数,并比较平均误差(mean deviation,MD)和校正模型标准变异(correc-ted pattern standard deviation CPSD)与青光眼组的视盘参数有无相关。结果原发性开角型青和正常组之间视盘参数的比较具有显著性差异。正常眼、POAG比较分别为:视盘面积(211 /-0.5,2.62 /-0.4)mm2,(P<0.01),视杯面积(0.65 /-0.5,1.79 /-0.6)mm2,(P<0.01),盘沿面积(1.44 /-0.4,0.89 /-0.4)mm2,(P<0.01),VIRA(1.53 /-0.4,1.11 /-0.3)mm2,(P<0.01),盘沿容积(0.42 /-0.1,0.26 /-0.1)mm3,(P<0.061),杯盘比(0.31 /-0.2,0.62 /-0.2),(P<0.01)。结论OCT在开角型青光眼的早期诊断中具有重要价值。     

Neuroprotective and anti-inflammatory effects of eicosane on glutamate and NMDA-induced retinal ganglion cell injury

AIM: To investigate the protective effects, antioxidant potential, and anti-inflammatory mechanisms of eicosane on glutamate-induced cell damage and on N-methyl-D-aspartate (NMDA)-induced retinal ganglion cell (RGC) injury in a mouse model of glaucoma. METHODS: The protective effects of eicosane on the rat R28 retinal precursor cell line were assessed using cell counting kit-8 assays and Hoechst-propidium iodide staining. Intracellular reactive oxygen species (ROS) production was measured using the fluorescent probe 2''-7''-dichlorofluorescin diacetate and flow cytometry. The protective role of eicosane on NMDA-induced RGC injury in a mouse glaucoma model was determined by immunostaining of frozen sections of retina. The effects of eicosane on the metabolome of the retina in mice with NMDA-induced RGC damage were evaluated by liquid chromatography-mass spectroscopy (LC-MS) and untargeted metabolomics analyses. RESULTS: Eicosane treatment significantly attenuated glutamate-induced damage to R28 cells in vitro. Eicosane also protected RGCs against NMDA-induced injury in a mouse glaucoma model. Untargeted metabolomics analyses showed that eicosane increased multiple metabolites, including L-arginine and L-carnitine, in the retina. CONCLUSION: Eicosane has protective effects, antioxidant potential, and anti-inflammatory properties in an in vitro model of glutamate-induced cell damage and in an in vivo model of NMDA-induced RGC injury in mouse glaucoma through modulation of L-arginine and/or L-carnitine metabolism.     

Expression of myocilin/TIGR in normal and glaucomatous primate optic nerves

Myocilin/TIGR was the first molecule discovered to be linked with primary open angle glaucoma (POAG), a blinding disease characterized by progressive loss of retinal ganglion cells. Mutations in myocilin/TIGR have been associated with age of disease onset and severity. The function of myocilin/TIGR and its role in glaucoma is unknown. Myocilin/TIGR has been studied in the trabecular meshwork to determine a role in regulation of intraocular pressure. The site of damage to the axons of the retinal ganglion cells is the optic nerve head (ONH). The myocilin/TIGR expression was examined in fetal through adult human optic nerve as well as in POAG. Myocilin/TIGR was expressed in the myelinated optic nerve of children and normal adults but not in the fetal optic nerve before myelination. Also examined was the expression in monkeys with experimental glaucoma. The results demonstrate that optic nerve head astrocytes constitutively express myocilin/TIGR in vivo in primates. Nevertheless, myocilin/TIGR is apparently reduced in glaucomatous ONH. The colocalization of myocilin/TIGR to the myelin suggests a role of myocilin/TIGR in the myelinated optic nerve.     

Morphological and functional differences between normal‐tension and high‐tension glaucoma

Purpose: To compare visual field (VF) and nerve fibre loss in patients with normal‐tension (NTG) and high‐tension glaucoma (HTG) at an equal level of glaucomatous structural damage of the optic nerve head (ONH). Methods: In a retrospective, pair‐matched, comparative study, 126 eyes with NTG and 126 eyes with HTG were matched according to the same glaucomatous ONH damage based on rim volume, rim area and disc size measured by the Heidelberg Retina Tomograph (HRT III). Visual field by Humphrey perimetry and nerve fibre layer thickness measured by scanning laser polarimetry (GdxVCC) were compared between both groups. Results: Based on the HRT, NTG and HTG displayed comparable structural damage of the ONH without a statistically significant difference between both groups (mean, NTG/HTG: disc area 2.32/2.32 mm², p =0.342; rim area 1.03/1.00 mm², p = 0.279; rim volume 0.2/0.19 mm³; p = 0.274). Eyes with NTG had significantly less VF damage than eyes with HTG (mean, NTG/HTG: mean deviation (MD) ?3.69/?9.77 dB, p = 0.0001; pattern standard deviation (PSD) 4.80/7.17 dB, p = 0.0001). The nerve fibre layer of NTG patients was thicker than that of HTG patients (mean, NTG/HTG: GDx total: 46.9/44.0 μm, p = 0.073; GDx superior: 57.2/49.9 μm, p = 0.0001; GDx inferior: 54.9/49.7 μm, p = 0.001). Conclusions: At an equal level of glaucomatous structural damage of the ONH indicated by cupping, rim area and rim volume, NTG patients seem to have a less affected visual field and a better preserved nerve fibre layer than HTG patients.     

Blood flow of the optic nerve head and peripapillary retina in exfoliation syndrome with unilateral glaucoma or ocular hypertension

BACKGROUND: The purpose was to study whether any differences exist in the optic nerve head (ONH) and peripapillary retinal blood flow between the two eyes of patients with unilateral exfoliation glaucoma or ocular hypertension (OHT) with exfoliation syndrome. METHODS: This cross-sectional study included 50 patients. All had exfoliation syndrome with glaucoma or OHT in one eye, and these eyes comprised the study group. The fellow eyes, all normotensive, comprised the control group. Blood flow was measured with scanning laser Doppler flowmetry in the lamina cribrosa region, in the rim area, and on the peripapillary retina. Multiple linear regression analyses were used to identify any associations between different factors and differences in flow. RESULTS: Flow in the rim area was significantly higher in the study eyes than in the control eyes, with a mean difference of 172 arbitrary units (P = 0.001). The difference of 40 units in the laminar area was of borderline significance (P = 0.065) and no significant difference was found in the peripapillary retina (P = 0.530). In the study eyes, blood flow of the ONH lamina and rim area decreased with increasing glaucomatous damage, and treatment with topical timolol was associated with reduced blood flow in the lamina cribrosa and rim area. Perfusion pressure was associated only with flow in the peripapillary area (P = 0.021). CONCLUSIONS: Advanced glaucomatous damage was associated with reduced flow both in the lamina cribrosa and the rim area but not in the peripapillary retina. Treatment with topical timolol was associated with decreased flow in the ONH.