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Translational Vision Science &... Jul 2023Glaucomatous optic neuropathy (GON) is the major cause of irreversible visual loss worldwide and can result from a range of disease etiologies. The defining features of...
Glaucomatous optic neuropathy (GON) is the major cause of irreversible visual loss worldwide and can result from a range of disease etiologies. The defining features of GON are retinal ganglion cell (RGC) degeneration and characteristic cupping of the optic nerve head (ONH) due to tissue remodeling, while intraocular pressure remains the only modifiable GON risk factor currently targeted by approved clinical treatment strategies. Efforts to understand the mechanisms that allow species such as the zebrafish to regenerate their retinal cells have greatly increased our understanding of regenerative signaling pathways. However, proper integration within the retina and projection to the brain by the newly regenerated neuronal cells remain major hurdles. Meanwhile, a range of methods for in vitro differentiation have been developed to derive retinal cells from a variety of cell sources, including embryonic and induced pluripotent stem cells. More recently, there has been growing interest in the implantation of glial cells as well as cell-derived products, including neurotrophins, microRNA, and extracellular vesicles, to provide functional support to vulnerable structures such as RGC axons and the ONH. These approaches offer the advantage of not relying upon the replacement of degenerated cells and potentially targeting earlier stages of disease pathogenesis. In order to translate these techniques into clinical practice, appropriate cell sourcing, robust differentiation protocols, and accurate implantation methods are crucial to the success of cell-based therapy in glaucoma. Translational Relevance: Cell-based therapies for glaucoma currently under active development include the induction of endogenous regeneration, implantation of exogenously derived retinal cells, and utilization of cell-derived products to provide functional support.
Topics: Animals; Zebrafish; Glaucoma; Optic Disk; Retina; Intraocular Pressure; Optic Nerve Diseases
PubMed: 37494052
DOI: 10.1167/tvst.12.7.23 -
Molecular Aspects of Medicine Dec 2023The optic nerve consists of the glia, vessels, and axons including myelin and axoplasm. Since axonal degeneration precedes retinal ganglion cell death in glaucoma, the... (Review)
Review
The optic nerve consists of the glia, vessels, and axons including myelin and axoplasm. Since axonal degeneration precedes retinal ganglion cell death in glaucoma, the preceding axonal degeneration model may be helpful for understanding the molecular mechanisms of optic nerve degeneration. Optic nerve samples from these models can provide information on several aspects of autophagy. Autophagosomes, the most typical organelles expressing autophagy, are found much more frequently inside axons than around the glia. Thus, immunoblot findings from the optic nerve can reflect the autophagy state in axons. Autophagic flux impairment may occur in degenerating optic nerve axons, as in other central nervous system neurodegenerative diseases. Several molecular candidates are involved in autophagy enhancement, leading to axonal protection. This concept is an attractive approach to the prevention of further retinal ganglion cell death. In this review, we describe the factors affecting autophagy, including nicotinamide riboside, p38, ULK, AMPK, ROCK, and SIRT1, in the optic nerve and propose potential methods of axonal protection via enhancement of autophagy.
Topics: Animals; Humans; Disease Models, Animal; Optic Nerve; Glaucoma; Axons; Autophagy
PubMed: 37839231
DOI: 10.1016/j.mam.2023.101217 -
Scientific Reports Sep 2023The purpose of this study was to identify the effect of antihypertensive medication on risks of open-angle glaucoma (OAG) among patients diagnosed with hypertension...
The purpose of this study was to identify the effect of antihypertensive medication on risks of open-angle glaucoma (OAG) among patients diagnosed with hypertension (HTN). A total of 5,195 patients, who were diagnosed with HTN between January 1, 2006 and December 31, 2015, and subsequently diagnosed with OAG, were selected for analysis. For each OAG patient, 5 non-glaucomatous, hypertensive controls were matched (n = 25,975) in hypertension diagnosis date, residential area, insurance type and economic status. Antihypertensive medications were stratified into 5 types: angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), β-blockers and diuretics. Relative risks were calculated. After adjusting for age, sex, body mass index, lifestyle, comorbidities, blood pressure (BP), follow-up duration, and use of other types of antihypertensive drugs, ARB and CCB were found to slightly increase OAG risks (RR 1.1087 (95% CI 1.0293-1.1942); 1.0694 (1.0077-1.1349), respectively). Combinations of ARB with diuretics (1.0893 (1.0349-1.1466)) and CCB (1.0548 (1.0122-1.0991)) also increased OAG risks. The risks for OAG were found to increase by antihypertensive medication use, but the effects appeared to be small. Further studies are necessary to identify the associations of increased BP, medication and therapeutic effect with OAG.
Topics: Humans; Antihypertensive Agents; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Glaucoma, Open-Angle; Calcium Channel Blockers; Hypertension; Diuretics
PubMed: 37758842
DOI: 10.1038/s41598-023-43420-3 -
Indian Journal of Ophthalmology Jun 2024Glaucoma, the silent thief of sight, is one of the most common vision-threatening conditions. Even though POAG (primary open angle glaucoma) is more common, PACG... (Review)
Review
BACKGROUND
Glaucoma, the silent thief of sight, is one of the most common vision-threatening conditions. Even though POAG (primary open angle glaucoma) is more common, PACG (primary angle closure glaucoma) is the dreaded variant. ISGEO (International Society for Geographical and Epidemiological Ophthalmology) has classified primary angle closure as PACS (primary angle closure suspect), PAC (primary angle closure), and PACG (primary angle closure glaucoma. The inconspicuous nature of PACS makes its diagnosis and treatment very tricky.
PURPOSE
To determine which cases are best suited for laser peripheral iridotomy.
SYNOPSIS
Laser peripheral iridotomy is the gold standard for acute primary angle closure glaucoma treatment. But there is a lot of confusion regarding its use in PACS as a prophylactic measure. We have tried to throw light on laser peripheral iridotomy, a much debatable topic. The video focuses on various trials regarding laser peripheral iridotomy, the indications, side effects, and contraindications. We have also discussed its use as a therapeutic and prophylactic procedure.
HIGHLIGHTS
The video highlights that the approach of laser peripheral iridotomy should be on a case-by-case basis.
VIDEO LINK
https://youtu.be/kiEYI9ct2Oo.
Topics: Humans; Glaucoma, Angle-Closure; Iridectomy; Intraocular Pressure; Laser Therapy; Iris; Gonioscopy
PubMed: 38804805
DOI: 10.4103/IJO.IJO_1362_23 -
Advances in Therapy Sep 2023This multicenter, randomized, comparative, and investigator-masked crossover clinical trial sought to compare the efficacy and tolerability of fixed combinations of 0.1%... (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized Multicenter Clinical Trial Comparing 0.1% Brimonidine/0.5% Timolol Versus 1% Dorzolamide/0.5% Timolol as Adjuncts to Prostaglandin Analogues: Aibeta Crossover Study.
INTRODUCTION
This multicenter, randomized, comparative, and investigator-masked crossover clinical trial sought to compare the efficacy and tolerability of fixed combinations of 0.1% brimonidine/0.5% timolol (BTFC) versus 1% dorzolamide/0.5% timolol (DTFC) as adjunctive therapies to prostaglandin analogues.
METHODS
A total of 110 patients with open-angle glaucoma or ocular hypertension previously treated with prostaglandin analogue monotherapy were randomized to receive either BTFC or DTFC as adjunctive therapy for 8 weeks. These patients were then crossed over to the alternative treatment arm for another 8 weeks. The reduction in intraocular pressure (IOP) (primary outcome), occurrence of adverse events, ocular discomfort after instillation, and patient preference (secondary outcomes) were recorded through patient interviews.
RESULTS
BTFC instillation for 8 weeks reduced IOP by 3.55 mmHg, demonstrating non-inferiority to DTFC instillation (3.60 mmHg; P < 0.0001, mixed-effects model). Although adverse events were rare with both combinations, patients reported greater discomfort with DTFC than with BTFC (P < 0.0001). More patients preferred BTFC (P < 0.0001) over DTFC, as BTFC caused minimal or no eye irritation.
CONCLUSION
As BTFC offered better tolerability than DTFC with comparable reduction in IOP, we recommend it as an alternative for patients who experience ocular discomfort with DTFC-prostaglandin analogue combination therapy.
TRIAL REGISTRATION NUMBER
jRCTs051190125.
Topics: Humans; Timolol; Glaucoma, Open-Angle; Cross-Over Studies; Antihypertensive Agents; Ophthalmic Solutions; Brimonidine Tartrate; Intraocular Pressure; Prostaglandins, Synthetic; Drug Combinations
PubMed: 37452961
DOI: 10.1007/s12325-023-02589-9 -
Cells Dec 2023Glaucoma, a leading cause of irreversible blindness globally, primarily affects retinal ganglion cells (RGCs). This review dives into the anatomy of RGC subtypes,... (Review)
Review
Glaucoma, a leading cause of irreversible blindness globally, primarily affects retinal ganglion cells (RGCs). This review dives into the anatomy of RGC subtypes, covering the different underlying theoretical mechanisms that lead to RGC susceptibility in glaucoma, including mechanical, vascular, excitotoxicity, and neurotrophic factor deficiency, as well as oxidative stress and inflammation. Furthermore, we examined numerous imaging methods and functional assessments to gain insight into RGC health. Finally, we investigated the current possible neuroprotective targets for RGCs that could help with future glaucoma research and management.
Topics: Humans; Retinal Ganglion Cells; Glaucoma; Neuroprotection
PubMed: 38132117
DOI: 10.3390/cells12242797 -
BMJ Open Aug 2023Glaucoma, a major cause of irreversible blindness, is a highly heritable human disease. Currently, the majority of the risk genes for glaucoma are unknown. We...
PURPOSE
Glaucoma, a major cause of irreversible blindness, is a highly heritable human disease. Currently, the majority of the risk genes for glaucoma are unknown. We established the Genetics of Glaucoma Study (GOGS) to identify disease genes and improve genetic prediction of glaucoma risk and response to treatment.
PARTICIPANTS
More than 5700 participants with glaucoma or a family history of glaucoma were recruited through a media campaign and the Australian Government healthcare service provider, Services Australia, making GOGS one of the largest genetic studies of glaucoma globally. The mean age of the participants was 65.30±9.36 years, and 62% were female. Participants completed a questionnaire obtaining information about their glaucoma-related medical history such as family history, glaucoma status and subtypes, surgical procedures, and prescriptions. The questionnaire also obtained information about other eye and systemic diseases. Approximately 80% of the participants provided a DNA sample and ~70% consented to data linkage to their Australian Government Medicare and Pharmaceutical Benefits Scheme schedules.
FINDINGS TO DATE
4336 GOGS participants reported that an optometrist or ophthalmologist has diagnosed them with glaucoma and 3639 participants reported having a family history of glaucoma. The vast majority of the participants (N=4393) had used at least one glaucoma-related medication; latanoprost was the most commonly prescribed drug (54% of the participants who had a glaucoma prescription). A subset of the participants reported a surgical treatment for glaucoma including a laser surgery in 2008 participants and a non-laser operation in 803 participants. Several comorbid eye and systemic diseases were also observed; the most common reports were ocular hypertension (53% of the participants), cataract (48%), hypertension (40%), nearsightedness (31%), astigmatism (22%), farsightedness (16%), diabetes (12%), sleep apnoea (11%) and migraines (10%).
FUTURE PLANS
GOGS will contribute to the global gene-mapping efforts as one of the largest genetic studies for glaucoma. We will also use GOGS to develop or validate genetic risk prediction models to stratify glaucoma risk, particularly in individuals with a family history of glaucoma, and to predict clinical outcomes (eg, which medication works better for an individual and whether glaucoma surgery is required). GOGS will also help us answer various research questions about genetic overlap and causal relationships between glaucoma and its comorbidities.
Topics: Aged; Humans; Female; Middle Aged; Male; Antihypertensive Agents; Australia; National Health Programs; Glaucoma; Ocular Hypertension; Intraocular Pressure
PubMed: 37536973
DOI: 10.1136/bmjopen-2022-068811 -
Investigative Ophthalmology & Visual... Sep 2023Keratin 8/18 (KRT8/18), paired members of the intermediate filament family, have shown vital functions in regulating physiological activities more than supporting the...
PURPOSE
Keratin 8/18 (KRT8/18), paired members of the intermediate filament family, have shown vital functions in regulating physiological activities more than supporting the mechanic strength for cells and organelles. However, the KRT8/18 presence in retinal ganglion cells (RGCs) and functions on neuroprotection in a mouse model of acute ocular hypertension (AOH) are unknown and worthy of exploration.
METHODS
We identified the existence of KRT8/18 in normal human and mouse retinas and primary RGCs. KRT8/18 levels were detected after AOH modeling. The adeno-associated virus (AAV) system was intravitreally used for selective KRT8 knockdown in RGCs. The histological changes, the loss and dysfunction of RGCs, and the gliosis in retinas were detected. The markers of cell apoptosis and MAPK pathways were investigated.
RESULTS
KRT8/18 existed in all retinal layers and was highly expressed in RGCs, and they increased after AOH induction. The KRT8 knockdown in RGCs caused no histopathological changes and RGC loss in retinas without AOH modeling. However, after the KRT8 deficiency, AOH significantly promoted the loss of whole retina and inner retina thickness, the reduction, apoptosis, and dysfunction of RGCs, and the glial activation. Besides, downregulated Bcl-2 and upregulated cleaved-Caspase 3 were found in the AOH retinas with KRT8 knockdown, which may be caused by the increased phosphorylation level of MAPK pathways (JNK, p38, and ERK).
CONCLUSIONS
The KRT8 deficiency promoted RGC apoptosis and neurodegeneration by abnormal activation of MAPK pathways in AOH retinas. Targeting KRT8 may serve as a novel treatment for saving RCGs from glaucomatous injuries.
Topics: Animals; Humans; Mice; Apoptosis; Glaucoma; Ocular Hypertension; Retina; Retinal Ganglion Cells
PubMed: 37656477
DOI: 10.1167/iovs.64.12.1 -
Exosome-based crosstalk in glaucoma pathogenesis: a focus on oxidative stress and neuroinflammation.Frontiers in Immunology 2023Exosomes are membrane-bound tiny particles that are released by all live cells that contain multiple signal molecules and extensively participate in numerous normal... (Review)
Review
Exosomes are membrane-bound tiny particles that are released by all live cells that contain multiple signal molecules and extensively participate in numerous normal physical activities and pathologies. In glaucoma, the crucial role of exosome-based crosstalk has been primarily revealed in animal models and cell studies in the recent decade. In the aqueous drainage system, exosomes derived from non-pigment ciliary epithelium act in an endocrine manner and specifically regulate the function of the trabecular meshwork to cope with persistent oxidative stress challenges. In the retina, a more complicated regulatory network among microglia, retinal neurons, retinal ganglial cells, retinal pigment epithelium, and other immune effector cells by exosomes are responsible for the elaborate modulation of tissue homeostasis under physical state and the widespread propagation of neuroinflammation and its consequent neurodegeneration in glaucoma pathogenesis. Accumulating evidence indicates that exosome-based crosstalk depends on numerous factors, including the specific cargos they carried (particularly micro RNA), concentration, size, and ionization potentials, which largely remain elusive. In this narrative review, we summarize the latest research focus of exosome-based crosstalk in glaucoma pathogenesis, the current research progress of exosome-based therapy for glaucoma and provide in-depth perspectives on its current research gap.
Topics: Animals; Exosomes; Neuroinflammatory Diseases; Glaucoma; Retinal Pigment Epithelium; Oxidative Stress
PubMed: 37529047
DOI: 10.3389/fimmu.2023.1202704 -
Investigative Ophthalmology & Visual... Nov 2023To investigate whether nicotinamide (NAM) modulates retinal vasculature in glaucoma.
PURPOSE
To investigate whether nicotinamide (NAM) modulates retinal vasculature in glaucoma.
METHODS
This was a prospective controlled clinical trial investigating animal and human histopathology. Participants included normotensive and ocular hypertensive rats, postmortem human ocular tissue, glaucoma patients (n = 90), and healthy controls (n = 30). The study utilized histopathology, computer-assisted retinal vasculature analysis, optical coherence tomography angiography (OCTA), and NAM treatment. The main outcome measures included retinal vascular parameters in rats as assessed by AngioTool; retinal vasculature integrity in rats and humans as assessed by histopathology, antibody-staining, and ImageJ-based measurements; and retinal perfusion density (PD) and flux index in humans as assessed by OCTA.
RESULTS
A number of vessel parameters were altered in ocular hypertension/glaucoma compared to healthy controls. NAM treatment improved the retinal vasculature in ocular hypertensive rats, with an increase in mean vessel area, percentage area covered by vessels, total vessel length, total junctions, and junction density as assessed by AngioTool (all P < 0.05); vessel wall integrity as assessed by VE-cadherin antibody staining was also improved (P < 0.01). In humans, as assessed by OCTA, increases in PD in the optic nerve head and macula complete image (0.7%, P = 0.04 and 1.0%, P = 0.002, respectively) in healthy controls, and an increase in the temporal quadrant of the macula (0.7%, P = 0.02) in glaucoma patients was seen after NAM treatment.
CONCLUSIONS
NAM can prevent retinal vascular damage in an animal model of glaucoma. After NAM treatment, glaucoma patients and healthy controls demonstrated a small increase in retinal vessel parameters as assessed by OCTA.
Topics: Animals; Humans; Rats; Fluorescein Angiography; Glaucoma; Glaucoma, Open-Angle; Ocular Hypertension; Optic Disk; Prospective Studies; Retinal Vessels; Tomography, Optical Coherence; Visual Fields
PubMed: 38010699
DOI: 10.1167/iovs.64.14.34