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Purpose: Retinal ganglion cell death occurs during the glaucoma pathological process, and it is significant because of the poor regeneration capacity of retinal ganglion cells. With a constantly increasing understanding of retinal cell death mechanisms, we now know that simply blocking a specific mechanism of cell death might not prevent retinal ganglion cell death. This review aimed to summarize the mechanisms of retinal cell death in glaucoma models and discuss the caveats in restoring visual function in these studies. Methods: A literature search was done on PubMed using key words including glaucoma, ocular hypertension, retinal ganglion cell, cell death, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagic cell death, and parthanatos. The literature was reviewed to summarize the information about the lethal pathways of retinal ganglion cell in the glaucoma-like animal models. Results: Based on the purpose, 100 studies were selected and discussed in this review. Conclusions: The damage to ganglion cells in glaucoma-like animals can occur via multiple lethal pathways and the molecular mechanisms are still incompletely understood. Further investigations on the crosstalk between different cell death pathways and the common upstream regulators could augment the development of novel targeting agents for the curative treatment of glaucoma.

Background: Prostaglandin analogs (PGAs) are the first-line treatment for primary open-angle glaucoma (POAG) and ocular hypertension (OH). This study aimed to confirm the effectiveness and safety of Tapros® (0.0015% tafluprost eye drops) in Chinese patients with POAG and OH., Methods: This phase IV, multicenter, non-comparative, prospective study enrolled patients with POAG and OH in China between 12/27/2017 and 04/15/2020. Patients who were treatment-naïve or untreated within one month (group A) or with unreached intraocular pressure (IOP) target after previous monotherapy of other PGAs (group B) or non-PGA IOP-lowering drugs (group C) were treated with 0.0015% tafluprost for three months. The IOP reduction, response rate, and safety were observed., Results: There were 165, 89, and 31 patients in groups A, B, and C, with baseline IOPs of 22.4 ± 4.7, 21.0 ± 3.5, and 22.5 ± 3.2 mmHg, respectively. The least-square means and percentages of IOP reduction at 3 months for groups A, B, and C were 4.7 (19.8%), 1.6 (6.1%), and 4.6 mmHg (20.3%), respectively. A significant reduction in IOP was observed at each visit compared with baseline (all P < 0.05). At the final visit, 57.0% of the participants in group A achieved an IOP reduction of ≥ 20%, while 40.4% and 77.4% in groups B and C achieved an IOP reduction of ≥ 10%. Fifty-eight treatment-related adverse events occurred in 46 participants (15.7%), of which the most common one was conjunctival hyperemia (34/293, 11.6%)., Conclusions: Tafluprost showed a sustained and significant effect with tolerable adverse events in Chinese patients with POAG and OH who were treatment-naïve or untreated within one month or received prior treatments with unsatisfying outcomes., (© 2022. The Author(s).)

Despite of various therapeutic methods for treating ocular hypertension and glaucoma, it still remains the leading cause of irreversible blindness. Intraocular pressure (IOP) lowering is the most effective way to slow disease progression and prevent blindness. Among the ocular hypotensive drugs currently in use, only a couple act on the conventional outflow system, which is the main pathway for aqueous humor outflow and the major lesion site resulting in ocular hypertension. Nitric oxide (NO) is a commendable new class of glaucoma drugs that acts on the conventional outflow pathway. An increasing number of nitric oxide donors have been developed for glaucoma and ocular hypertension treatment. Here, we will review how NO lowers IOP and the types of nitric oxide donors that have been developed. And a brief analysis of the advantages and challenges associated with the application will be made. The literature used in this review is based on Pubmed database search using 'nitric oxide' and 'glaucoma' as key words.

Background: Particulate matter (PM) is strongly linked to human health and has detrimental effects on the eye. Studies have, however, focused on the ocular surface, with limited research on the impact of PM 2.5 on intraocular pressure (IOP)., Methods: To investigate the impact of PM 2.5 on IOP and the associated mechanism, C57BL/6 mouse eyes were topically exposed to a PM 2.5 suspension for 3 months, and human trabecular meshwork (HTM) cells were subjected to various PM 2.5 concentrations in vitro. Cell viability, NLRP3/caspase-1, IL-1β, and GSDMD expression, reactive oxygen species (ROS) production and cell contractility were measured by western blot, ELISA, cell counting kit-8, ROS assay kit or a cell contractility assay. ROS scavenger N-acetyl-L-cysteine (NAC) and caspase-1 inhibitor VX-765 were used to intervene in PM 2.5 -induced damages., Results: The results revealed that the IOP increased gradually after PM 2.5 exposure, and upregulations of the NLRP3 inflammasome, caspase-1, IL-1β, and GSDMD protein levels were observed in outflow tissues. PM 2.5 exposure decreased HTM cell viability and affected contraction. Furthermore, elevated ROS levels were observed as well as an activation of the NLRP3 inflammasome and downstream inflammatory factors caspase-1 and IL-1β. NAC improved HTM cell viability, inhibited the activation of the NLRP3 inflammasome axis, and HTM cell contraction by scavenging ROS. VX-765 showed similar protection against the PM 2.5 induced adverse effects., Conclusion: This study provides novel evidence that PM 2.5 has a direct toxic effect on intraocular tissues and may contribute to the initiation and development of ocular hypertension and glaucoma. This occurs as a result of increased oxidative stress and the subsequent induction of NLRP3 inflammasome mediated pyroptosis in trabecular meshwork cells.

Nitric oxide (NO) donors are promising therapeutic candidates for treating intraocular hypertension (IOP) and glaucoma. This study aims to investigate the effect of prolonged use of NO donor sodium nitroprusside (SNP) on IOP. Since SNP has a short biological half-life, a nanoparticle drug delivery system (mesoporous silica nanoparticles) has been used to deliver SNP to the target tissues (trabecular meshwork and Schlemm's canal). We find that the sustained use of NO donor initially reduced IOP followed, surprisingly, by IOP elevation, which could not recover by drug withdraw but could be reversed by the antioxidant MnTMPyP application. The IOP elevation and normalization coincide with increased and reduced protein nitration in the mouse conventional outflow tissue. These findings suggest that the prolonged use of NO donor SNP may be problematic as it can cause outflow tissue damage by protein nitration. MnTMPyP is protective of the nitrative damage which could be considered to be co-applied with NO donors., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Vessel density (VD) of the elderly ocular hypertension patients measured by optical coherence tomography angiography (OCTA) have been reported. However, the studies of VD in juvenile ocular hypertension (JOHT) are limited. We wished to evaluate VD changes using OCTA in JOHT. We also investigated the potential risk parameters of intraocular pressure (IOP) and vertical cup/disc ratio (CDR) with OCTA for observing the development of JOHT., Methods: We examined 86 eyes in 45 control (Ctrl) subjects and 65 eyes in 34 patients with JOHT using OCTA at the glaucoma clinic of the Eye, Ear, Nose, and Throat Hospital of Fudan University. The VD of radial peripapillary capillaries (RPC) and the perifoveal superficial vascular plexus (SVP) was compared between the Ctrl and JOHT groups. Other basic study factors such as age, sex, blood pressure, best-corrected visual acuity, central corneal thickness, IOP, CDR, the thickness of the retinal nerve fiber layer, ganglion cell complex, visual field mean deviation, and pattern standard deviation were also recorded., Results: Bare difference was found in the nasal-inferior and temporal RPC-VD between the Ctrl and JOHT groups (P = 0.042 and P = 0.033, respectively) while SVP-VD was not (all P > 0.05). In the mixed linear regression model analysis, temporal RPC-VD was marginally negatively associated with high IOP (r = - 1.379, P = 0.043). Five additional sections of nasal, inferior-nasal, inferior-temporal, superior-temporal, and superior-nasal RPC-VD showed positive correlation with large CDR (all P <  0.05). SVP-VD in the superior and nasal regions was marginally negatively correlated with high IOP (r = - 1.877, P = 0.023; r = - 1.693, P = 0.049). No other regions were found statistical different of relationship between IOP, CDR and VD., Conclusions: Nasal-inferior and temporal peripapillary VD was marginally lower in JOHT subjects. Regarding parameters of IOP and CDR, peripapillary temporal VD had a borderline level of negative correlation with IOP more than 21 mmHg while additional five regions were strongly positively correlated with large CDR. Some macular regions only found marginal positive correlation with parameter of high IOP. We conclude that OCTA can be used as a potential technique to evaluate the VD in JOHT and peripapillary scans should be analyzed individually based on different levels of CDR.

Glaucoma, the second leading cause of irreversible blindness worldwide, is characterized by the selective death of retinal ganglion cells (RGCs). The group II metabotropic glutamate receptor (mGluR II) activation has been linked to RGC survival, however, the mechanism by which it promotes neuronal survival remains poorly defined. In the present work, we show that extracellular application of LY341495, an mGluR II antagonist could increase the RGC firing frequency, suggesting that activation of mGluR II by endogenously released glutamate could modulate RGC excitability. LY354740, an mGluR II agonist, significantly decreased RGC excitability and the reduced presynaptic excitatory inputs and post-synaptic Ca2+-permeable currents mediated the LY354740-induced effects. By using a well-characterized in vivo male Sprague-Dawley rat glaucoma model, we further demonstrate that in the early stage of experimental glaucoma, the expression of mGluR II dimer-formed protein was significantly reduced, and pre-activation of mGluR II by intravitreal injection of LY354740 before establishment of the glaucoma model could effectively reduce excitatory inputs, thereby reversing hyperexcitability induced by elevated intraocular pressure. Furthermore, LY354740 could increase the expression level of brain-derived neurotrophic factor in the glaucomatous retinas, further protecting RGCs. Our study indicates that the abnormal expression of mGluR II may accelerate RGC apoptosis in glaucoma, and demonstrates that mGluR II agonist LY354740 can be used as a novel method to counter RGC apoptosis in glaucoma., Competing Interests: Declarations of competing interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: To physiologically examine the impairment of cortical sensitivity to visual motion during acute elevation of intraocular pressure (IOP)., Methods: Motion processing in the cat brain is well characterized, its X and Y cell visual pathways being functionally analogous to parvocellular and magnocellular pathways in primates. Using this model, we performed ocular anterior chamber perfusion to reversibly elevate IOP over a range from 30 to 90 mm Hg while monitoring cortical activity with intrinsic signal optical imaging. Drifting random-dot fields and gratings were used to characterize cortical population responses to motion direction and orientation in early visual areas 17 and 18., Results: We found that acute IOP elevations at 50 mm Hg and above, which is often observed in acute glaucoma, suppressed cortical motion direction responses. This suppression was more profound in area 17 than in area 18, and more profound in central than peripheral visual field (eccentricities 0°-4° vs. 4°-8°) within area 17. In addition, orientation responses were more suppressed than motion direction responses for the same IOP modulation., Conclusions: In contrast to human chronic glaucoma that may cause greater dysfunction in large-cell magnocellular than in small-cell parvocellular visual pathways, our direct measurement of cortical processing networks implies that the small X-cell pathway shows greater vulnerability to acute IOP elevation than the large Y-cell pathway in visual motion processing. The results demonstrate that fine discrimination mechanisms for motion in the central visual field are particularly impacted by acute IOP attacks, suggesting a neural basis for immediate visual deficits in the fine motion perception of acute glaucoma patients.

Purpose: To evaluate the efficacy and safety of travoprost 0.004% versus timolol 0.5% as an initial intraocular pressure (IOP)-lowering medication for ocular hypertension secondary to vitrectomy., Patients and Methods: We performed a randomized, controlled, observer-blinded clinical trial in the Eye & ENT Hospital of Fudan University in China. This trial was registered at www.chictr.org.cn (ChICTR1800014942) before patient enrollment. Seventy-nine adults with IOP of 25-45 mmHg secondary to vitrectomy in the latest one month were enrolled and randomized to receive travoprost 0.004% or timolol 0.5%. More drugs were administered to patients with IOP > 25 mmHg during follow-up., Results: The mean IOP reduction at day 1 was -10.97 mmHg in the timolol group and -15.02 mmHg in the travoprost group ( P = 0.006); no significant difference was observed between the groups at later time points. The number of IOP-lowering medications at day 21 was 0.64 in the timolol group and 1.15 in the travoprost group ( P = 0.038), while no significant differences were observed at other time points. The proportion of single IOP-lowering medications used during the 4-week follow-up was 72.73% in the timolol group and 68.42% in the travoprost group ( P = 0.692). Inflammation scores were not significantly different in the two groups at any time point. Increased ocular hyperemia occurred in 8 patients (19%) in the travoprost group and none in the timolol group ( P = 0.005). There were no significant differences in other adverse events between the two groups. After logistic regression model analysis, IOP ≥ 30 mmHg, inflammation score ≥ 2, and silicone oil as tamponade were found to be the factors with significant effects on the number of IOP-lowering medications used during the 4-week follow-up., Conclusion: Travoprost and timolol have similar efficacy and safety for treating ocular hypertension secondary to vitrectomy., Competing Interests: The authors report no conflicts of interest with this work., (© 2019 Fang et al.)

Purpose: To investigate the role of endothelial nitric oxide synthase (eNOS) on conventional outflow function using NOS3 knockout (KO) mice., Methods: Intraocular pressure was measured in both NOS3 KO and wild type (WT) by rebound tonometry. Outflow facility was measured by perfusing enucleated mouse eyes at multiple pressure steps. A subset of eyes was sectioned and stained for histology. Mock aqueous humor ± the nitric oxide (NO) donors nitroprusside dihydrate (SNP) or S-Nitroso-N-Acetyl-D,L-Penicillamine (SNAP) was perfused into enucleated eyes. SNP and SNAP was administered topically at 0, 1, 2, and 3 hours while the contralateral eyes served as vehicle controls. Intraocular pressure was measured in both eyes before and after the last drug treatment., Results: Intraocular pressure was higher in KO mice (18.2 ± 0.7 mm Hg vs. 13.9 ± 0.5 mm Hg, mean ± SEM, n = 30, P < 0.05), and pressure-dependent conventional drainage was significantly lower (0.0058 ± 0.0005 μL/min/mm Hg, mean ± SEM, n = 21) compared with WT mice (0.0082 ± 0.0013 μL/min/mm Hg, n = 23, P < 0.05). No obvious morphological differences in iridiocorneal angle tissues were observed in hematoxylin and eosin (H&E)-stained sections. SNP and SNAP significantly increased pressure-dependent drainage in KO animals (n = 12, P < 0.05). In WT mice, SNP and SNAP caused a significant increase in pressure dependent drainage (n = 12, P < 0.05) to a similar degree as in KO mice. Topical application of SNP significantly reduced IOP in WT and KO mice (n = 12, P < 0.05), but SNAP did not change IOP significantly (n = 19)., Conclusions: NOS3 KO mice have elevated IOP, which is likely the result of reduced pressure-dependent drainage. These findings are consistent with human data showing polymorphisms in the NOS3 gene associate with ocular hypertension and the development of glaucoma.

Glaucoma is a common eye disease that can lead to irreversible vision loss if left untreated. The early diagnosis and treatment of primary open-angle glaucoma is challenging, and visual impairment in Chinese glaucoma patients is a serious concern. Most of these patients need more than one topical antiglaucoma agent to control their intraocular pressures (IOPs). In the People's Republic of China, the daily cost of different glaucoma medication varies greatly, and the treatment habits differ throughout the country. Prostaglandin analogs (PGAs) are recommended as first-line monotherapy, because of their efficacy and low risk of systemic side effects. Fixed-combination drops, particularly PGA-based fixed combinations, have recently been developed and used in patients with progression or who have failed to achieve their target IOPs. Here, we reviewed the current literature on the use of bimatoprost-timolol fixed combination (BTFC) in the People's Republic of China. BTFC has achieved good efficacy and tolerability in Chinese clinical trials. In addition, BTFC is more cost effective compared with other fixed combinations available in the People's Republic of China. Fixed-combination drops may offer benefits, such as keeping the ocular surface healthy, convenience of administration, and improvement in long-term adherence and quality of life. Therefore, BTFC has great potential for the treatment of Chinese glaucoma patients. However, the long-term efficacy of BTFC, comparisons of BTFC with other fixed-combination drugs, and treatment adherence and persistence with treatment in Chinese patients are unknown and will require further study.

Objective: To confirm the non-inferiority of the IOP-lowering effect of the 0.0015% Tafluprost ophthalmic solution to the 0.005% Latanoprost ophthalmic solution in patients with primary open-angle glaucoma or ocular hypertension.Safety was also compared between two groups., Methods: This study was conducted from August 2008 to December 2009, at five clinical trial sites in China. Patients of this study population was diagnosed with primary open-angle glaucoma or ocular hypertension in both eyes.Subjects were randomized into 0.0015% Tafluprost group or 0.005% Latanoprost group.Intraocular pressure (IOP) measurement by Goldmann applanation tonometer, slit-lamp microscopy, Gonioscopy, Fundascopy, Visual acuity test, Perimetry, Blood pressure and pulse rate, Subjective symptoms were compered between two groups at Week 0, Week 2 and Week 4.For main effectiveness evaluation index adopt the bad effect evaluation, safety evaluation index by Fisher's exact test probability method., Results: The 246 subjects/246 eyes were randomized (Tafluprost group:122 subjects/122 eyes, Latanoprost group:124 subjects/ 124 eyes). Change in the IOP at 17:00 of Week 2 is (8.8 ± 3.8) mmHg and (8.9 ± 4.4) mmHg (1 mmHg = 0.133 kPa) in Tafluprost group and Latanoprost group. Percent change in the IOP at 17:00 of Week 2 is (33.2 ± 12.8)% and (34.4 ± 14.1)% in Tafluprost group and Latanoprost group. Change in the IOP at 17:00 at the end of treatment is (9.8 ± 4.0) mmHg and (9.2 ± 4.1) mmHg in Tafluprost group and Latanoprost group. Percent change in the IOP at 17:00 at the end of treatment is 37.2% ± 13.4% group and 35.7% ± 13.0% in Tafluprost and Latanoprost group.In addition, distribution of subjects with percentage decrease of IOP > 30% was 72.5% in Tafluprost group higher than 63.8% in Latanoprost group. The major adverse reactions were conjunctival hyperemia, eye irritation, eye pain and foreign body sensation. The incidence of adverse reactions is 31.7% in Tafluprost group and 20.8% in Latanoprost group. The inter-group difference had no statistical significance., Conclusion: Efficacy and safety of Tafluprost ophthalmic solution are no less than Latanoprost ophthalmic solution in patients with primary open-angle glaucoma or ocular hypertension.

Background: To report the clinical outcomes in Chinese patients with primary open-angle glaucoma and ocular hypertension treated with bimatoprost 0.03% therapy., Methods: Two hundred sixty-three Chinese patients with primary open-angle glaucoma and ocular hypertension who needed initial or additional intraocular pressure (IOP) lowering were recruited in this prospective, open-label, multicenter clinical study and were treated with bimatoprost 0.03%. Patients received bimatoprost 0.03% as initial, replacement or adjunctive IOP-lowering therapy, and follow-up visits were performed at week 1, and month 1 and 3 of the bimatoprost treatment. The efficacy outcome measure was the post-treatment IOP level. The safety outcome measures included the rate of medication-related symptoms, physical signs, reported adverse events, and the level of conjunctival hyperemia., Results: Among 240 patients who could be categorized by pre-existing therapies and the bimatoprost therapy regimen in the study, IOP values observed in all medication conditions showed significant IOP reduction at all study visits compared with baseline. At 3 months, 8.0 ± 3.7 mmHg (32.0%) reduction in IOP was observed in treatment-naive patients after bimatoprost monotherapy; in the patients previously on various therapy regimens, 1.9 ± 2.8 mmHg (9.5%) to 6.4 ± 6.1 mmHg (24.8%) additional IOP lowering was achieved after switching to bimatoprost monotherapy or bimatoprost combination therapy. The most common adverse event was conjunctival hyperemia, mainly of trace and mild intensity., Conclusions: Our results show that bimatoprost 0.03% was effective in lowering IOP with favorable safety in Chinese primary open-angle glaucoma and ocular hypertension patients.

Background: Lowering intraocular pressure (IOP) is currently the only therapeutic approach in primary open-angle glaucoma. and the fixed-combination medications are needed to achieve sufficiently low target IOP. A multicenter prospective study in the Chinese population was needed to confirm the safety and efficacy of Bimatoprost/Timolol Fixed Combination Eye Drop in China. In this study, we evaluated the safety and efficacy of Bimatoprost/Timolol Fixed Combination with concurrent administration of its components in Chinese patients with open-angle glaucoma or ocular hypertension., Methods: In this multicenter, randomized, double-masked, parallel controlled study, patients with open-angle glaucoma or ocular hypertension who were insufficiently responsive to monotherapy with either topical β-blockers or prostaglandin analogues were randomized to one of two active treatment groups in a 1:1 ratio at 11 Chinese ophthalmic departments. Bimatoprost/timolol fixed combination treatment was a fixed combination of 0.03% bimatoprost and 0.5% timolol (followed by vehicle for masking) once daily at 19:00 P.M. and concurrent treatment was 0.03% bimatoprost followed by 0.5% timolol once daily at 19:00 P.M. The primary efficacy variable was change from baseline in mean diurnal intraocular pressure (IOP) at week 4 visit in the intent-to-treat (ITT) population. Primary analysis evaluated the non-inferiority of bimatoprost/ timolol fixed combination to concurrent with respect to the primary variable using a confidence interval (CI) approach. Bimatoprost/timolol fixed combination was to be considered non-inferior to concurrent if the upper limit of the 95% CI for the between-treatment (bimatoprost/timolol fixed combination minus concurrent) difference was ≤ 1.5 mmHg. Adverse events were collected and slit-lamp examinations were performed to assess safety. Between-group comparisons of the incidence of adverse events were performed using the Pearson chi-square test or Fisher's exact test., Results: Of the enrolled 235 patients, 121 patients were randomized to receive bimatoprost/timolol fixed combination and, 114 patients were randomized to receive concurrent treatment. At baseline the mean value of mean diurnal IOP was (25.20 ± 3.06) mmHg in the bimatoprost/timolol fixed combination group and (24.87 ± 3.88) mmHg in the concurrent group. The difference between the treatment groups was not statistically significant. The mean change from baseline in mean diurnal IOP (± standard deviation) in the bimatoprost/timolol fixed combination group was (-9.38 ± 4.66) mmHg and it was (-8.93 ± 4.25) mmHg in the concurrent group (P < 0.01). The difference between the two treatment groups (bimatoprost/timolol fixed combination minus concurrent) in the change from baseline of mean diurnal IOP was -0.556 mmHg (95% CI: -1.68, 0.57, P = 0.330). The upper limit of the 95% CI was less than 1.5 mmHg, the predefined margin of non-inferiority. Adverse events occurred in 26.4% (32/121) of the bimatoprost/timolol fixed combination patients and 30.7% (35/114) of the concurrent patients. The most frequent adverse event was conjunctival hyperemia, which was reported as treatment related in 16.5% (20/121) in the bimatoprost/timolol fixed combination group and 18.4% (21/114) in the concurrent group (P > 0.05)., Conclusions: Bimatoprost/Timolol Fixed Combination administered in Chinese patients with open-angle glaucoma or ocular hypertension was not inferior to concurrent dosing with the individual components. Safety profiles were similar between the treatment groups.

Purpose: To compare intraocular pressure (IOP) measurements obtained using the Topocon noncontact tonometer (NCT), the Goldmann applanation tonometer (GAT), and the Corvis ST (CST), a newly developed tonometer with features of visualization and measurement of the corneal deformation response to an air impulse. A secondary objective was to assess the agreement among the devices., Methods: Fifty-nine participants, including glaucoma patients (36 cases) and control volunteers (23 cases), were enrolled. One eye was selected randomly for further study. IOP measurements were obtained with the CST, NCT, and GAT by two experienced clinicians. IOP values were compared. Intraobserver variability and interobserver variability were assessed by the coefficient of variation and intraclass correlation coefficient. Device agreement was calculated by Bland-Altman analysis., Results: Mean IOP for all examined eyes was 18.9 ± 5.8 mm Hg for CST, 21.3 ± 6.8 mm Hg for NCT, and 20.3 ± 5.7 mm Hg for GAT. There was no statistically significant difference in IOP measurements among the tonometers except between the CST and NCT. Correlation analysis showed a high correlation between each pair of devices (all P < 0.001). The CST displayed the best intraobserver variability and interobserver variability. Bland-Altman analysis revealed a bias between CST and GAT, CST and NCT, and GAT and NCT of -1.3, -2.4, and -1.1 mm Hg, with 95% limits of agreement of -6.2 to 3.5 mm Hg, -10.1 to 5.2 mm Hg, and -8.3 to 6.2 mm Hg, respectively., Conclusions: The CST offers an alternative method for measuring IOP. IOP measurements taken with these devices may not be interchangeable.

Purpose: To investigate how OPA1 expression and distribution are altered by increased nitric oxide (NO) and whether aminoguanidine, a relative selective NO synthase (NOS)-2 inhibitor, can restore OPA1 expression and subsequently increase retinal ganglion cell (RGC) survival in ocular hypertensive rats., Methods: Elevated intraocular pressure was induced unilaterally by translimbal laser photocoagulation of the trabecular meshwork in Sprague-Dawley rats. Aminoguanidine (100 mg/kg) was administered by intraperitoneal injection for 3 consecutive days in rats after laser treatment. Preservation of fluorochrome-labeled RGCs was assessed 2 weeks later. GFAP, NOS-2, or OPA1 protein expression and distribution were assessed by Western blot analysis and immunohistochemistry. OPA1 mRNA was measured by qPCR., Results: OPA1 mRNA and protein expression were significantly increased in the vehicle-treated hypertensive rat retina. Aminoguanidine treatment significantly reduced expression of the 90- and 65-kDa OPA1 isoforms but did not significantly change the 80-kDa OPA1 isoform in hypertensive retina. In addition, the increases in NOS-2 and GFAP protein expression were blocked by aminoguanidine treatment in the hypertensive retina. NOS-2 immunoreactivity was induced in cells of the ganglion cell layer in the vehicle-treated hypertensive retina. Aminoguanidine treatment significantly increased RGC survival at 2 weeks after IOP elevation., Conclusions: Although NOS-2/NO induction may contribute to hypertensive retinal cell death, an increase in mitochondrial OPA1 may provide an important cellular defense mechanism against pressure-mediated retinal damage. These findings suggest that mitochondrial preservation after inhibition of NOS-2 may be useful for protecting RGCs against glaucomatous damage.

Purpose: To determine sonic hedgehog (Shh) expression and whether it exerts neuroprotective effects on retinal ganglion cells (RGCs) in a rat chronic ocular hypertension model., Methods: Intraocular pressure (IOP) elevation in adult rat was induced by episcleral vein cautery. Retinal expression of Shh protein and mRNA was determined by immunohistochemistry, Western blot analysis, and real-time PCR. Exogenous Shh and its inhibitor cyclopamine were intravitreally injected to examine their effects on RGC survival after ocular hypertension by the counting of retrograde DiI-labeled RGCs. Shh pathway components mediating neuroprotective effects were characterized using Western blot analysis and real-time PCR., Results: Shh was mainly detected in the RGCs in normal adult rat. Retinas from the elevated IOP group had 2.1- to 4.4-fold greater Shh expression than control retinas (P < 0.05). Shh promoted RGC survival at 2 and 4 weeks after IOP elevation in a dose-dependent manner, resulting in a loss of only 4.54% +/- 0.36% RGCs at 2 weeks (P < 0.01; vs. PBS-treated groups). In contrast, cyclopamine increased RGC loss. Protein and mRNA levels of the Shh signal transducer Smo and the downstream transcription factor Gli1 were significantly upregulated in RGCs after chronic ocular hypertension or intravitreal injection of Shh., Conclusions: Shh and Smo are upregulated in a time-dependent manner in retinas exposed to ocular hypertension, and Shh has neuroprotective effects on damaged RGCs in a rat chronic hypertension model. Shh may exert neuroprotective effects by relieving the inhibition of Smo and subsequently activating Gli1.

Glaucoma is the leading cause of irreversible blindness, affecting 111 million people by 2040 worldwide. Intraocular pressure (IOP) is the only controllable risk factor for the disease and current treatment options seek to reduce IOP via daily taking eye drops. However, shortcomings of eye drops, such as poor bioavailability and unsatisfied therapeutic effects, may lead to inadequate patient compliance. In this study, an effective brimonidine (BRI)-loaded silicone rubber (SR) implant coated with polydimethylsiloxane (BRI@SR@PDMS) is designed and fully investigated for IOP reduction treatment. The in vitro BRI release from BRI@SR@PDMS implant reveals a more sustainable trend lasting over 1 month, with a gradually declined immediate drug concentration. The carrier materials show no cytotoxicity on human corneal epithelial cells and mice corneal epithelial cells in vitro. After administrated into rabbit's conjunctival sac, the BRI@SR@PDMS implant releases BRI in a sustained fashion and effectively reduces IOP for 18 days with great biosafety. In contrast, BRI eye drops only maintain IOP-lowering effect for 6 h. Therefore, as a substitute of eye drops, the BRI@SR@PDMS implant can be applied as a promising non-invasive platform to achieve long-term IOP-lowering in patients suffering from ocular hypertension or glaucoma. [ABSTRACT FROM AUTHOR]

Elevated intraocular pressure (IOP) is the major risk factor for glaucoma. The molecular mechanism of elevated IOP is unclear, which impedes glaucoma therapy. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible Poly-ADP-ribose Polymerase (TIPARP), a member of the PARP family, catalyses mono-ADP-ribosylation. Here we showed that TIPARP was widely expressed in the cornea, trabecular meshwork, iris, retina, optic nerve, sclera, and choroid of human eyes. The expression of TIPARP was significantly upregulated in the blood and trabecular meshwork of patients with primary open angle glaucoma compared with that of healthy controls. Transcriptome analysis revealed that the expression of genes related to extracellular matrix deposition and cell adhesion was decreased in TIPARP-upregulated human trabecular meshwork (HTM) cells. Moreover, western blot analysis showed that collagen types I and IV, fibronectin, and α-SMA were increased in TIPARP-downregulated or TIPARP-inhibited HTM cells. In addition, cross-linked actin networks were produced, and vinculin was upregulated in these cells. Subconjunctival injection of the TIPARP inhibitor RBN-2397 increased the IOP in Sprague–Dawley rats. Therefore, we identified TIPARP as a regulator of IOP through modulation of extracellular matrix and cell cytoskeleton proteins in HTM cells. These results indicate that TIPARP is a potential therapeutic target for ocular hypertension and glaucoma. TIPARP, an inducible poly-ADP-ribose polymerase, is identified as a novel regulator of intraocular pressure through modulation of extracellular matrix and cell cytoskeleton proteins in trabecular meshwork cells. [ABSTRACT FROM AUTHOR]

Scleral extracellular matrix (ECM) remodeling is thought to play a critical role in the pathogenesis of glaucoma. Mechanical strain induced by elevated intraocular pressure can promote myofibroblast differentiation of fibroblasts and result in scleral ECM remodeling; however, the underlying mechanism remains poorly understood. Yes-associated protein (YAP) is a mechanosensory protein and the key downstream transcriptional effector of the Hippo signaling pathway. Here, we investigated the role of YAP in mechanical strain-induced myofibroblast transformation during glaucoma scleral ECM remodeling. Integrative bioinformatics analyses were performed to identify the key pathways for the ECM remodeling of the sclera in glaucoma. Sprague–Dawley rats were used to establish a chronic ocular hypertension model, and the expression of collagen type I (COL1) and YAP in the sclera was analyzed by immunohistochemical analysis and Western blotting. Furthermore, human scleral fibroblasts (HSFs) were cultured and subjected to mechanical strain. In groups with or without the YAP siRNA or YAP inhibitor, cell proliferation, migration capacity, and the expression levels of YAP, COL1, and α-smooth muscle actin (α-SMA) were evaluated by Cell Counting Kit-8 assay, scratch assay, and Western blotting. The interactions between YAP and Smad3 were demonstrated by coimmunoprecipitation, and the expression levels of COL1 and α-SMA were evaluated in groups treated with or without the Smad3 inhibitor. We first revealed that the Hippo signaling pathway may be involved in mechanical strain-induced scleral ECM remodeling through bioinformatics analysis. Furthermore, the in vivo study showed upregulated YAP, COL1, and α-SMA expression in the hypertensive sclera of rats. In vitro , mechanical strain increased YAP and COL1 expression in HSFs and promoted myofibroblast differentiation. After YAP knockdown or inhibition with verteporfin, mechanical strain-induced fibrotic changes in HSFs were markedly suppressed. Additionally, YAP showed a protein interaction with Smad3, and the upregulation of a-SMA and COL1 in response to mechanical strain was also significantly downregulated following the inhibition of Smad3. In conclusion, mechanical strain activated scleral myofibroblast differentiation via YAP. The YAP pathway may play an important role in regulating scleral myofibroblast differentiation and ECM remodeling of the sclera in glaucoma. [ABSTRACT FROM AUTHOR]

Background: Particulate matter (PM) is strongly linked to human health and has detrimental effects on the eye. Studies have, however, focused on the ocular surface, with limited research on the impact of PM2.5 on intraocular pressure (IOP). Methods: To investigate the impact of PM2.5 on IOP and the associated mechanism, C57BL/6 mouse eyes were topically exposed to a PM2.5 suspension for 3 months, and human trabecular meshwork (HTM) cells were subjected to various PM2.5 concentrations in vitro. Cell viability, NLRP3/caspase-1, IL-1β, and GSDMD expression, reactive oxygen species (ROS) production and cell contractility were measured by western blot, ELISA, cell counting kit-8, ROS assay kit or a cell contractility assay. ROS scavenger N-acetyl-L-cysteine (NAC) and caspase-1 inhibitor VX-765 were used to intervene in PM2.5-induced damages. Results: The results revealed that the IOP increased gradually after PM2.5 exposure, and upregulations of the NLRP3 inflammasome, caspase-1, IL-1β, and GSDMD protein levels were observed in outflow tissues. PM2.5 exposure decreased HTM cell viability and affected contraction. Furthermore, elevated ROS levels were observed as well as an activation of the NLRP3 inflammasome and downstream inflammatory factors caspase-1 and IL-1β. NAC improved HTM cell viability, inhibited the activation of the NLRP3 inflammasome axis, and HTM cell contraction by scavenging ROS. VX-765 showed similar protection against the PM2.5 induced adverse effects. Conclusion: This study provides novel evidence that PM2.5 has a direct toxic effect on intraocular tissues and may contribute to the initiation and development of ocular hypertension and glaucoma. This occurs as a result of increased oxidative stress and the subsequent induction of NLRP3 inflammasome mediated pyroptosis in trabecular meshwork cells. [ABSTRACT FROM AUTHOR]

Circular RNAs are characterized as a class of covalently closed circular RNA transcripts and are associated with a variety of cellular processes and neurological diseases by sponging microRNAs. Expression profiling of circular RNAs in glaucoma, which is a form of optic neuropathy, has not been performed to date. The most common characteristic of all forms of glaucoma is the loss of retinal ganglion cells. While the pathogenesis of glaucoma is not fully understood, intraocular pressure is unquestionably the only proven modifiable factor which makes chronic ocular hypertension (COH) animals the classical glaucoma models. Based on these findings, we completed the first in-depth study of rat retinal circular RNA expression profiling to identify probable biomarkers for the diagnosis of glaucoma. Two ocular hypertension models were induced by episcleral vein ligation (EVL) and microbead injection in rats. Overall, 15,819 circular RNA were detected. Furthermore, 3,502 differentially expressed circular RNAs verified in both COH rats were identified, of which 691 were upregulated and 2,811 were downregulated. Seven significantly downregulated (both log2FoldChange < −2.5 and adjusted P < 0.001) and seven significantly upregulated (both log2FoldChange > 2.5 and adjusted P < 0.001) circular RNAs were shown. Six target microRNAs aligned with the top 14 circular RNAs were identified. According to the construction of the circular RNA-microRNA network and circBase information, only RNO_CIRCpedia_1775 had the homologous hsa_circ_0023826 in the human genome. The hsa_circ_0023826 and mRNA of the host gene TENM4 (teneurin transmembrane protein 4) were validated in aqueous humor samples of five glaucoma patients and five cataract control patients. The expression of hsa_circ_0023826 showed a significant decrease in glaucoma patients, while TENM4 mRNA showed no significant difference compared to cataract patients (P = 0.024 and P = 0.294, respectively). The results of this study comprehensively characterized the expression profiles of circular RNA in glaucoma-affected eyes, as verified by two different ocular hypertension rat models. Together with the target microRNAs underlying the top differentially expressed circular RNAs, a new target of hsa_circ_0023826 and its host gene TENM4 were identified and further verified in the aqueous humor of glaucoma patients, indicating a promising biomarker for the disease. [ABSTRACT FROM AUTHOR]

Intraocular pressure (IOP) generates stress and strains in the laminar cribrosa and sclera, which may affect the development and progression of glaucoma. Scleral stiffness and material components have changed under elevated IOP. However, the detailed changes of the components of the hypertensive sclera are not well understood. In this study, we aimed to investigate the changes of the main components in the scleral extracellular matrix (ECM), and matrix metalloproteinase 2 (MMP2) and their relationship with time under chronic elevated IOP in Sprague–Dawley rats. An ocular hypertension model was established in the right eyes by anterior chamber injection with 0.3% carbomer solution. The left eye was used as the contralateral control. Immunofluorescent imaging of the tissue frozen sections, Western blot analysis, and quantitative PCR (qPCR) were performed to detect the expressions of type I collagen (COL1), elastin, and MMP2 in the sclera. The ocular hypertension model was successfully established. As compared to the left eyes, the immunofluorescence imaging, Western blot analysis, and qPCR showed that COL1, elastin, and MMP2 were significantly increased in the right eyes at 1 week (all P < 0.05). At 2 weeks, COL1 in the right eyes tended to be lower than that in the left eyes, while elastin and MMP2 were still higher (all P < 0.05) in the right eyes. When the IOP was elevated for 4 weeks, both COL1 and MMP2 were lower than those in the left eyes (all P < 0.05), while elastin between the two eyes was similar (P > 0.05). Under this 4-week hypertensive state, COL1 and elastin were initially elevated at 1 week, and then obviously reduced from 2 to 4 weeks. Consistently, MMP2 was gradually increased, with a peak at 2 weeks, and then decreased at 4 weeks. In conclusion, the chronic elevated IOP induced dynamic scleral ECM alterations in rats in a pressure- and time-dependent manner. MMP2 may play an important role in the balance between ECM synthesis and degradation and could potentially be a novel target for glaucoma intervention. [ABSTRACT FROM AUTHOR]

Epidemiological studies suggest that ambient particulate matter exposure may be a new risk factor of glaucoma, but it lacks solid experimental evidence to establish a causal relationship. In this study, young mice (4 weeks old) were exposed concentrated ambient PM 2.5 (CAP) for 9 months, which is throughout most of the life span of a mouse under heavy pollution. CAP was introduced using a versatile aerosol concentration enrichment system which mimics natural PM 2.5 exposure. CAP exposure caused a gradual elevation of intraocular pressure (IOP) and an increase in aqueous humor outflow resistance. In the conventional outflow tissues that regulates IOP, inducible nitric oxide synthase (iNOS) was up-regulated and 3-nitrotyrosine (3-NT) formation increased. At the cellular level, PM 2.5 exposure increased the transendothelial electrical resistance of cells that control IOP (AAP cells). This is accompanied by increased reactive oxygen species (ROS), iNOS and 3-NT levels. Peroxynitrite scavenger MnTMPyP successfully treated the IOP elevation and restored it to normal levels by reducing 3-NT formation in outflow tissues. This study provides the novel evidence that in young mice, lifetime whole-body PM 2.5 exposure has a direct toxic effect on intraocular tissues, which imposes a significant risk of IOP elevation and may initiate the development of ocular hypertension and glaucoma. This occurs as a result of protein nitration of conventional aqueous humor outflow tissues. • This study provides the first evidence that lifetime whole-body exposure to PM 2.5 leads to intraocular pressure (IOP) elevation. • PM 2.5 elicits IOP elevation by causing excessive protein nitration, which can be prevented by a peroxynitrite scavenger. [ABSTRACT FROM AUTHOR]