Shouyue Huang

Relevant variations and neuroprotecive effect of hydrogen sulfide in a rat glaucoma model

Glaucoma is an irreversible and blinding neurodegenerative disease of the eye, and is characterized by progressive loss of retinal ganglion cells (RGCs). Since endogenous hydrogen sulfide (H2S) was reported to be involved in neurodegeneration in the central nervous system, the authors aimed to develop a chronic ocular hypertension (COH) rat model simulating glaucoma and therein test the H2S level together with the retinal protein expressions of related synthases, and further investigated the effect of exogenous H2S supplement on RGC survival. COH rat model was induced by cross-linking hydrogel injection into anterior chamber, and the performance of the model was assessed by intraocular pressure (IOP) measurement, RGC counting and retinal morphological analysis. Endogenous H2S level was detected along with the retinal protein expressions of H2S-related synthases cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST) in the COH rats. Retinal H2S level and RGC survival were evaluated again after NaHS (a H2S donor) treatment in the COH rats. The results showed that the COH model succeeded in simulating glaucoma features, and retinal H2S level decreased significantly when the retinal protein expressions of CBS, CSE and 3-MST were downregulated generally in the COH rats. Furthermore, the decrease of retinal H2S level and loss of RGCs were both improved by NaHS treatment in experimental glaucoma, without obvious variation of IOP. Our study revealed that the intracameral injection of cross-linking hydrogel worked efficiently in modeling glaucoma, and H2S had protective effect on RGCs and might be involved in the pathological mechanism of glaucomatous neuropathy.

Peripapillary Choroidal Thickness and Open-Angle Glaucoma: A Meta-Analysis

Purpose. To investigate the potential relationship between open-angle glaucoma (OAG) and peripapillary choroidal thickness (PPCT). Materials and Methods. Relevant publications were searched systematically through various databases from inception to January 2016. Studies comparing PPCT in OAG patients and healthy controls were retrieved. All qualified articles were analyzed using Stata 14.0 and Revman 5.3 software. Results. A total of 13 studies were identified for inclusion. There was a significant reduction of average PPCT in OAG patients compared to control participants (WMD = −24.07, 95% CI: −34.29, −13.85). Reduction of PPCT was significant in the superior (WMD = −28.87, 95% CI: −44.96, −12.78) and nasal (WMD = −21.75, 95% CI: −41.52, −1.98) sectors, but there was no significant reduction of PPCT in the inferior (WMD = −9.57, 95% CI: −36.55, 17.40) and temporal (WMD = −13.85, 95% CI: −35.40, 7.70) sectors. No obvious publication bias was detected. Conclusions. This meta-analysis suggests that open-angle glaucoma patients have significantly decreased peripapillary choroidal thickness compared to healthy individuals. Peripapillary choroidal thickness measured by optical coherence tomography may be an important parameter to consider in open-angle glaucoma.

The Effect of A2A Receptor Antagonist on Microglial Activation in Experimental Glaucoma.

PURPOSE We investigated the effect of A2A receptor (A2AR) antagonist on microglial activation and retinal ganglion cell (RGC) survival under chronic ocular hypertension (COH), and explored the relationship between microglial activation and RGC survival by means of in vitro and in vivo experiments. METHODS An animal model of COH was induced in one eye of male Sprague-Dawley (SD) rats by ligation of three episcleral veins. The survival of RGCs and the activation of microglia under COH without or with intravitreous injection of A2AR antagonist ZM241385 were assessed by fluorescent labeling, real time PCR and Western blot. ELISA was used to measure the secretion of inflammatory mediators by microglia when glutamate and/or ZM241385 was added into the culture system. RESULTS Compared to the baseline, RGC density 2 weeks after COH induction decreased at the central (2436 ± 143 cells/mm2 pre- and 2130 ± 148 cells/mm2 post-COH induction) and peripheral (2219 ± 140 cells/mm2 pre- and 1953 ± 142 cells/mm2 post-COH induction) retina. The microglia changed their ramified morphology to an amoeboid form with increase in TNF-α and IL-1β expression after COH. These changes, however, were ameliorated with intravitreous ZM241385 (RGC density only dropped to 2287 ± 135 cells/mm2). The upregulation of those proinflammatory cytokines secreted by microglia in vitro under high concentration of glutamate was downregulated when ZM241385 was added into the culture system. CONCLUSIONS A2AR antagonist ZM241385 could reduce the activation of microglia and downregulate the proinflammatory cytokines expression under the conditions of COH and high concentration of glutamate, which may be one of the mechanisms that protected RGCs in experimental glaucoma.

Effect of adenosine and adenosine receptor antagonist on Müller cell potassium channel in Rat chronic ocular hypertension models

Müller cells are principal glial cells in rat retina and have attracted much attention in glaucoma studies. However, it is not clear whether adenosine and adenosine receptor (AR) antagonists play any roles in the regulation of potassium channels in Müller cells and subsequently in the promotion of glutamine synthetase (GS) and L-Glutamate/L-Aspartate Transporter (GLAST) functions. We found that chronic ocular hypertension (COH) in rat down-regulated Müller cells Kir2.1, Kir4.1, TASK-1, GS and GLAST expressions and attenuated the peak of inward potassium current. Retinal ganglion cells (RGC) count was lower in the COH rats than that in the sham operation animals. Intravitreal injection of selective A2A AR antagonist SCH442416 up-regulated Müller cell Kir4.1, TASK-1, GS and GLAST expressions and enhanced inward potassium currents compared with those in the COH rats with vehicle control. Meanwhile, the RGC count was higher following intravitreal injection of SCH442416 in the COH rats than that after vehicle injection. The fact that PKA inhibitor H-89 blocked these SCH442416 effects suggested that the PKA signaling pathway was involved in the observed ocular responses following the intravitreal SCH442416 injection.

Color Doppler Imaging Analysis of Ocular Blood Flow Velocities in Normal Tension Glaucoma Patients: A Meta-Analysis.

Background. To evaluate the potential diagnostic value of CDI of retrobulbar hemodynamic changes in NTG patients. Methods. Relevant publications which included PSV, EDV, and RI of OA, CRA, NPCA, and TPCA in NTG patients and normal controls measured by CDI were retrieved from the Cochrane Central Register of Controlled Trials, PubMed, the ISI Web of Knowledge, and EMBASE from 1990 to 2014. Subgroup analyses were made based on IOP-lowering medications uses. Result. In OA, there was significant decrease of PSV with moderate heterogeneity (P < 0.00001, I 2 = 49%) and significant decrease of EDV with significant heterogeneity (P = 0.0005, I 2 = 87%) in NTG patients. In CRA, similar results of PSV (P < 0.00001, I 2 = 42%) and EDV (P < 0.00001, I 2 = 80%) were detected. Significant decrease of PSV and EDV with significant heterogeneity was also found in both NPCA (P < 0.0001, I 2 = 70%; P < 0.0001, I 2 = 76%; resp.) and TPCA (P < 0.00001, I 2 = 54%; P < 0.00001, I 2 = 65%; resp.). Statistically significant increases of RI were found in CRA (P = 0.0002, I 2 = 89%) and TPCA (P = 0.02, I 2 = 81%) with significant heterogeneities, though RI in OA (P = 0.25, I 2 = 94%) and in NPCA (P = 0.15, I 2 = 86%) showed no statistical changes with significant heterogeneities. Conclusions. Ischemic change of retrobulbar hemodynamics is one of the important manifestations of NTG. Hemodynamic parameters measured by CDI might be potential diagnostic tools for NTG.

Hydrogen sulfide supplement attenuates the apoptosis of retinal ganglion cells in experimental glaucoma

ABSTRACT Glaucoma is a group of neurodegenerative eye diseases characterized by progressive impairment of visual function due to loss of retinal ganglion cells (RGC). As hydrogen sulfide (H2S) was reported to play a role in the process of glaucomatous neuropathy and improve RGC survival in experimental glaucoma, the authors aimed to investigate the anti‐apoptosis effect of H2S supplement in a rat glaucoma model, and further tried to explore the involved factors in the neuroprotection. A chronic ocular hypertension (COH) rat model induced by intracameral injection of cross‐linking hydrogel was employed to simulate glaucoma and 288 rats were subjected to experimental procedures in the present study. After 4 weeks of sodium hydrosulfide (NaHS) administration following COH induction, the apoptosis of RGC isolated from experimented rats as well as apoptosis of neurons in ganglion cell layer (GCL), intrinsic apoptotic pathway activity, mitochondrial function, glial activation, NF‐&kgr;B pathway activity, NADPH oxidase activity, autophagy activity and TNF‐&agr; level in retina were evaluated. The results showed that H2S supplement effectively attenuated the apoptosis of RGC in experimental glaucoma, and the neuroprotection by H2S might correlate with preservation of mitochondrial function, attenuation of oxidative stress, suppression of glial activation, inhibition of inflammatory pathways and downregulation of autophagy. Our study indicated that H2S supplement resulted in significant neuroprotection through attenuation of RGC apoptosis which might be linked with multiple factors in experimental glaucoma. The new therapeutic strategy might potentially contribute to benefit glaucoma treatment, which is worth further concerns. HIGHLIGHTSAimed to investigate how H2S took part in the neuroprotection of glaucoma.H2S supplement attenuated the apoptosis of RGC in experimental glaucoma.Various factors might be involved in the protection by H2S on RGC.

Comparison of canaloplasty and trabeculectomy for open angle glaucoma: a Meta-analysis.

AIM To evaluate the advantage of canaloplasty compared to trabeculectomy for patients with open angle glaucoma. METHODS Potentially relevant studies were systematically searched using various databases from inception until December 2015. The outcome analyses performed automatically using Revman 5.3 included intraocular pressure reduction (IOPR), postoperative success rate, anti-glaucoma medications reduction and the incidence of adverse events. RESULTS We included four qualified studies incorporating a total of 215 eyes for quantitative synthesis. The weighted mean difference (WMD) of IOPR between canaloplasty and trabeculectomy from baseline to 12mo was -2.33 (95%CI: -4.00, -0.66). There was not significant improvement in the complete or qualified success rate (OR: 0.58, 95%CI: 0.26, 1.31; OR: 0.50, 95%CI: 0.10, 2.44, respectively). Similarly, no statistically significance was observed in anti-glaucoma mediations reduction (WMD: -0.54, 95%CI: -1.18, 0.09). Sensitivity analysis of the primary outcome estimate confirmed the stability of the Meta-analysis result. CONCLUSION Trabeculectomy seems to be more effective in lowering IOP up to 12mo when comparing with canaloplasty. Canaloplasty does not seem to be inferior to trabeculectomy considering the postoperative success rate or the number of postoperative anti-glaucoma medications. Meanwhile, it has an advantage of less bleb related complications.

Effect of SCH442416 on glutamate uptake in retinal Müller cells at increased hydrostatic pressure.

The A2A receptor (A2AR) antagonist has been considered as an attractive option to improve the treatment of neurological disorders, and the function of A2AR antagonist may inhibit the release of glutamate and prevent neuron damage. The aim of the present study was to investigate whether SCH442416 can modulate the glutamate uptake in retinal Müller cells under increased hydrostatic pressure. The levels of glutamine synthetase (GS) and glutamate aspartate transporter (GLAST) were assessed in retinal Müller cells under 40 mmHg pressure for 24 h using reverse transcription‑quantitative polymerase chain reaction and western blotting, and a glutamate uptake assay was performed using a scintillation counting method. Following treatment of the Müller cells with 100 nM SCH442416 under 40 mmHg pressure for 24 h, the mRNA and protein expression levels of GS and GLAST, and glutamate uptake activity were investigated. Under 40 mmHg pressure, the expression levels of GS and GLAST in the Müller cells, and glutamate uptake activity were significantly reduced. Treatment with SCH442416 significantly ameliorated the decreased expression levels of GS and GLAST, and improved the glutamate uptake activity in the retinal Müller cells exposed to 40 mmHg pressure, resulting in increased expression levels of GS and GLAST, and increased glutamate uptake activity in the Müller cells under pressure. These results suggested that SCH442416 may be a potential candidate as a beneficial neuroprotective agent for the treatment of glaucoma by accelerating the clearance of extracellular glutamate.

Concordance of 24‑h intraocular pressure curve in patients with untreated unilateral primary open‑angle glaucoma

The present study aimed to assess the concordance of 24-h intraocular pressure (IOP) curves between glaucomatous and contralateral eyes for patients with untreated unilateral primary open-angle glaucoma (POAG). A total of 32 patients with unilateral POAG and 32 age-matched normal subjects were enrolled. The IOP measurements were performed every 2 h over a 24-h period. The concordance of the 24-h IOP curves was assessed via the correlation coefficient (r), intraclass correlation coefficient (ICC) and repeated-measures analysis of variance (ANOVA). No significant difference was identified between all IOPs, as well as the mean, peak and trough IOP or IOP fluctuations of the paired eyes in the two groups. The strength of association of all IOPs was moderate in the glaucoma group (r, 0.752-0.867) and the normal controls (r, 0.625-0.873). IOP readings at each time-point indicated a high agreement in the glaucoma group (ICC, 0.857-0.929) and the normal controls (ICC, 0.768-0.932). Repeated-measures ANOVA indicated that the 24-h IOP curves of the paired eyes had parallel profiles in the two study groups (P=0.837 and P=0.897, respectively). The glaucoma patients had significantly higher proportions of all IOPs displaying absolute differences of ≥2 and ≥3 mmHg (46.09 vs. 35.68%, P<0.001; 29.69 vs. 12.50%, P<0.001, respectively). In conclusion, the 24-h IOP curves of the paired eyes had parallel profiles in unilateral glaucoma patients and normal subjects. However, unilateral glaucoma patients had a significantly larger proportion of IOP differences of ≥2 and ≥3 mmHg.

Effect of Adenosine and Adenosine Receptor Antagonists on Retinal Müller Cell Inwardly Rectifying Potassium Channels under Exogenous Glutamate Stimulation

The vitreousness of glaucoma subjects contains elevated glutamate, and excessive extracellular glutamate is toxic to retinal neurons. Therefore, glutamate clearance is potentially impaired in the retina of glaucoma subjects. Müller cells play an important role in maintaining low extracellular levels of neurotransmitters, such as glutamate. A better understanding of the cross-talk between adenosine and glutamate may provide a better characterization of the regulatory network in Müller cells. Here, Müller cells were purified from the rat retina on postnatal day 5 using the papain digestion method. Application of increasing concentrations of glutamate (0-20 mmol/L) caused a dose-dependent decrease in the expression levels of Kir4.1, Kir2.1, GLAST, and GS. Exogenous adenosine regulated Kir channels and subsequently promoted GLAST and GS expression levels in Müller cells under exogenous glutamate stimulation. These effects were partly dependent on adenosine receptors.