Therapeutic Targets For Glaucoma Research Articles

The Application of MicroRNAs in Glaucoma Research: A Bibliometric and Visualized Analysis.

Glaucoma is similar to a neurodegenerative disorder and leads to global irreversible loss of vision. Despite extensive research, the pathophysiological mechanisms of glaucoma remain unclear, and no complete cure has yet been identified for glaucoma. Recent studies have shown that microRNAs can serve as diagnostic biomarkers or therapeutic targets for glaucoma; however, there are few bibliometric studies that focus on using microRNAs in glaucoma research. Here, we have adopted a bibliometric analysis in the field of microRNAs in glaucoma research to manifest the current tendencies and research hotspots and to present a visual map of the past and emerging tendencies in this field. In this study, we retrieved publications in the Web of Science database that centered on this field between 2007 and 2022. Next, we used VOSviewer, CiteSpace, Scimago Graphica, and Microsoft Excel to present visual representations of a co-occurrence analysis, co-citation analysis, tendencies, hotspots, and the contributions of authors, institutions, journals, and countries/regions. The United States was the main contributor. Investigative Ophthalmology and Visual Science has published the most articles in this field. Over the past 15 years, there has been exponential growth in the number of publications and citations in this field across various countries, organizations, and authors. Thus, this study illustrates the current trends, hotspots, and emerging frontiers and provides new insight and guidance for searching for new diagnostic biomarkers and clinical trials for glaucoma in the future. Furthermore, international collaborations can also be used to broaden and deepen the field of microRNAs in glaucoma research.

Differentially expressed circRNAs in peripheral blood samples as potential biomarkers and therapeutic targets for acute angle-closure glaucoma

Glaucoma is the leading cause of irreversible blindness globally. Circular RNAs (circRNAs) play vital roles in various biological processes as microRNA (miRNA) sponges and, thus, have been investigated as potential biomarkers and therapeutic targets in numerous human diseases. However, the underlying mechanisms of circRNAs in the pathogenesis of glaucoma remain unclear. Therefore, transcriptome sequencing was performed to identify relevant circRNAs in peripheral blood samples from patients with primary angle-closure glaucoma. Bioinformatics analysis was performed to investigate the potential roles of differentially expressed circRNAs (DEcircRNAs) in the pathogenesis of glaucoma. In total, 481 differentially expressed genes in addition to 345 DEcircRNAs were identified in patients with glaucoma. Based on a public database, targeted gene analysis identified 11 DEcircRNAs that potentially regulate the expression of five genes as miRNA sponges in glaucoma. In addition, quantitative reverse transcription PCR analysis verified that expression of the circRNA hsa-circ-0000745 was positively correlated with the expression of NEAT1 as a potential target gene. These results suggest that DEcircRNAs are involved in a gene expression regulatory network related to immune cell function and progression of glaucoma. Thus, DEcircRNAs in peripheral blood are potential biomarkers and therapeutic targets for glaucoma.

Identification of hub genes for glaucoma: a study based on bioinformatics analysis and experimental verification.

To explore hub genes for glaucoma based on bioinformatics analysis and an experimental model verification. In the Gene Expression Omnibus (GEO) database, the GSE25812 and GSE26299 datasets were selected to analyze differentially expressed genes (DEGs) by the GEO2R tool. Through bioinformatics analysis, 9 hub genes were identified. Receiver operating characteristic (ROC) curves and principal component analysis (PCA) were performed to verify whether the hub gene can distinguish glaucoma from normal eyes. The mouse model of glaucoma was constructed, and the real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) assay was performed to detect the expression levels of hub genes in glaucoma. There were 128 overlapping DEGs in the GSE25812 and GSE26299 datasets, mainly involved in intracellular signalling, cell adhesion molecules and the Ras signalling pathway. A total of 9 hub genes were screened out, including GNAL, BGN, ETS2, FCGP4, MAPK10, MMP15, STAT1, TSPAN8, and VCAM1. The area under the curve (AUC) values of 9 hub genes were greater than 0.8. The PC1 axle could provide a 70.5% interpretation rate to distinguish glaucoma from normal eyes. In the ocular tissues of glaucoma in the mice model, the expression of BGN, ETS2, FCGR4, STAT1, TSPAN8, and VCAM1 was increased, while the expression of GNAL, MAPK10, and MMP15 was decreased. Nine hub genes in glaucoma are identified, which may provide new biomarkers and therapeutic targets for glaucoma.

TrkB Receptor Agonist 7,8 Dihydroxyflavone is Protective Against the Inner Retinal Deficits Induced by Experimental Glaucoma

Glaucoma is an age-related neurodegenerative disorder characterized by retinal ganglion cell (RGC) degeneration and excavation of the optic nerve head (ONH). It is associated with an increase in intraocular pressure (IOP) and progressive decline in the visual field. Reduction in the retrograde axonal transport of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) from the brain to the neuronal cell bodies in retina, has been suggested as one of the key mechanisms underlying selective degeneration of ganglion cells and optic nerve in glaucoma. Multiple studies have indicated that BDNF and its high affinity receptor Tropomyosin receptor kinase B (TrkB) play crucial roles in survival of RGCs and that upregulating BDNF/TrkB signalling using gene therapy can protect the ganglion cells against degeneration. This study corroborates previous findings and demonstrates that glaucoma is associated with downregulation of TrkB downstream signalling and enhanced levels of amyloid β (Aβ 1–42) accumulation in the retina. 7,8 dihydroxyflavone (7,8 DHF) is a TrkB agonist and regular administration of this compound imparted significant protection against loss of GCL density and preserved inner retinal function in experimental glaucoma models. 7,8 DHF treatment stimulated activation of TrkB intracellular signalling as well as ameliorated the increase in the levels of soluble Aβ (1–42) in the retinas of rats and mice exposed to high IOP. The protective effects of 7,8 DHF were also evident in BDNF+/− mice indicating that TrkB agonist mediated activation of TrkB signalling was not altered upon BDNF allelic impairment. These data support BDNF/TrkB axis as a promising therapeutic target in glaucoma and highlight that the detrimental effects of high IOP exposure can be compensated by the exogenous administration of a TrkB agonist.

The Roles of Transient Receptor Potential Ion Channels in Pathologies of Glaucoma.

Transient receptor ion potential (TRP) channels are a cluster of non-selective cation channels present on cell membranes. They are important mediators of sensory signals to regulate cellular functions and signaling pathways. Alterations and dysfunction of these channels could disrupt physiological processes, thus leading to a broad array of disorders, such as cardiovascular, renal and nervous system diseases. These effects position them as potential targets for drug design and treatment. Because TRP channels can mediate processes such as mechanical conduction, osmotic pressure, and oxidative stress, they have been studied in the context of glaucoma. Glaucoma is an irreversible blinding eye disease caused by an intermittent or sustained increase in intraocular pressure (IOP), which results in the apoptosis of retinal ganglion cells (RGCs), optic nerve atrophy and eventually visual field defects. An increasing number of studies have documented that various TRP subfamilies are abundantly expressed in ocular structures, including the cornea, lens, ciliary body (CB), trabecular meshwork (TM) and retina. In alignment with these findings, there is also mounting evidence supporting the potential role of the TRP family in glaucoma progression. Therefore, it is of great interest and clinical significance to gain an increased understanding of these channels, which in turn could shed more light on the identification of new therapeutic targets for glaucoma. Moreover, this role is not understood completely to date, and whether the activation of TRP channels contributes to glaucoma, or instead aggravates progression, needs to be explored. In this manuscript, we aim to provide a comprehensive overview of recent research on TRP channels in glaucoma and to suggest novel targets for future therapeutic interventions in glaucoma.

Astrocyte polarization in glaucoma: a new opportunity.

Astrocyte polarization is a new concept which is similar to microglia polarization and in which astrocytes are classified as A1 (neurotoxic) and A2 (neuroprotective). Several studies on astrocyte polarization have focused mainly on neurodegenerative diseases, trauma, and infections. However, the role of astrocyte polarization in glaucoma, a neurodegenerative disease, has not been fully explored. In this review, we first describe the characteristics of astrocyte astrogliosis in glaucoma, including morphological, molecular, proliferative and functional changes. We then summarize understanding of astrocyte polarization in other diseases, and show that A1 astrocytes are involved in the death of retinal ganglion cells in glaucoma, and that their neurotoxins kill only damaged retinal ganglion cells. Based on this, we propose new interesting conjecture on astrocyte polarization in glaucoma: (1) That the neurotoxin from A1 astrocytes is a product of the complement system (membrane-attacking complex), since this system is known to mediate synaptic elimination and the C3 expression is clearly increased in A1 astrocytes; (2) that reactive scar-forming astrocytes in the optic nerve head may be classified as A2 astrocytes since their ablation leads to a worse prognosis in glaucoma. Finally, current therapeutic research progress on astrocyte polarization in other diseases is also addressed. Regulation of astrocyte polarization can be achieved by extracellular microglia-related and intracellular pathways. Reduced A1 or increased A2 astrocytes can rescue the nerve. For example, glucagon-like peptide-1 receptor agonist rescues retinal ganglion cells by reducing A1 astrocytes via the extracellular microglia-related pathway in an ocular hypertension model, suggesting that regulation of astrocyte polarization as a therapeutic target in glaucoma is feasible.

Downregulation of secreted protein acidic and rich in cysteine in human trabecular meshwork cells.

Secreted protein acidic and rich in cysteine (SPARC) may play a notable role in aqueous humor outflow through the trabecular meshwork (TM). SPARC is a potential therapeutic target in glaucoma, and the mechanism by which it regulates intraocular pressure remains unclear. The present study aimed to observe the effects of SPARC in human TM cells (HTMCs) in vitro. SPARC was downregulated by recombinant lentiviral vectors in HTMCs, and the subsequent levels of F-actin expression, zonula occludens-1 (ZO-1) expression and cellular phagocytosis were observed and calculated. It was revealed that after 48 h of culture, the expression levels of SPARC, F-actin and ZO-1 were significantly decreased in the lentivirus group compared with those in the blank control and empty vector control groups. The downregulation of SPARC promoted phagocytosis in HTMCs after 24 or 48 h of culture. This indicated that the downregulation of SPARC decreased the expression levels of the cytoskeleton-associated proteins F-actin and ZO-1, promoted phagocytosis in HTMCs and may affect the outflow of aqueous humor via the TM pathway.

TET-dependent GDF7 hypomethylation impairs aqueous humor outflow and serves as a potential therapeutic target in glaucoma

Glaucoma is the leading cause of irreversible vision loss, affecting more than 70 million individuals worldwide. Circulatory disturbances of aqueous humor (AH) have long been central pathological contributors to glaucomatous lesions. Thus, targeting the AH outflow is a promising approach to treat glaucoma. However, the epigenetic mechanisms initiating AH outflow disorders and the targeted treatments remain to be developed. Studying glaucoma patients, we identified GDF7 (growth differentiation factor 7) hypomethylation as a crucial event in the onset of AH outflow disorders. Regarding the underlying mechanism, the hypomethylated GDF7 promoter was responsible for the increased GDF7 production and secretion in primary open-angle glaucoma (POAG). Excessive GDF7 protein promoted trabecular meshwork (TM) fibrosis through bone morphogenetic protein receptor type 2 (BMPR2)/Smad signaling and upregulated pro-fibrotic genes, α-smooth muscle actin (α-SMA) and fibronectin (FN). GDF7 protein expression formed a positive feedback loop in glaucomatous TM (GTM). This positive feedback loop was dependent on the activated TET (ten-eleven translocation) enzyme, which kept the GDF7 promoter region hypomethylated. The phenotypic transition in TM fortified the AH outflow resistance, thus elevating the intraocular pressure (IOP) and attenuating the nerve fiber layer. This methylation-dependent mechanism is also confirmed by a machine-learning model in silico with a specificity of 84.38% and a sensitivity of 89.38%. In rhesus monkeys, we developed GDF7 neutralization therapy to inhibit TM fibrosis and consequent AH outflow resistance that contributes to glaucoma. The neutralization therapy achieved high-efficiency control of the IOP (from 21.3 ± 0.3 to 17.6 ± 0.2 mmHg), a three-fold improvement in the outflow facility (from 0.1 to 0.3 μL/min · mmHg), and protection of nerve fibers. This study provides new insights into the epigenetic mechanism of glaucoma and proposes an innovative GDF7 neutralization therapy as a promising intervention.

Caveolin-1 Ablation Imparts Partial Protection Against Inner Retinal Injury in Experimental Glaucoma and Reduces Apoptotic Activation.

Retinal ganglion cell degeneration is a characteristic feature of glaucoma, and accordingly, protection of these cells constitutes a major therapeutic objective in the disease. Here, we demonstrate the key influence of caveolin (Cav) in regulating the inner retinal homeostasis in two models of experimentally elevated intraocular pressure (IOP). Two groups of Cav-1-/- and wild-type mice were used in the study. Animals were subjected to experimentally induced chronic and acutely elevated IOP and any changes in their retinal function were assessed by positive scotopic threshold response recordings. TUNEL and cleaved caspase-3 assays were performed to evaluate apoptotic changes in the retina while Brn3a immunostaining was used as a marker to assess and quantify ganglion cell layer (GCL) changes. H&E staining was carried out on retinal sections to evaluate histological differences in retinal laminar structure. Cav-1 ablation partially protected the inner retinal function in both chronic and acute models of elevated IOP. The protective effects of Cav-1 loss were also evident histologically by reduced loss of GCL density in both models. The phenotypic protection in Cav-1-/- glaucoma mice paralleled with increased TrkB phosphorylation and reduced endoplasmic reticulum stress markers and apoptotic activation in the inner retinas. This study corroborated previous findings of enhanced Shp2 phosphorylation in a chronic glaucoma model and established a novel role of Cav-1 in mediating activation of this phosphatase in the inner retina in vivo. Collectively, these findings highlight the critical involvement of Cav-1 regulatory mechanisms in ganglion cells in response to increased IOP, implicating Cav-1 as a potential therapeutic target in glaucoma.

An injectable peptide hydrogel for reconstruction of the human trabecular meshwork

Glaucoma is a leading cause of irreversible blindness worldwide. Current treatments of glaucoma involve lowering the IOP by means of decreasing aqueous humor production or increasing non-trabecular aqueous humor outflow with the help of IOP-lowering eye drops, nanotechnology enabled glaucoma drainage implants, and trabeculectomy. However, there is currently no effective and permanent cure for this disease. In order to investigate new therapeutic strategies, three dimensional (3D) biomimetic trabecular meshwork (TM) models are in demand. Therefore, we adapted MAX8B, a peptide hydrogel system to bioengineer a 3D trabecular meshwork scaffold. We assessed mechanical and bio-instructive properties of this engineered tissue matrix by using rheological analysis, 3D cell culture and imaging techniques. The scaffold material exhibited shear-thinning ability and biocompatibility for proper hTM growth and proliferation indicating a potential utilization as an injectable implant. Additionally, by using a perfusion system, MAX8B scaffold was tested as an in vitro platform for investigating the effect of Dexamethasone (Dex) on trabecular meshwork outflow facility. The physiological response of hTM cells within the scaffold to Dex treatment clearly supported the effectiveness of this 3D model as a drug-testing platform, which can accelerate discovery of new therapeutic targets for glaucoma. Statement of significanceArtificial 3D-TM (3-dimentional Trabecular Meshwork) developed here with hTM (human TM) cells seeded on peptide-hydrogel scaffolds exhibits the mechanical strength and physiological properties mimicking the native TM tissue. Besides serving a novel and effective 3D-TM model, the MAX8B hydrogel could potentially function as an injectable trabecular meshwork implant.

LncRNA NR_003923 promotes cell proliferation, migration, fibrosis, and autophagy via the miR-760/miR-215-3p/IL22RA1 axis in human Tenon\u2019s capsule fibroblasts

Noncoding RNAs (ncRNAs), including long ncRNAs (lncRNA) have manifested an important role in the pathophysiology of many diseases. Glaucoma is a primary cause of irreversible blindness worldwide. However, the involvement of lncRNAs in glaucoma remains largely unknown. Here, we performed the lncRNA expression assay based on clinical tissues and identified a specific functional lncRNA, NR_003923, and investigated its potential role in glaucoma. Knockdown of NR_003923 in human Tenon’s capsule fibroblast cells (HTFs) inhibited TGF-β-induced cell migration, proliferation, fibrosis, and autophagy. The dual luciferase reporter assay confirmed that miR-760 and miR-215-3p interacted with NR_003923. miR-760 and miR-215-3p inhibitor reversed the effects of NR_003923 and TGF-β-induced cell apoptosis. Moreover, the expression of miR-760 and miR-215-3p was decreased in glaucoma comparing with control. Furthermore, through microarray we found IL22RA1 was increased in glaucoma and both of miR-760 and miR-215-3p bound to the 3′ UTR of IL22RA1. Overexpression of IL22RA1 enhanced HTFs migration and proliferation, while miR-760 and miR-215-3p mimics reversed these promotive biological roles induced by IL22RA1. In conclusion, NR_003923 and IL22RA1 might contribute to glaucoma progression and be a novel and potential biomarkers and therapeutic targets for glaucoma.

Identification of pathogenic genes and transcription factors in glaucoma.

Glaucoma is a group of eye diseases characterized by alterations in the contour of the optic nerve head, with corresponding visual field defects and progressive loss of retinal ganglion cells. The present study aimed to identify the key genes and upstream regulators in glaucoma. To screen the pathogenic genes involved in glaucoma, an integrated analysis was performed by using the microarray datasets in glaucoma derived from the Gene Expression Omnibus (GEO) database. The functional annotation and potential pathways of differentially expressed genes (DEGs) were additionally examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A glaucoma‑specific transcriptional regulatory network was constructed to identify crucial transcriptional factors that target the DEGs in glaucoma. From two GEO datasets, 1,935 DEGs (951 upregulated and 984 downregulated genes) between glaucoma and normal controls were identified. GO and KEGG analyses identified that 'eye development' [false discovery rate (FDR)=0.00415533] and 'visual perception' (FDR=0.00713283) were significantly enriched pathways for DEGs. The expression of lipocalin 2 (LCN2), monoamine oxidase A (MAOA), hemoglobin subunit β (HBB), paired box 6 (PAX6), fibronectin (FN1) and cAMP responsive element binding protein 1 (CREB1) were demonstrated to be involved in the pathogenesis of glaucoma. In conclusion, LCN2, MAOA, HBB, PAX6, FN1 and CREB1 may serve roles in glaucoma, regulated by PAX4, solute carrier family 22 member 1, hepatocyte nuclear factor 4 α and ELK1, ETS transcription factor. These data may contribute to the development of novel potential biomarkers, reveal the underlying pathogenesis and additionally identify novel therapeutic targets for glaucoma.

Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Regulate Intraocular Pressure.

PurposeIt has been known for nearly 50 years that cannabis and the psychoactive constituent Δ9-tetrahydrocannabinol (THC) reduce intraocular pressure (IOP). Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a major cause of blindness. THC likely acts via one of the known cannabinoid-related receptors (CB1, CB2, GPR18, GPR119, GPR55) but this has never been determined explicitly. Cannabidiol (CBD) is a second major constituent of cannabis that has been found to be without effect on IOP in most studies.MethodsEffects of topically applied THC and CBD were tested in living mice by using tonometry and measurements of mRNA levels. In addition the lipidomic consequences of CBD treatment were tested by using lipid analysis.ResultsWe now report that a single topical application of THC lowered IOP substantially (∼28%) for 8 hours in male mice. This effect is due to combined activation of CB1 and GPR18 receptors each of which has been shown to lower ocular pressure when activated. We also found that the effect was sex-dependent, being stronger in male mice, and that mRNA levels of CB1 and GPR18 were higher in males. Far from inactive, CBD was found to have two opposing effects on ocular pressure, one of which involved antagonism of tonic signaling. CBD prevents THC from lowering ocular pressure.ConclusionsWe conclude that THC lowers IOP by activating two receptors—CB1 and GPR18—but in a sex-dependent manner. CBD, contrary to expectation, has two opposing effects on IOP and can interfere with the effects of THC.

Hub Genes of Astrocyte Involved in Glaucoma with Ocular Hypertension by Integrated Bioinformatics Analysis

ABSTRACT Objective This study was conducted to elucidate the potential key candidate genes and pathways in role of astrocyte involved in glaucoma with ocular hypertension. Methods Expression profiles GSE2378 and GSE758 including 27 reactive optic nerve head astrocytes (ONHAs) by hypertensions and 26 normal controls, were integrated and deeply analyzed. Differentially expressed genes (DEGs) were sorted and candidate genes and pathways enrichment were analyzed. DEGs-associated protein-protein interaction network (PPI) was performed. Results A total of 119 consistently expressed genes were identified from 281 commonly changed DEGs, including 68 up-regulated genes and 51 down-regulated genes. PPI network complex filtered 75 DEGs (43 up-regulated and 32 down-regulated genes) of the 119 consistently altered DEGs and developed 117 edges, and 10 hub genes were identified. The most significant 3 modules were filtered from PPI, pathway enrichment analysis showed that module 1 was associated with extracellular exosome. Module 2 was mainly associated with antibody-dependent cellular cytotoxicity (ADCC) and module 3 was mainly associated with Hippo signaling pathway. Conclusion Taken above, using integrated bioinformatical analysis, we have identified DEGs candidate genes and pathways in role of astrocyte involved in glaucoma with ocular hypertension, which could improve our understanding of the cause and underlying molecular events, and these candidate genes and pathways could be therapeutic targets for glaucoma.

Src mediates TGF-β-induced intraocular pressure elevation in glaucoma.

Glaucoma, a progressive and irreversible optic neuropathy, is one of the leading causes of vision impairment worldwide. Elevation of intraocular pressure (IOP) due to transforming growth factor-β (TGF-β)-induced dysfunction of the trabecular meshwork is a risk factor for glaucoma, but the underlying molecular mechanisms remain elusive. Here, we show that Src kinase is involved in TGF-β-induced IOP elevation. We observed that dasatinib, a potent Src inhibitor, suppressed TGF-β2-induced IOP in rat eyes. Mechanistic analyses in human trabecular meshwork cells showed that TGF-β2 activated Src signaling and concomitantly increased cytoskeletal remodeling, cell adhesion, and extracellular matrix (ECM) accumulation. Src was activated via TGF-β2-induced upregulation of the Src scaffolding protein CasL, which mediates the assembly of focal adhesions, cytoskeletal remodeling, and ECM deposition. Activation of Src suppressed the expression of tissue plasminogen activator, thereby attenuating ECM degradation. Furthermore, the Src inhibitor ameliorated TGF-β2-induced changes in the contractile and adhesive characteristics of trabecular meshwork cells, and ECM deposition. These findings underscore the crucial role of Src activity in TGF-β-induced IOP elevation and identify Src signaling as a potential therapeutic target in glaucoma.

Retinal Renin-Angiotensin System Modulators: A Recent Implication for Therapy in Glaucomatous Patients

Glaucoma is the ultimate commonly acquired optic neuropathy. It signifies a public health challenge since it causes an irreversible blindness. The single known treatment of the disease is decreasing of intraocular pressure (IOP), which has been revealed to lessen glaucoma progress in a diversity of large proportions of clinical trials. Herein in this literature, we briefly define the optical Renin Angiotensin system (RAS) signaling pathway and define the most essential components, physiological actions of major angiotensin peptides, and the Renin Angiotensin system blockers. And discuss the potential implications of their modulators as a new therapeutic target in glaucoma. The literature has shown that the individual RAS modulators including, Angiotensin converting enzymes 1(ACE1) inhibitors, Angiotensin converting enzymes 2 (ACE2) Activators, Angiotensin receptor-1 (AT-1) blocker, and renin inhibitors have a potentials role in modulation of aqueous humour homodynamic, by neuroprotection of the retinal ganglion cells (RGC) and acceleration of the aqueous humour outflow. In conclusion, RAS modulators have an imperious role in lowering IOP, these compounds will pave the approach for prospect innovation, improvement, and publicizing of novel drugs to treat glaucoma and therefore, aid save vision for millions of people suffering with this slow progressive optic neuropathy.

Controlled-Deactivation CB1 Receptor Ligands as a Novel Strategy to Lower Intraocular Pressure.

Nearly half a century has passed since the demonstration that cannabis and its chief psychoactive component Δ9-THC lowers intraocular pressure (IOP). Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a condition that places millions at risk of blindness. It is likely that Δ9-THC exerts much of its IOP-lowering effects via the activation of CB1 cannabinoid receptors. However, the initial promise of CB1 as a target for treating glaucoma has not thus far translated into a credible therapeutic strategy. We have recently shown that blocking monoacylglycerol lipase (MAGL), an enzyme that breaks the endocannabinoid 2-arachidonoyl glycerol (2-AG), substantially lowers IOP. Another strategy is to develop cannabinoid CB1 receptor agonists that are optimized for topical application to the eye. Recently we have reported on a controlled-deactivation approach where the “soft” drug concept of enzymatic deactivation was combined with a “depot effect” that is commonly observed with Δ9-THC and other lipophilic cannabinoids. This approach allowed us to develop novel cannabinoids with a predictable duration of action and is particularly attractive for the design of CB1 activators for ophthalmic use with limited or no psychoactive effects. We have tested a novel class of compounds using a combination of electrophysiology in autaptic hippocampal neurons, a well-characterized model of endogenous cannabinoid signaling, and measurements of IOP in a mouse model. We now report that AM7410 is a reasonably potent and efficacious agonist at CB1 in neurons and that it substantially (30%) lowers IOP for as long as 5 h after a single topical treatment. This effect is absent in CB1 knockout mice. Our results indicate that the direct targeting of CB1 receptors with controlled-deactivation ligands is a viable approach to lower IOP in a murine model and merits further study in other model systems.

Knockout of tissue transglutaminase ameliorates TGFβ2-induced ocular hypertension: A novel therapeutic target for glaucoma?

Glaucoma is a vision threatening optic neuropathy that affects millions of people worldwide. In primary open angle, increased intraocular pressure (IOP) is the main risk factor for the development of this disease. Studies investigating the causes and mechanisms of increased IOP show fibrotic changes in the trabecular meshwork (TM) that are different from those of age-matched controls. Tissue transglutaminase (TGM2), an extracellular matrix (ECM) crosslinking enzyme, covalently crosslinks ECM proteins and causes excessive ECM protein deposition in the TM that could cause increased IOP. Previous literature reports increased expression of TGM2 in glaucomatous eyes compared to controls. We recently have shown that overexpression of TGM2 causes increased ECM crosslinking in the TM, increases IOP, and decreases aqueous humor (AH) outflow facility in mouse eyes. Therefore, we wanted to study the effect of TGM2 knockout (KO) on IOP in TGM2 floxed mice. Ad5.Cre transduction caused partial KO of TGM2, which decreased TGM2 expression in the TM region of mouse eyes. TGM2 KO significantly decreased IOP by itself and also in TGFβ2 induced ocular hypertensive mice. TGM2 KO also restores the outflow facility in TGFβ2 transduced eyes. Overall, TGM2 KO rescued the TGFβ2-induced ocular hypertensive phenotype. Thus, TGM2 may offer potential as a new therapeutic target for glaucoma.

Lipid mediators regulating intraocular pressure and therapeutic target for glaucoma

Lipid mediators regulating intraocular pressure and therapeutic target for glaucoma

The Role of Sigma 1 Receptor as a Neuroprotective Target in Glaucoma.

The role of sigma 1 receptor (S1R) in glaucoma is emerging as a promising field of study. Glaucoma is an optic neuropathy that shares common pathogenic mechanisms with other neurodegenerative diseases such as Alzheimer's and Parkinson's disease . S1R modulates multiple cellular functions associated with neurodegeneration . These include Ca2+ ion homeostasis, endoplasmic reticulum (ER) and oxidative stress , survival signaling pathways, neurotrophin secretion, and glial activation. S1R may also have neurorestorative properties including enhancement of neuronal plasticity and neurite outgrowth. Recent studies using agonists for S1R within the eye provide hope that it could be a therapeutic target for glaucoma. Understanding the role of S1R in glaucoma may help us to stop the progression of this sight threatening disease.