Important Risk Factor For Glaucoma Research Articles

Retinal Neurodegeneration in an Intraocular Pressure Fluctuation Rat Model.

Increased intraocular pressure (IOP) is the most important risk factor for glaucoma. The role of IOP fluctuation, independently from elevated IOP, has not yet been confirmed in glaucoma. We investigated the effects of IOP fluctuation itself on retinal neurodegeneration. Male rats were treated with IOP-lowering eyedrops (brinzolamide and latanoprost) on Mondays and Thursdays (in the irregular instillation group) or daily (in the regular instillation group), and saline was administered daily in the normal control group for 8 weeks. The IOP standard deviation was higher in the irregular instillation group than the regular instillation group or the control group. The degree of oxidative stress, which was analyzed by labeling superoxide, oxidative DNA damage, and nitrotyrosine, was increased in the irregular instillation group. Macroglial activation, expressed by glial fibrillary acidic protein in the optic nerve head and retina, was observed with the irregular instillation of IOP-lowering eyedrops. Microglial activation, as indicated by Iba-1, and the expression of TNF-α did not show a significant difference between the irregular instillation and control groups. Expression of cleaved caspase-3 was upregulated and the number of retinal ganglion cells (RGCs) was decreased in the irregular instillation group. Our findings indicate that IOP fluctuations could be induced by irregular instillation of IOP-lowering eyedrops and this could lead to the degeneration of RGCs, probably through increased oxidative stress and macrogliosis.

Connective tissue growth factor: Role in trabecular meshwork remodeling and intraocular pressure lowering.

Connective tissue growth factor (CTGF) is a distinct signaling molecule modulating many physiological and pathophysiological processes. This protein is upregulated in numerous fibrotic diseases that involve extracellular matrix (ECM) remodeling. It mediates the downstream effects of transforming growth factor beta (TGF-β) and is regulated via TGF-β SMAD-dependent and SMAD-independent signaling routes. Targeting CTGF instead of its upstream regulator TGF-β avoids the consequences of interfering with the pleotropic effects of TGF-β. Both CTGF and its upstream mediator, TGF-β, have been linked with the pathophysiology of glaucomatous optic neuropathy due to their involvement in the regulation of ECM homeostasis. The excessive expression of these growth factors is associated with glaucoma pathogenesis via elevation of the intraocular pressure (IOP), the most important risk factor for glaucoma. The raised in the IOP is due to dysregulation of ECM turnover resulting in excessive ECM deposition at the site of aqueous humor outflow. It is therefore believed that CTGF could be a potential therapeutic target in glaucoma therapy. This review highlights the CTGF biology and structure, its regulation and signaling, its association with the pathophysiology of glaucoma, and its potential role as a therapeutic target in glaucoma management.

Pathologically high intraocular pressure induces mitochondrial dysfunction through Drp1 and leads to retinal ganglion cell PANoptosis in glaucoma

Glaucoma is a common neurodegenerative disease characterized by progressive retinal ganglion cell (RGC) loss and visual field defects. Pathologically high intraocular pressure (ph-IOP) is an important risk factor for glaucoma, and it triggers molecularly distinct cascades that control RGC death and axonal degeneration. Dynamin-related protein 1 (Drp1)-mediated abnormalities in mitochondrial dynamics are involved in glaucoma pathogenesis; however, little is known about the precise pathways that regulate RGC injury and death. Here, we aimed to investigate the role of the ERK1/2-Drp1-reactive oxygen species (ROS) axis in RGC death and the relationship between Drp1-mediated mitochondrial dynamics and PANoptosis in ph-IOP injury. Our results suggest that inhibiting the ERK1/2-Drp1-ROS pathway is a potential therapeutic strategy for treating ph-IOP-induced injuries. Furthermore, inhibiting Drp1 can regulate RGC PANoptosis by modulating caspase3-dependent, nucleotide-binding oligomerization domain-like receptor-containing pyrin domain 3(NLRP3)-dependent, and receptor-interacting protein (RIP)-dependent pathways in the ph-IOP model. Overall, our findings provide new insights into possible protective interventions that could regulate mitochondrial dynamics to improve RGC survival.

Retinal microglia and aging: Changes in the healthy and experimental glaucoma mouse model

AbstractGlaucoma is an age‐related neurodegenerative pathology, characterized by retinal ganglion cells (RGCs) death, which leads to irreversible blindness. Clinical studies have shown that one of the risk factors for glaucoma is high intraocular pressure (IOP). The only therapeutic strategy currently used in this pathology is the reduction of IOP, which does not always reverse neurodegeneration and stop the progression of the disease. However, there is another more important risk factor for glaucoma than IOP, which is aging. It has been observed that aging can increase the vulnerability of the central nervous system to damage. Changes that occur with aging can make RGCs more vulnerable to damage in the glaucomatous neurodegeneration process. The effects of oxidative stress and chronic exposure to light and inflammation mainly cause alterations in the retina due to aging.In glaucomatous neurodegeneration, as in most neurodegenerative diseases, the immune system is involved. Glial cells are immune cells of the retina and optic nerve. When damage occurs, these cells respond quickly, becoming activated, to help restore tissue homeostasis and ensure the immune privilege of nerve tissue. In addition, with aging, a state of chronic parainflammation occurs, leading to the activation of the microglia and release of cytotoxic factors, such as TNF‐α, nitric oxide and other molecules, that which could significantly exacerbate glaucomatous neurodegeneration.One of the main models for raising IOP is the unilateral model of laser‐induced ocular hypertension (OHT). Studies have analysed RGC death and the neuroinflammatory process (focusing on glial cell changes) in this unilateral laser‐induced OHT model in young adult mice. Considering that glaucoma is an age‐related pathology, and that age is the main risk factor, aged in these studies should have been considered a determinate factor.We have used 15‐month‐old mice, which is the beginning point of the aging process of the mice, which is well established from 18 months. In this study, we found morphological signs of microglial activation and changes in the expression of MHCII, CD68 and P2RY12 in the naïve eyes of 15‐month‐old mice (early stage of aging), compared to young naïve adults.On this study we have also analysed the microglial behaviour in response to an increase in IOP in 15‐month‐old mice in a unilateral laser‐induced OHT mouse model of both OHT and contralateral eyes. We also found microglial morphologic alterations and changes in the expression of MHCII, CD68 and P2RY12 in the eyes of 15‐month‐old OHT mice and in the eyes contralateral to them, compared to the eyes of young adult OHT mice and the eyes contralateral to them.In neurodegenerative diseases associated with aging, such as glaucoma, the neuroinflammatory mechanisms induced by microglial cells have an important implication in the development of disease. The use of aging models to analyses the age‐related retinal pathologies could help to improve our understanding of the progression of these pathologies.

Association between sodium glucose co-transporter 2 inhibitors and incident glaucoma in patients with type 2 diabetes: A multi-institutional cohort study in Taiwan

PurposeType 2 diabetes (T2D) is an important risk factor for glaucoma, and sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to protect the optic nerves. We therefore aimed to evaluate the association between SGLT2 inhibitors and incident glaucoma. MethodsThis retrospective cohort study analyzed the largest multi-institutional electronic medical records database in Taiwan, containing data of over a million individuals. We included T2D patients newly prescribed SGLT2 inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1 RAs) from 2016 to 2018. Our primary outcome was incident glaucoma diagnosis between initiation of SGLT2 inhibitors or GLP-1 RAs, and 31st March 2021. After applying inverse probability of treatment weighting (IPTW) to increase homogeneity between the two treatment groups, we estimated hazard ratios (HR) with 95% confidence intervals (CI) for the risk of glaucoma, based on Cox proportional hazards regression models. ResultsWe included 9,927 and 1,065 T2D patients who had been newly prescribed SGLT2 inhibitors or GLP-1 RAs, respectively. Lower risk of incident glaucoma was observed in patients receiving SGLT2 inhibitors (7.9 events per 1,000 person-years), compared to those receiving GLP-1 RAs (10.0 events per 1,000 person-years), with an HR of 0.81 (95% CI: 0.69–0.95). Multiple sensitivity analyses and a negative control outcome analysis confirmed the robustness of our main findings. ConclusionThis study suggests that T2D patients newly prescribed SGLT2 inhibitors have a reduced risk of incident glaucoma, compared to those prescribed GLP-1 RAs, in clinical practice. Future prospective studies are suggested to confirm this association.

Wearable electronic devices for glaucoma monitoring and therapy

Glaucoma is a leading cause of irreversible blindness worldwide, which is estimated to affect approximately 112 million people by 2040. Elevated intraocular pressure (IOP) is the most important risk factor for glaucoma, as well as the primary target for the treatment. Current therapies aim at IOP reduction to prevent the disease progression. The accurate and real-time measurement of IOP is therefore critical to evaluate treatment response and guide medical decisions. However, IOP fluctuates throughout the 24-hour cycle with different patterns from day to day in the same individual and also different patterns among individuals. The current clinical practice typically captures a single IOP measurement during “in-office hours”, and this is insufficient for disease monitoring. With the development of wearable electronic devices, a variety of IOP monitoring devices provide a unique potential for continuous IOP monitoring. In addition to IOP monitoring for glaucoma management, this mini-review also summarizes novel drug delivery devices for treating glaucoma. Because certain types of glaucoma do not show elevated IOP, we also discuss the potential to incorporate biomarker detection with IOP measurement for more accurate and reliable glaucoma diagnostics and therapies.

Targeting the vascular-specific phosphatase PTPRB protects against retinal ganglion cell loss in a pre-clinical model of glaucoma.

Elevated intraocular pressure (IOP) due to insufficient aqueous humor outflow through the trabecular meshwork and Schlemm's canal (SC) is the most important risk factor for glaucoma, a leading cause of blindness worldwide. We previously reported loss of function mutations in the receptor tyrosine kinase TEK or its ligand ANGPT1 cause primary congenital glaucoma in humans and mice due to failure of SC development. Here, we describe a novel approach to enhance canal formation in these animals by deleting a single allele of the gene encoding the phosphatase PTPRB during development. Compared to Tek haploinsufficient mice, which exhibit elevated IOP and loss of retinal ganglion cells, Tek+/-;Ptprb+/- mice have elevated TEK phosphorylation, which allows normal SC development and prevents ocular hypertension and RGC loss. These studies provide evidence that PTPRB is an important regulator of TEK signaling in the aqueous humor outflow pathway and identify a new therapeutic target for treatment of glaucoma.

DDIT3 (CHOP) contributes to retinal ganglion cell somal loss but not axonal degeneration in DBA/2J mice

Glaucoma is an age-related neurodegenerative disease characterized by the progressive loss of retinal ganglion cells (RGCs). Chronic ocular hypertension, an important risk factor for glaucoma, leads to RGC axonal injury at the optic nerve head. This insult triggers molecularly distinct cascades governing RGC somal apoptosis and axonal degeneration. The molecular mechanisms activated by ocular hypertensive insult that drive both RGC somal apoptosis and axonal degeneration are incompletely understood. The cellular response to endoplasmic reticulum stress and induction of pro-apoptotic DNA damage inducible transcript 3 (DDIT3, also known as CHOP) have been implicated as drivers of neurodegeneration in many disease models, including glaucoma. RGCs express DDIT3 after glaucoma-relevant insults, and importantly, DDIT3 has been shown to contribute to both RGC somal apoptosis and axonal degeneration after acute induction of ocular hypertension. However, the role of DDIT3 in RGC somal and axonal degeneration has not been critically tested in a model of age-related chronic ocular hypertension. Here, we investigated the role of DDIT3 in glaucomatous RGC death using an age-related, naturally occurring ocular hypertensive mouse model of glaucoma, DBA/2J mice (D2). To accomplish this, a null allele of Ddit3 was backcrossed onto the D2 background. Homozygous Ddit3 deletion did not alter gross retinal or optic nerve head morphology, nor did it change the ocular hypertensive profile of D2 mice. In D2 mice, Ddit3 deletion conferred mild protection to RGC somas, but did not significantly prevent RGC axonal degeneration. Together, these data suggest that DDIT3 plays a minor role in perpetuating RGC somal apoptosis caused by chronic ocular hypertension-induced axonal injury, but does not significantly contribute to distal axonal degeneration.

Monitoring retinal responses to acute intraocular pressure elevation in rats with visible light optical coherence tomography.

Elevated intraocular pressure (IOP) is an important risk factor for glaucoma. However, the role of IOP in glaucoma progression, as well as retinal physiology in general, remains incompletely understood. We demonstrate the use of visible light optical coherence tomography to measure retinal responses to acute IOP elevation in Brown Norway rats. We monitored retinal responses in reflectivity, angiography, blood flow, oxygen saturation ( ), and oxygen metabolism over a range of IOP from 10 to 100mmHg. As IOP was elevated, nerve fiber layer reflectivity was found to decrease. Vascular perfusion in the three retinal capillary plexuses remained steady until IOP exceeded 70mmHg and arterial flow was noted to reverse periodically at high IOPs. However, a significant drop in total retinal blood flow was observed first at 40mmHg. As IOP increased, the venous demonstrated a gradual decrease despite steady arterial , which is consistent with increased arterial-venous oxygen extraction across the retinal capillary beds. Calculated total retinal oxygen metabolism was steady, reflecting balanced responses of blood flow and oxygen extraction, until IOP exceeded 40mmHg, and fell to 0 at 70 and 80mmHg. Above this, measurements were unattainable. All measurements reverted to baseline when the IOP was returned to 10mmHg, indicating good recovery following acute pressure challenge. These results demonstrate the ability of this system to monitor retinal oxygen metabolism noninvasively and how it can help us understand retinal responses to elevated IOP.

Polygenic Risk Score Is Associated With Intraocular Pressure and Improves Glaucoma Prediction in the UK Biobank Cohort.

PurposeElevated intraocular pressure (IOP) is an important risk factor for glaucoma. We constructed polygenic risk scores (PRSs) for IOP using the UK Biobank (UKB) data set to test whether the PRSs are associated with IOP and whether using them improves glaucoma prediction.MethodsWe conducted this study using 435,678 European participants from the UKB. We constructed weighted and unweighted PRSs using single nucleotide polymorphisms (SNPs) derived from the UKB data and previously reported IOP SNPs. We examined the associations of the PRSs with IOP and primary open-angle glaucoma (POAG) using linear and logistic regression, respectively. To quantify the discriminatory ability of the PRSs on POAG, we used the area under the receiver operating characteristic curve (AUC).ResultsThe weighted PRS was significantly associated with IOP (P ∼ 10−200), after adjusting for age and sex. The PRS explained an additional 4% of variance in IOP. The weighted PRS was also significantly associated with POAG (P = 1.8 × 10−77). Subjects in the top quintile of the IOP PRS were 6.34 (95% confidence interval [CI]: 4.82–8.33; P = 2.1 × 10−57) times more likely to have POAG, compared to those in the bottom category. The weighted PRS improved the discriminatory power for POAG (AUC increased by 5%, P = 6.2 × 10−22) when added to the other covariates. The unweighted PRS exhibited similar results.ConclusionsWe determined that IOP PRSs are significantly associated with IOP and improve the prediction of POAG.Translational RelevancePRSs help reduce the burden of glaucoma by early detection of genetically susceptible individuals.

Ascorbic acid metabolites are involved in intraocular pressure control in the general population

Elevated intraocular pressure (IOP) is an important risk factor for glaucoma. Mechanisms involved in its homeostasis are not well understood, but associations between metabolic factors and IOP have been reported. To investigate the relationship between levels of circulating metabolites and IOP, we performed a metabolome-wide association using a machine learning algorithm, and then employing Mendelian Randomization models to further explore the strength and directionality of effect of the metabolites on IOP. We show that O-methylascorbate, a circulating Vitamin C metabolite, has a significant IOP-lowering effect, consistent with previous knowledge of the anti-hypertensive and anti-oxidative role of ascorbate compounds. These results enhance understanding of IOP control and may potentially benefit future IOP treatment and reduce vision loss from glaucoma.

Glaucoma and Alzheimer Disease: One Age-Related Neurodegenerative Disease of the Brain.

Background: Open Angle Glaucoma (POAG) is the leading causes of irreversible blindness worldwide. Elevated intraocular pressure is considered an important risk factor for glaucoma; however, a subset of patients experiences a progression of the disease even in presence of normal intraocular pressure values. This implies that risk factors other than intraocular pressure are involved in the pathogenesis of glaucoma. A possible relationship between glaucoma and neurodegenerative diseases such as Alzheimer Disease has been suggested. In this regard, we recently described a high prevalence of alterations typical of glaucoma, using Heidelberg Retinal Tomograph-3, in a group of patients with Alzheimer Disease. Interestingly, these alterations were not associated with elevated intraocular pressure or abnormal Central Corneal Thickness values. Alzheimer Disease is the most common form of dementia with progressive deterioration of memory and cognition. Complaints related to vision are common among Alzheimer Disease patients.Methods: In this paper researches related to glaucoma and Alzheimer disease are reviewed.Results: Diseases characteristics, i.e. common features, risk factors and pathophysiological mechanisms gathered in the recent literature do suggest that Alzheimer Disease and glaucoma can be considered both age-related neurodegenerative diseases that may co-exist in the elderly.Conclusion: In conclusion, preclinical and clinical evidence gathered so far support the notion that glaucoma is a widespread neurodegenerative condition whose common pathogenetic mechanisms with other diseases, i.e. Alzheimer Disease, should be further investigated as they may shed new light on these diseases improving both diagnosis and treatments.

Purinergic dysregulation causes hypertensive glaucoma-like optic neuropathy.

Glaucoma is an optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs) and visual loss. Although one of the highest risk factors for glaucoma is elevated intraocular pressure (IOP) and reduction in IOP is the only proven treatment, the mechanism of IOP regulation is poorly understood. We report that the P2Y6 receptor is critical for lowering IOP and that ablation of the P2Y6 gene in mice (P2Y6KO) results in hypertensive glaucoma-like optic neuropathy. Topically applied uridine diphosphate, an endogenous selective agonist for the P2Y6 receptor, decreases IOP. The P2Y6 receptor was expressed in nonpigmented epithelial cells of the ciliary body and controlled aqueous humor dynamics. P2Y6KO mice exhibited sustained elevation of IOP, age-dependent damage to the optic nerve, thinning of ganglion cell plus inner plexiform layers, and a reduction of RGC numbers. These changes in P2Y6KO mice were attenuated by an IOP lowering agent. Consistent with RGC damage, visual functions were impaired in middle-aged P2Y6KO mice. We also found that expression and function of P2Y6 receptors in WT mice were significantly reduced by aging, another important risk factor for glaucoma. In summary, our data show that dysfunctional purinergic signaling causes IOP dysregulation, resulting in glaucomatous optic neuropathy.

α-Aminoadipic acid protects against retinal disruption through attenuating Müller cell gliosis in a rat model of acute ocular hypertension.

ObjectiveOcular hypertension is an important risk factor for glaucoma. The purpose of this study was to investigate the gliotoxic effects of α-aminoadipic acid (AAA) in a rat model of AOH and its underlying mechanisms.Materials and methodsIn the rat model of acute ocular hypertension (AOH), intraocular pressure was increased to 110 mmHg for 60 minutes. Animals were divided into four groups: sham operation (Ctrl), AOH, AOH + phosphate-buffered saline (PBS), and AOH + AAA. Cell apoptosis in the ganglion cell layer was detected with the terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling (TUNEL) assay, and retinal ganglion cells (RGCs) immunostained with Thy-1 were counted. Müller cell activation was detected using immunostaining with glutamine synthetase and glial fibrillary acidic protein. Tumor necrosis factor-α (TNF-α) was examined using Western blot.ResultsIn the rat model of AOH, cell apoptosis was induced in the ganglion cell layer and the number of RGCs was decreased. Müller cell gliosis in the retinas of rats was induced, and retinal protein levels of TNF-α were increased. Intravitreal treatment of AAA versus PBS control attenuated these retinal abnormalities to show protective effects in the rat model of AOH.ConclusionIn the retinas of the rat model of AOH, AAA treatment attenuated retinal apoptosis in the ganglion cell layer and preserved the number of RGCs, likely through the attenuation of Müller cell gliosis and suppression of TNF-α induction. Our observations suggest that AAA might be a potential therapeutic target in glaucoma.

Association of clusterin (CLU) variants and exfoliation syndrome: An analysis in two Caucasian studies and a meta-analysis

Exfoliation syndrome (XFS) is an important risk factor for glaucoma (XFG) worldwide. LOXL1 variants are highly associated with XFS in most populations; however, the high frequency of risk alleles in normal individuals and the reversal of risk alleles in different ethnic populations suggest that other factors contribute to XFS pathogenesis. Clusterin (CLU) is an extracellular matrix chaperone that prevents protein aggregation and is highly expressed in ocular tissues affected by XFS. Studies examining common CLU variants for association with XFS have been inconsistent. The purpose of this study was to evaluate CLU variants for association with XFS in two independent datasets from the United States (222 cases and 344 controls) and Israel (92 cases and 102 controls). Seven tag SNPs that captured >95% of alleles at r2 greater than 0.8 across the CLU genomic region were genotyped using TaqMan assays. Genotypes for an additional SNP, rs2279590, were imputed using phased haplotypes of HapMap reference CEU samples. Of the 8 CLU SNPs selected for the study, none were significantly associated with XFS in either case–control group (age and sex adjusted P > 0.14 and 0.36, respectively, in the US and Israeli datasets), or when they were meta-analyzed together (age and sex adjusted P > 0.13). Haplotype analysis using all 8 SNPs or only the promoter region SNPs also did not show significant associations of CLU with XFS in the combined US and Israeli dataset (P > 0.28). Meta-analysis of the data from this study and previous studies in Caucasian populations (1184 cases and 978 controls) resulted in statistically significant association of rs2279590 with XFS (summary OR = 1.18, 95% CI: 1.03–1.33, P = 0.01). Significant association between rs2279590 and XFS was also found in Indian populations (summary OR = 0.76, 95% CI: 0.61–0.96; P = 0.02); however, significant heterogeneity between the Caucasian and Indian populations possibly due to reversal of the risk allele precluded an overall meta-analysis for rs2279590 (Q = 0.001, I2 = 91%). No significant association was identified for rs3087554 in either Caucasian populations (summary OR = 0.90, 95% CI: 0.77–1.05, P = 0.17) or Indian populations (summary OR = 0.89, 95% CI: 0.72–1.10, P = 0.28), or in both populations combined (1705 cases and 3713 controls; summary OR = 0.90, 95% CI: 0.79–1.01, P = 0.08). Significant heterogeneity precluded the addition of the Japanese data to the meta-analysis for rs3087554 (Q = 0.006, I2 = 87%). Our results suggest that common CLU variants may contribute to modest XFS risk but even larger datasets are required to confirm these findings.

Vascular optic neuropathies versus glaucomatous optic neuropathy

AbstractGlaucoma is a group of progressive optic neuropathies characterized by excavation of the optic nerve head and associated visual field changes. Elevated intraocular pressure (IOP) is the most important risk factor for glaucoma. The pathophysiology of glaucoma is not well understood, but mechanical compression of the optic nerve head (ONH) appears to play a role. Anterior ischemic optic neuropathy (AION) is the second most common cause of optic nerve‐related loss of vision and comprises non‐arteritic AION (NAION) and arteritic AION (AAION). Factors that help in separating AION cases from glaucoma cases are: IOP is typically in the normal range or reduced, ONH cupping does not involve the peripapillary zones, visual field loss usually occurs in the central or cecocentral visual field and disk pallor. Whereas AION is ischemic in nature, the vascular involvement in glaucoma is still a matter of debate. The difference in appearance of the two diseases does, however, not argue against the vascular component in glaucoma.

Selected autoantibodies and normal-tension glaucoma.

BackgroundAlthough intraocular pressure is an important risk factor in glaucoma, there is growing body evidence indicating an immunological component in the pathogenesis of normal-tension glaucoma (NTG). The aim of this study was to determine if NTG coexists with elevated levels of autoantibodies detected in rheumatic diseases.Material/MethodsWe enrolled 105 patients into the study: 35 with NTG, 34 with primary open-angle glaucoma (POAG), and 36 controls. All patients underwent ophthalmic examination and blood tests. Blood was examined for the level of: antibodies against antinuclear antibodies (ANA), antibodies to extractable nuclear antigens (ENA), immunoglobulins (IgG, IgA, IgM), rheumatoid factor, anti-citrullinated protein antibodies (ACPA), and antiphospholipid antibodies (anticardiolipin antibodies, beta2-glycoprotein I antibodies, antiprothrombin antibodies).ResultsThe level of ANA was increased among 6 patients in the NTG group (17.1%), 8 in the POAG group (23.5%), and 6 in the control group (16.5%). The difference was not statistically significant (p=0.97). None of the patients in the NTG, POAG, or control group had positive antibodies to ENA. The level of immunoglobulins IgG, IgM, and IgA in the 3 groups was similar and within normal values. The median level of rheumatoid factor and ACPA was the highest in the NTG group, but it was within normal laboratory values. There was a statistically significant difference between antiprothrombin antibodies IgG between the NTG and POAG group (p=0.01), but not between the NTG and control group (p=0.24).ConclusionsThe results of our study do not confirm the hypothesis that NTG coexists with elevated blood levels of antibodies, which are a characteristic feature of rheumatic diseases.

Anatomical and functional damage in experimental glaucoma

Glaucoma is a progressive neurodegenerative disease caused by retinal ganglion cell (RGC) loss. One important risk factor for glaucoma is elevated intraocular pressure and thus many animal models are based on spontaneous or induced ocular hypertension (OHT). Using these models it has been shown that RGCs initially suffer an impairment of the active axonal transport that progresses to a lack of passive diffusion along the axon. This axonal damage eventually causes the death of the parent RGCs in pie-shaped sectors of the retina, but there is also diffuse RGC loss, without involving displaced amacrine cells. Recent data show that OHT results in a protracted insult to the inner and outer retina that causes functional alterations and ultimately, degeneration and death of cones.

Under Pressure: Cellular and Molecular Responses During Glaucoma, a Common Neurodegeneration with Axonopathy

Glaucoma is a complex neurodegenerative disorder that is expected to affect 80 million people by the end of this decade. Retinal ganglion cells (RGCs) are the most affected cell type and progressively degenerate over the course of the disease. RGC axons exit the eye and enter the optic nerve by passing through the optic nerve head (ONH). The ONH is an important site of initial damage in glaucoma. Higher intraocular pressure (IOP) is an important risk factor for glaucoma, but the molecular links between elevated IOP and axon damage in the ONH are poorly defined. In this review and focusing primarily on the ONH, we discuss recent studies that have contributed to understanding the etiology and pathogenesis of glaucoma. We also identify areas that require further investigation and focus on mechanisms identified in other neurodegenerations that may contribute to RGC dysfunction and demise in glaucoma.

Metabolism of Ophthalmic Timolol: New Aspects of an Old Drug

Glaucoma is a common eye disease that can cause irreversible blindness if not diagnosed and treated in the early stages of progression. This disease is often, albeit not always, associated with increased intraocular pressure, which is also the most important risk factor for glaucoma. Currently, the only treatment option of glaucoma is reduction of intraocular pressure. A β-adrenergic antagonist, timolol, has been used for the treatment of glaucoma and increased intraocular pressure for more than 30 years and still remains the drug of choice. Locally, timolol is well tolerated. However, it has been reported that approximately 80% of a topically administered eye drop is systemically absorbed. Thus, ophthalmic timolol may cause severe adverse cardiovascular and respiratory effects. On the basis of the aforementioned situation, it is somewhat surprising to notice that the metabolism of timolol has only recently been studied in detail even though the drug has been used for decades. Earlier clinical studies have suggested that timolol is metabolized by CYP2D6, an important member of the cytochrome P450 family. Our recent in vitro studies demonstrated convincingly that CYP2D6 is the main enzyme contributing to timolol metabolism, although also CYP2C19 may have a minor role. Liver is the principal site of timolol metabolism, because - according to our recent findings - only negligible amounts of CYP2D6 are expressed in human ocular tissues. After topical administration, systemic timolol concentrations may be high enough to cause cardiovascular and respiratory adverse effects especially in patients who are CYP2D6 poor metabolizers or use concomitant CYP2D6 inhibitors.