Search

Purpose: To investigate that the changes of lamina cribrosa (LC) thickness and depth after latanoprost therapy in primary open-angle glaucoma (POAG) and ocular hypertension (OHT) patients., Methods: In this single-center prospective cross-sectional study, 35 eyes from 35 patients with POAG or OHT (study group) and 26 age- and gender- matched healthy individuals (control group) were included. All participants were examined by spectral domain optical coherence tomography (SD-OCT) with enhanced depth imaging (EDI) mode for LC thickness and depth measurements at the first visit before latanoprost therapy and at visits after 1 (second visit) and 3 (third visit) months of latanoprost therapy., Results: The mean LC thickness in both horizontal and vertical scans of the study group were thinner than the control group (p < 0.001, for both). During latanoprost therapy in the study group, the LC thickness values in horizontal scans significantly differed over the three visits, gradually increased (p < 0.05). There was significantly decrease in LC depth in horizontal scans between the first and third visits, and the second and third visits (p = 0.003 and p = 0.008, respectively). The gradual decrease in LC depth in vertical scans was observed at all visits, but the statistically significant difference was between the first and third visits only (p = 0.048)., Conclusion: POAG/OHT patients showed more LC thinning compared with healthy individuals. The significant increase in LC thickness and the significant decrease in LC depth were detected after IOP reduction therapy with latanoprost in ocular hypertensive/ glaucomatous eyes., Competing Interests: Declaration of competing interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper., (Copyright © 2024. Published by Elsevier B.V.)

In April 2018, a 20-year-old man with a history of methanol intoxication from an alcoholic drink two years ago, when he was 18 years old, was referred to Nikookari Eye Hospital in Tabriz, Iran. He was admitted to emergency service and underwent eight hours of hemodialysis at the time of poisoning. His past medical history was negative, and he did not take any medication after discharge. The patient had a driving license and never experienced any visual problems before. At presentation, his visual acuity was 160/200 in both eyes with the main complaint of visual field deterioration. Other neurologic exams and brain magnetic resonance imaging (MRI) were reported normal by a neurologist. Optic disc cupping was near total in both eyes with a very narrow remaining rim. Optic disc cupping was very similar to glaucomatous cupping. Intraocular pressure was checked several times via Goldmann tonometry and was 13 mmHg. There was no history of refractive surgery leading to thin cornea. Based on this case, methanol poisoning can mimic glaucomatous optic disc cupping. This is the first case report of methanol toxicity-related optic disc cupping from Iran., Competing Interests: Conflict of Interest: None declared., (Copyright: © Iranian Journal of Medical Sciences.)

Glaucoma is a group of optic neuropathies that leads to irreversible vision loss. The optic nerve head (ONH) is the site of initial optic nerve damage in glaucoma. ONH-derived lamina cribrosa (LC) cells synthesize extracellular matrix (ECM) proteins; however, these cells are adversely affected in glaucoma and cause detrimental changes to the ONH. LC cells respond to mechanical strain by increasing the profibrotic cytokine transforming growth factor-beta 2 (TGFβ2) and ECM proteins. Moreover, microRNAs (miRNAs or miR) regulate ECM gene expression in different fibrotic diseases, including glaucoma. A delicate homeostatic balance between profibrotic and anti-fibrotic miRNAs may contribute to the remodeling of ONH. This study aimed to determine whether modulation of miRNAs alters the expression of ECM in human LC cells. Primary human normal and glaucoma LC cells were grown to confluency and treated with or without TGFβ2 for 24 h. Differences in expression of miRNAs were analyzed using miRNA qPCR arrays. miRNA PCR arrays showed that the miR-29 family was significantly decreased in glaucomatous LC cell strains compared to age-matched controls. TGFβ2 treatment downregulated the expression of multiple miRNAs, including miR-29c-3p, compared to controls in LC cells. LC cells transfected with miR-29c-3p mimics or inhibitors modulated collagen expression.

Background/aim: To evaluate the effect of the long-term use of systemic immunosuppressive drugs on druse formation in patients aged over 50 years., Materials and Methods: The current retrospective cohort study includes 420 eyes of 420 patients. 210 eyes of 210 patients who used immunosuppressive drugs (Group 1) at least for the last 5 years and 210 eyes of 210 control patients (Group 2) who did not use any drugs were compared. All patients were older than 50 years and selected among patients who were followed by rheumatology and ophthalmology clinic at a tertiary university hospital. All patients had complete ophthalmic examination, fundus photography and optical coherence tomography (OCT). The primary outcome of this study is the difference in macular and paramacular druse formation rates between two groups., Results: Small, intermediate, large, soft, and paramacular druse formation rates were significantly lower in Group 1 than those in Group 2 (P = 0.028, P = 0.001, P = 0.001, P = 0.001, and P = 0.001, respectively)., Conclusion: Patients who used long-term systemic immunosuppressive drugs had significantly lower hard and soft druse formation rate than age and sex matched control subjects., Competing Interests: None of the authors have any proprietary interests or conflicts of interest related to this submission., (This work is licensed under a Creative Commons Attribution 4.0 International License.)

Purpose: We determined whether δ-opioid receptor agonist (SNC-121) regulates acetylation homeostasis via controlling histone deacetylases (HDACs) activity and expression in optic nerve head (ONH) astrocytes., Methods: ONH astrocytes were treated with SNC-121 (1 µM) for 24 hours. The HDAC activity was measured using HDAC-specific fluorophore-conjugated synthetic substrates, Boc-Lys(Ac)-AMC and (Boc-Lys(Tfa)-AMC). Protein and mRNA expression of each HDAC was determined by Western blotting and quantitative real-time PCR. IOP in rats was elevated by injecting 2.0 M hypertonic saline into the limbal veins., Results: Delta opioid receptor agonist, SNC-121 (1 µM), treatment increased acetylation of histone H3, H2B, and H4 by 128 ± 3%, 45 ± 1%, and 68 ± 2%, respectively. The addition of Garcinol, a histone-acetyltransferase inhibitor, fully blocked SNC-121-induced histone H3 acetylation. SNC-121 reduced the activities of class I and IIb HDACs activities significantly (17 ± 3%) and this decrease in HDACs activities was fully blocked by a selective δ-opioid receptors antagonist, naltrindole. SNC-121 also decrease the mRNA expression of HDAC-3 and HDAC-6 by 19% and 18%, respectively. Furthermore, protein expression of HDAC 1, 2, 3, and 6 was significantly (P < 0.05) decreased by SNC-121 treatment. SNC-121 treatment also reduced lipopolysaccharide-induced TNF-α production from ONH astrocytes and glial fibrillary acidic protein immunostaining in the optic nerve of ocular hypertensive animals., Conclusions: We provided evidence that δ-opioid receptor agonist activation increased histone acetylation, decrease HDACs class I and class IIb activities, mRNA, and protein expression, lipopolysaccharide-induced TNF-α production in ONH astrocytes. Our data also demonstrate that SNC-121 treatment decrease glial fibrillary acidic protein immunostaining in the optic nerves of animals with ocular hypertension.

It has been hypothesized that besides its intraocular pressure (IOP) lowering potential, tetrahydrocannabinol (THC) may also improve ocular hemodynamics. The aim of the present study was to investigate whether single oral administration of dronabinol, a synthetic THC, alters optic nerve head blood flow (ONHBF) and its regulation in healthy subjects. The study was carried out in a randomized, placebo-controlled, double-masked, two-way crossover design in 24 healthy subjects. For each study participant, 2 study days were scheduled, on which they either received capsules containing 5 mg dronabinol or placebo. ONHBF was measured with laser Doppler flowmetry at rest and while the study participants performed isometric exercise for 6 minutes to increase mean arterial blood pressure (MAP). This was repeated 1 hour after drug intake. Ocular perfusion pressure (OPP) was calculated as 2/3MAP-IOP. Dronabinol was well tolerated and no cannabinoid-related psychoactive effects were reported. Neither administration of dronabinol nor placebo had an effect on IOP, MAP, or OPP. In contrast, dronabinol significantly increased ONHBF at rest by 9.5 ± 8.1%, whereas placebo did not show a change in ONHBF (0.3 ± 7.4% vs. baseline, P < 0.001 between study days). Dronabinol did not alter the autoregulatory response of ONHBF to isometric exercise. In conclusion, the present data indicate that low-dose dronabinol increases ONHBF in healthy subjects without affecting IOP, OPP, or inducing psychoactive side effects. In addition, dronabinol does not alter the autoregulatory response of ONHBF to an experimental increase in OPP. Further studies are needed to investigate whether this effect can also be observed in patients with glaucoma., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: To assess if there are any differences in macular and papillary thickness using optical coherence tomography (OCT) in patients with attention deficit hyperactivity disorder (ADHD) compared with a control group, including if there are differences between ADHD patients with and without treatment., Methods: Prospective observational study including 92 eyes of 46 patients divided into 2 groups: 46 eyes of 23 patients with ADHD, and a control group of 46 eyes of 23 healthy patients. The group of patients with ADHD was subdivided into those on treatment with methylphenidate (n=28) and those not on treatment (n=18). The macular thickness, the ganglion cell complex (GCC), and the retinal nerve fibre layer (RNFL) at the papillary level were measured in 12 sectors., Results: A lower central macular thickness was observed in the ADHD patients than in the controls (257.4±20μm versus 267.5±20μm, P=.013), with no differences observed in the GCC (P=.566), or in the RNFL (P=.095). There were no differences in the patients with ADHD with and without treatment, as regards macular thickness and the GCC (P=.160 and P=.375 respectively), but a lower foveal thickness (P=.018) and RNFL in 5/12 sectors at the papillary level (P=.033) were observed in those without treatment., Conclusions: A lower macular thickness was observed in patients with ADHD than in controls. In addition, patients with ADHD without treatment had a lower thickness of the fovea and RNFL than those patients on treatment., (Copyright © 2020 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.)

Purpose: To investigate the function and expression of the PGE2 receptors EP1-4 in rat retinal ischemia-reperfusion (I/R) injury and to determine the regulatory role of resveratrol (RES) in this process., Methods: In vitro, we stimulated primary astrocytes extracted from the optic disc of rats with epidermal growth factor (EGF) and RES, and detected the location of EP1-4 expression with immunofluorescence. The expression of antiglial fibrillary acidic protein (GFAP), EGF receptor (EGFR), inducible NOS (iNOS), and EP1-4 in astrocytes was detected with western blotting. In vivo, we established an I/R injury model and RES treatment model with Sprague-Dawley rats. Changes in the thickness of the inner retina were observed with hematoxylin and eosin (H&E) staining. EP1-4 localization in the retina was observed with immunohistochemistry. The expression of COX-2, iNOS, and EP1-4 in the control and model groups was detected with western blotting., Results: In this study, immunofluorescence and immunohistochemistry showed that EP1-4 are expressed in astrocytes and the rat retina. EGF stimulation increased the expression of EGFR, iNOS, EP1, EP2, and EP4 in astrocytes. The expression of EP1-4 was statistically significantly increased on the third day after model induction, and EP1-4 expression decreased to normal levels on day 7. EGF and RES mediated the decrease in the expression of EP2. RES treatment significantly reduced retinal damage and RGC loss, as demonstrated by the relatively intact tissue structure on day 7 observed with H&E staining. Moreover, inflammation was associated with this I/R injury model, as demonstrated by the early induction of proinflammatory mediators, and this inflammation was significantly attenuated after RES treatment., Conclusions: These results indicate that the COX-2/PGE2/EPs pathway is involved in retinal damage and astrocyte inflammation. In addition, the results suggest that the neuroprotective effects of RES may be associated with decreased production of inflammatory mediators. These results suggest that the PGE2 receptor may be a key factor in the treatment of neurodegenerative diseases, and that RES may be used as a possible therapeutic strategy for glaucoma., (Copyright © 2020 Molecular Vision.)

Purpose: To evaluate the effects of intravitreal ranibizumab (IVR) treatment on the blood flow of the optic nerve head (ONH) and of retinal vessels of the peripapillary region of eyes with diabetic macular edema (DME) assessed using laser speckle flowgraphy (LSFG)., Methods: Forty eyes of 30 patients treated with IVR for DME were included in this prospective clinical study. Mean blur rate (MBR) and relative flow volume (RFV) of the ONH and of a superior retinal artery and an inferior retinal vein of the peripapillary region were measured using LSFG at baseline, 2 weeks (T1), and 1 month (T2) after IVR injection. In addition, best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were measured in all cases., Results: The BCVA improved and CRT decreased significantly during the follow-up period ( p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA., Conclusion: IVR injection leads to a reduction of ocular blood flow both in the ONH and in the retinal peripapillary vessels associated with peripapillary vessel constriction. The reduction of CRT and related improvement of vision may be related to the changes in ocular blood flow., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Lisa Toto et al.)

Purpose: To evaluate acute and chronic changes in optic nerve head (ONH) structures and intraocular pressure (IOP) in patients receiving intravitreal injections (IVIs) of anti-VEGF., Methods: Twenty-nine eyes receiving IVIs for the first time were studied. IOP, retinal nerve fiber layer (RNFL) thickness, and ONH structures were evaluated by Spectralis optical coherence tomography with enhanced depth imaging technology. Structures were measured before and 5 min after each one of the three monthly injections of a loading dose treatment. In 13 eyes (44.8%) with more than six IVIs, another evaluation pre and immediately postinjection was performed after 1 year., Results: A significant acute and transient IOP increase (all p ≤ 0.001), Bruch's membrane opening (BMO) enlargement (p ≤ 0.001), cup widening (p < 0.05) and deepening (p ≤ 0.001), and prelaminar tissue thinning (p ≤ 0.001) were observed 5 min after each injection. Compared with baseline values, a significant BMO expansion (p = 0.001) and RNFL thinning (p < 0.001) were observed in the third month. In eyes with more than six IVIs, similar immediate postinjection changes, including IOP increase (p = 0.001), prelaminar tissue thinning (p = 0.007), and cup deepening (p = 0.012) were observed at 1 year, while BMO expansion was not significant (p = 0.556). Compared with baseline preinjection values, a significant BMO expansion (p = 0.003), prelaminar tissue thinning (p = 0.011), and cup deepening (p = 0.006) in the inferior region of the ONH occurred. No change in IOP was observed at the end of follow-up., Conclusions: Repeated IVIs could lead to irreversible changes in ONH structures. Large-scale, prospective studies are required to determine the long-term effects of anti-VEGF treatments in ONH tissues.

Competing Interests: There are no conflicts of interest.

Purpose: We assess if α retinal ganglion cells (αRGCs) and intrinsically photosensitive retinal ganglion cells (ipRGCs) survive in mouse models of glaucoma., Methods: Two microliters of N-methyl-D-aspartate (NMDA; 1 mM) or PBS were injected intraocularly 7 days before sacrifice. Immunohistochemical analyses of the retina were performed using antibodies against RNA-binding protein with multiple splicing (RBPMS), osteopontin, and melanopsin. Immunohistochemical analyses also were performed in adult mice with glutamate/aspartate transporter (GLAST) deletion (GLAST knockout [KO] mice), a mouse model of normal tension glaucoma., Results: NMDA-induced loss of RBPMS-positive total RGCs was 58.4% ± 0.4% compared to PBS-treated controls, whereas the loss of osteopontin-positive αRGCs was 5.0% ± 0.6% and that of melanopsin-positive ipRGCs was 7.6% ± 1.6%. In GLAST KO mice, the loss of total RGCs was 48.4% ± 0.9% compared to wild-type mice, whereas the loss of αRGCs and ipRGCs was 3.9% ± 0.4% and 9.3% ± 0.5%, respectively. The distribution of survived total RGCs, αRGCs, and ipRGCs was similar regardless of the location of the retina., Conclusions: These results suggest that αRGC and ipRGC are highly tolerant to NMDA-induced neurotoxicity and NTG-like neurodegeneration in GLAST KO mice.

The purpose of this study was to investigate the effects of latanoprost, an ocular hypotensive prostaglandin analog, on scleral collagen fibers and laminar pores in myopic guinea pigs. Young guinea pigs underwent monocular form deprivation (FD; white plastic diffusers) from 14-days of age for 10-weeks. After the first week, FD eyes also received daily topical A) latanoprost (Lat, 0.005%, n = 5) or B) artificial tears (AT; n = 5). At the end of the treatment period, animals were sacrificed, eyes enucleated and optic nerve heads (ONH) excised to include a 4 mm diameter ring of surrounding sclera for scanning electron microscopy (SEM), and an additional 6 mm ring of sclera surrounding the ONH was excised for transmission electron microscopy (TEM). For SEM, ONH samples were first immersed in 0.2M NaOH for 30 h to isolate the collagenous structures. All samples were stained with osmium tetroxide, dried through an ethanol series and finally subjected to critical point drying before imaging. Image J was used to analyze the dimensions of laminar pores (SEM images) and scleral collagen fibers (TEM images). As previously reported in a related study, latanoprost was effective in inhibiting myopia progression in FD eyes of the guinea pigs. The scleral fibers of FD myopic eyes treated with AT were smaller and more variable in cross-sectional areas compared to untreated (fellow) eyes (mean areas: 0.0059 ± 0.0013 vs. 0.0085 ± 0.002 μm 2 ; p < 0.001), consistent with scleral changes reported for human myopia. In contrast, the scleral fibers of the Lat-treated FD eyes were similar to those of fellow eyes (0.0083 ± 0.002 vs. 0.0078 ± 0.0014 μm 2 ). However, laminar pore size appeared unaffected by either the FD or drug treatments, with no significant difference found between FD eyes and their fellows, for either treatment group. That daily topical latanoprost appeared to protect against myopia-related changes in scleral collagen, rather than exaggerating them, as might be predicted from its known action on the uveoscleral extracellular matrix, lends further support its use for myopia control. In this guinea pig myopia model, the lamina cribrosa appeared unaffected., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To investigate the potential toxic effects of levetiracetam monotherapy on ocular tissues in cases of pediatric epilepsy using optical coherence tomography (OCT)., Methods: Thirty epileptic children (group 1) receiving levetiracetam monotherapy at a dosage of 20-40 mg/kg/day for at least 1 year with a first diagnosis of epilepsy and 30 age- and gender-matched healthy children (group 2) were included in the study. In addition to a detailed eye examination, peripapillary retinal nerve fiber layer (RNFL) thickness, ganglion cell complex (GCC) thickness, foveal thickness (FT), and central corneal thickness (CCT) were measured in all children by means of spectral domain OCT. The data obtained from the two groups were then subjected to statistical analysis., Results: The mean age of both groups was 12 ± 3.64 years [1-12]. The mean duration of levetiracetam in group 1 was 24.07 ± 12.82 months. Mean RNFL values in groups 1 and 2 were 106.1 ± 10.42 and 104.98 ± 10.04 μm, mean GCC values were 94.72 ± 6.26 and 94.4 ± 6 μm, mean FT values were 240.73 ± 17.94 and 240.77 ± 15.97 μm, and mean CCT values were 555.1 ± 44.88 and 540.97 ± 32.65 μm, respectively. No significant difference was determined between the two groups in terms of any parameter. Best corrected visual acuity values of the subjects in both groups were 10/10, and no color vision or visual field deficit was determined., Conclusion: Levetiracetam monotherapy causes no significant function or morphological change in ocular tissues in pediatric epilepsies.

Purpose: The purpose of this study was to investigate the association between long-term intranasal steroid use and intraocular pressure (IOP) elevation., Patients and Methods: In total, 100 eyes from 50 patients on long-term intranasal steroids (>2 y) for allergic rhinitis and 90 eyes from 45 controls were included in this study. Patients on other forms of steroids and risk factors for glaucoma were excluded. IOP was measured and nonmydriatic stereoscopic optic disc photos were taken for each eye. The vertical cup-to-disc ratio and the status of the optic disc were evaluated., Results: The mean IOP for intranasal steroids group was significantly higher (15.24±2.31 mm Hg) compared to the control group (13.91±1.86 mm Hg; P=0.000). However, there were no significant differences in the vertical cup-to-disc ratio and the status of glaucomatous optic disc changes between the groups., Conclusions: Prolonged use of intranasal steroids cause statistical significant increase in IOP in patients with allergic rhinitis although no significant glaucomatous disc changes were seen. We suggest patients on long-term use of intranasal steroid have a yearly eye examination to be monitored for IOP elevation and those with additional risk factors for glaucoma is closely monitored for glaucoma.

Purpose: To evaluate the effect of topically administrated ripasudil, a rho kinase inhibitor, on blood flow in the optic nerve head (ONH) of normal rats., Methods: Ripasudil (0.4%) or placebo was administered in the right eye of normal Brown Norway rats in a double-blind manner. Laser speckle flowgraphy was measured in the ONH of the right eye 20 or 40 min after a single instillation and before and after 7 or 14 days of twice daily instillation. Mean blur rate was evaluated in the total area (MA), the vessel region (MV), and the tissue region (MT). Intraocular pressure (IOP), blood pressure, ocular perfusion pressure (OPP), and heart rate were also recorded at each time point., Results: After a single instillation, MV was significantly larger at 40 min than 20 min in the ripasudil group (P = 0.044) and was significantly lower in the placebo group (P = 0.023). MA and MV 40 min after instillation were significantly larger in the ripasudil group than in the placebo group (P = 0.022 and P = 0.006, respectively). After continuous instillation, MA and MV in the ripasudil group significantly increased from baseline after 7 and 14 days of treatment (both P < 0.05) and MA, MV, and MT were significantly higher than in the placebo group (MA: 7 and 14 days, P < 0.01; MV: 7 days, P = 0.003, and 14 days, P = 0.012; MT: 7 days, P = 0.046). There were no significant changes in IOP, blood pressure, or OPP after single or continuous instillation., Conclusions: Topical instillation of ripasudil increased blood flow around the ONH in the eyes of normal rats.

Purpose: Brain-derived neurotrophic factor (BDNF) and activation of its high affinity receptor tropomyosin kinase (Trk) B promote retinal ganglion cells (RGCs) survival following injury. In this study, we tested the effects of LM22A-4, a small molecule TrkB receptor-specific partial agonist, on RGC survival in vitro and in experimental nonarteritic anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in those older than 50 years., Methods: We assessed drug effects on immunopanned, cultured RGCs and calculated RGC survival and assessed TrkB receptor activation by mitogen-activated protein (MAP) kinase translocation. To assess effects in vivo, we induced murine AION and treated the animals with one intravitreal injection and three-week systemic treatment. We measured drug effects using serial spectral-domain optical coherence tomography (OCT) and quantified retinal Brn3A + RGC density three weeks after ischemia., Results: In vitro, LM22A-4 significantly increased the survival of cultured RGCs at day 2 (95% CI control: 8.4-13.6; LM22A-4: 23.7-30.3; BDNF: 24.3-29.9; P ≤ 0.0001), similar to the effect of the endogenous TrkB receptor ligand BDNF. There was also significant nuclear and cytoplasmic translocation of MAP kinase (95% CI control: 0.9-6.8; LM22A-4: 38.8-84.4; BDNF: 64.0-93.0; P = 0.0002), a known downstream event of TrkB receptor activation. Following AION, LM22A-4 treatment led to significant preservation of the ganglion cell complex (95% CI: AION-PBS: 66.8-70.7%; AION-LM22A-4: 70.0-73.1; P = 0.03) and total retinal thickness (95% CI: AION-PBS: 185-196%; AION-LM22A-4: 195-203; P = 0.002) as measured by OCT compared with non-treated eyes. There was also significant rescue of the Brn3A + RGC density on morphometric analysis of whole mount retinae (95% CI control: 2360-2629; AION-PBS: 1647-2008 cells/mm 2 ; AION-LM22A-4: 1958-2216 cells/mm 2 ; P = 0.02)., Conclusions: TrkB receptor partial agonist LM22A-4 promoted survival of cultured RGCs in vitro by TrkB receptor activation, and treatment in vivo led to increased survival of RGCs after optic nerve ischemia, providing support that LM22A-4 may be effective therapy to treat ischemic optic neuropathy., Abbreviations: AION: anterior ischemic optic neuropathy, BDNF: Brain-derived neurotrophic factor, GCC: ganglion cell complex, MAP: mitogen-activated protein, OCT: spectral-domain optical coherence tomography, OD: right eye, ON: optic nerve, ONH: optic nerve head, OS: left eye, RGC: retinal ganglion cell; Trk: tropomyosin kinase.

Purpose: To study the dynamics and clinical determinants of chronic retinal nerve fiber layer thickness (RNFL) loss after methanol-induced optic neuropathy., Design: Prospective cohort study., Methods: All patients underwent complete ophthalmic evaluation including spectral-domain optical coherence tomography 3 times during 4 years of observation: 4.9 (±0.6), 25.0 (±0.6), and 49.9 (±0.5) months after discharge., Participants: Eighty-four eyes of 42 survivors of methanol poisoning, mean age (standard deviation) of 45.7 (±4.4) years; and 82 eyes of 41 controls, mean age 44.0 (±4.2) years., Main Outcome Measures: Global and temporal RNFL loss., Results: Abnormal RNFL thickness was registered in 13 of 42 (31%) survivors of methanol poisoning and chronic axonal loss in 10 of 42 (24%) patients. Significant decrease of global/temporal RNFL thickness during the observation period was found in the study population compared to the controls (P < .001). The risk estimate of chronic global RNFL loss for arterial blood pH < 7.3 at admission was 11.65 (95% confidence interval 1.91-71.12) after adjusting for age and sex. The patients with chronic axonal degeneration demonstrated progressive visual loss in 7 of 10 cases. The patients with abnormal RNFL thickness had magnetic resonance signs of brain damage in 10 of 13 vs 8 of 29 cases with normal RNFL thickness (P = .003). Signs of brain hemorrhages were present in 7 of 13 patients with abnormal RNFL thickness vs 5 of 29 cases with normal RNFL thickness (P = .015)., Conclusions: Methanol-induced optic neuropathy may lead to chronic retinal axonal loss during the following years. Arterial blood pH on admission is the strongest predictor of chronic RNFL thickness decrease. Chronic retinal neurodegeneration is associated with the progressive loss of visual functions and necrotic brain lesions., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

This study reports the short-term efficacy and safety of intravitreal conbercept injections for neovascularization at the disc (NVD) in patients with proliferative diabetic retinopathy (PDR). Conbercept is a recombinant fusion protein with a high affinity for all isoforms of vascular endothelial growth factor (VEGF)-A, placental growth factor and VEGF-B. A prospective case series study was conducted in 15 patients (15 eyes). Patients had complete ocular examinations and received a 0.5 mg intravitreal conbercept injection followed by supplemental pan-retinal photocoagulation (PRP). Optical coherence tomography angiography (OCTA) was performed before and after treatment. Before treatment, the mean NVD area was 1.05 ± 0.33 mm 2 , and it decreased to 0.56 ± 0.17 mm 2 after an interval of 7.5 d (p = 0.000). One eye required vitrectomy during follow-up. Recurrent NVD was observed in 2 eyes, which resolved after repeated injections. The remaining 12 eyes were stable over a mean follow-up period of 8.3 months. The mean area of the NVD in 14 patients without vitrectomy was 0.22 ± 0.11 mm 2 (p = 0.000) at the last visit. Intravitreal conbercept injections combined with intensive PRP are an effective and safe treatment for PDR with NVD. Quantitative information on NVD can be obtained with OCTA, which may be clinically useful in evaluating the therapeutic effect.

Purpose: Optic nerve cupping in glaucoma is characterized by remodeling of the extracellular matrix (ECM) and fibrosis in the lamina cribrosa (LC). We have previously shown that glaucoma LC cells express raised levels of ECM genes and have elevated intracellular calcium ([Ca2+]i). Raised [Ca2+]i is known to promote proliferation, activation, and contractility in fibroblasts via the calcineurin-NFAT (nuclear factor of activated T-cells) signaling pathway. In this study, we examine NFAT expression in normal and glaucoma LC cells, and investigate the effect of cyclosporin A (CsA, a known inhibitor of NFAT activity) on [Ca2+]i and ECM gene expression in normal and glaucoma LC cells., Methods: [Ca2+]i was measured with dual-wavelength Ca2+ imaging and confocal microscopy using Fura-2-AM and Fluo-4 under physiological isotonic and hypotonic cell stretch treatment. Human donor LC cells were cultured under normal physiological conditions or using a glaucoma-related stimulus, oxidative stress (H2O2, 100 μM), for 6 hours with or without CsA. NFATc3 protein levels were examined using Western blot analysis. Profibrotic ECM gene transcription (including transforming growth factor-β1 [TGFβ1], collagen 1A1 [Col1A1], and periostin) was analyzed using quantitative real time RT-PCR., Results: Basal and hypotonic cell membrane stretch-induced [Ca2+]i were significantly (P < 0.05) elevated in glaucoma LC cells compared to normal controls. There was a significant delay in [Ca2+]i reuptake into internal stores in the glaucoma LC cells. NFATc3 protein levels were increased in glaucoma LC cells. CsA (10 μM) significantly inhibited the H2O2-induced expression of NFATc3 in normal and glaucoma LC cells. CsA also reduced the H2O2-induced NFATc3 dephosphorylation (and nuclear translocation), and also suppressed the H2O2-induced elevation in profibrotic ECM genes (TGFβ1, Col1A1, and periostin), both in normal and in glaucoma LC cells., Conclusions: Intracellular Ca2+ and NFATc3 expression were significantly increased in glaucoma LC cells. CsA reduced the H2O2-induced enhancement in NFATc3 protein expression and nuclear translocation and the profibrotic gene expression both in normal and in glaucoma LC cells. Therefore, targeting the calcineurin-NFATc3 signaling pathway may represent a potential avenue for treating glaucoma-associated LC fibrosis.

Recent studies found that peripapillary microcirculation was damaged in glaucoma patients, indicating that blood flow in the optic nerve head is important in the pathogenesis of glaucoma. Effects of different antiglaucoma drugs on optic papilla blood flow deserve attention. Prostaglandins is the first line antiglaucoma drug. The experimental and clinical studies on the potential of prostaglandins to modify the blood flow in the optic papilla and related mechanisms are reviewed in this article. Effects of ocular blood flow increase on the treatment of glaucoma require further investigations. (Chin J Ophthalmol, 2017, 53: 73-76) .

Aim: to investigate neuromidin effectiveness in the treatment of patients with primary glaucoma and compensated intraocular pressure (IOP)., Material and Methods: A total of 40 patients (80 eyes) were examined. Of them, 10 eyes with early glaucoma, 36 eyes with moderate-stage glaucoma, 33 eyes with advanced glaucoma, and 1 eye with end-stage glaucoma. In 19 eyes, IOP was controlled through beta-blockers, in 11 eyes - through carbonic anhydrase inhibitors, in 10 eyes - through prostaglandin analogues, and in 39 eyes - through combination drugs. Twenty-six eyes had received glaucoma surgery some time earlier. Ipidacrine was prescribed in tablets at 20 mg 2 times daily for 25 days. Treatment effectiveness was judged by visual functions, hydrodynamics, and morphometric parameters of the optic disc., Results: In moderate-stage eyes, visual acuity improved in 66.6% of cases and remained unchanged in 33.3%. In advanced-stage eyes, visual acuity improved in 51.5% of cases and remained unchanged in 48.5%. Visual field broadened in all cases. Moreover, under the neuromidin therapy, the number of scotomas in early-stage eyes decreased, while the number of areas with normal sensitivity of the retina increased by 14.9%. In advanced-stage glaucoma, the effect was less pronounced: the number of type 1 and type 2 scotomas decreased by 3.0±0.6% and 2.9±0.8%, respectively; the number of absolute scotomas did not change; the number of areas with normal sensitivity of the retina increased by 7.4±2.0%. Also, P0 was found to be reduced and intraocular fluid outflow - activated. In early and moderate glaucoma, there was a significant reduction in the cup area as well as an increase in the neuroretinal rim area and retinal nerve fiber layer thickness. In advanced-stage cases, it was only the retinal nerve fiber layer thickness that changed., Conclusion: Neuromidin has a positive impact on visual function, hydrodynamics, and morphometric parameters of the optic disc.

Purpose: To study the effect of topical administration of bromfenac, a nonsteroidal anti-inflammatory drug (NSAID), on retinal gliosis and levels of prostaglandin E2 (PGE2) after complete optic nerve crush (ONC)., Methods: Adult albino rats were divided into the following groups (n = 8 retinas/group): (1) intact, (2) intact and bromfenac treatment (twice a day during 7 days), (3) ONC (7 days), and (4) ONC (7 days) + bromfenac treatment (twice a day during 7 days). Animals from groups 3 and 4 were imaged in vivo with spectral-domain optical coherence tomography (SD-OCT) before the procedure and 15 minutes, 3, 5, or 7 days later. Retinas from all groups were analyzed by immunodetection, Western blotting, or enzyme-linked immunoabsorbent assay (ELISA)., Results: Quantification of Brn3a (brain-specific homeobox/POU domain protein 3A) +RGCs (retinal ganglion cells) in cross sections showed that bromfenac treatment does not accelerate ONC-induced degeneration. Cellular retinaldehyde binding protein 1 regulation indicated that bromfenac improves retinal homeostasis in injured retinas. Spectral-domain OCT showed that the thickness of the retina and the retinal nerve fiber layer at 7 days post ONC was significantly reduced in bromfenac-treated animals when compared to untreated animals. In agreement with these data, hypertrophy of astrocytes and Müller cells and expression of glial fibrillary acidic protein and vimentin were greatly diminished by bromfenac treatment. While no changes in cyclooxygenase (COX) enzyme COX1 and COX2 expression were observed, there was a significant increase of PGE2 after ONC that was controlled by bromfenac treatment., Conclusions: Topical administration of bromfenac is an efficient and noninvasive treatment to control the retinal gliosis and release of proinflammatory mediators that follow a massive insult to the RGC population.

Objective: The aim of this study was to compare sonoelastographic findings in the retina-choroid-sclera (RCS) complex and vitreous in glaucomatous and healthy eyes., Methods: For this cross-sectional comparative study, 20 patients with primary open-angle glaucoma and 20 healthy volunteers were recruited. Ultrasound elastography measurements were taken with a sonographic scanner of the RCS complex, anterior vitreous (AV), posterior vitreous (PV), retrobulbar fat tissue (RFT), optic disc (OD) and optic nerve (ON) in each eye., Results: The elasticity index of the RCS complex, RFT, OD, ON, AV and PV was similar in both groups (p  >  0.05), although the AV/PV strain ratio in the group of patients with glaucoma was significantly higher (p  =  0.04)., Conclusion: Glaucoma increases the AV/PV strain ratio. In providing reproducible and consistent values, the real-time elastography (RTE) technique may be helpful in elucidating the mechanisms of glaucoma in some aspects., Advances in Knowledge: This study can help to evaluate the elasticity of the RCS complex and vitreous in glaucomatous eyes with RTE.

Purpose: To determine if oral losartan treatment decreases the retinal ganglion cell (RGC) death caused by experimental intraocular pressure (IOP) elevation in mice., Methods: We produced IOP increase in CD1 mice and performed unilateral optic nerve crush. Mice received oral losartan, spironolactone, enalapril, or no drug to test effects of inhibiting angiotensin receptors. IOP was monitored by Tonolab, and blood pressure was monitored by tail cuff device. RGC loss was measured in masked axon counts and RGC bodies by β-tubulin labeling. Scleral changes that could modulate RGC injury were measured including axial length, scleral thickness, and retinal layer thicknesses, pressure-strain behavior in inflation testing, and study of angiotensin receptors and pathways by reverse transcription polymerase chain reaction, Western blot, and immunohistochemistry., Results: Losartan treatment prevented significant RGC loss (median loss = 2.5%, p = 0.13), while median loss with water, spironolactone, and enalapril treatments were 26%, 28% and 43%; p < 0.0001). The lower RGC loss with losartan was significantly less than the loss with spironolactone or enalapril (regression model p = 0.001; drug treatment group term p = 0.01). Both losartan and enalapril significantly lowered blood pressure (p< 0.001), but losartan was protective, while enalapril led to worse than water-treated RGC loss. RGC loss after crush injury was unaffected by losartan treatment (difference from control p = 0.9). Survival of RGC in cell culture was not prolonged by sartan treatment. Axonal transport blockade after 3 day IOP elevations was less in losartan-treated than in control glaucoma eyes (p = 0.007). Losartan inhibited effects of glaucoma, including reduction in extracellular signal-related kinase activity and modification of glaucoma-related changes in scleral thickness and creep under controlled IOP., Conclusions: The neuroprotective effect of losartan in mouse glaucoma is associated with adaptive changes in the sclera expressed at the optic nerve head.

Purpose: To assess the frequency and significance of optic disk cupping after methanol poisoning., Methods: We retrospectively reviewed the medical records of 50 consecutive patients with methanol poisoning, including visual acuity, pupillary reaction, and optic disk features such as the presence and degree of cupping. All patients were examined in the chronic phase after optic nerve damage., Results: Optic disk cupping ≥0.8 c/d was present in at least one eye of 22 of these 50 patients (43/100 eyes). Severity of cupping was statistically symmetric in the two eyes, and increasing severity of cupping was correlated with worse visual acuity (p=0.007) and increasing visual field loss. Degree of cupping was significantly correlated with increasing patient age but not with putaminal necrosis., Conclusions: Optic disk cupping after methanol poisoning may be more common than previously recognised. Cupping in this setting may reflect toxicity of methanol metabolites to axons and glial cells in the prelaminar, laminar and retrolaminar regions, and seems to be important as a marker for worse optic nerve damage., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Glaucoma is the leading cause of irreversible blindness and is characterized by slow and progressive degeneration of the optic nerve head axons and retinal ganglion cell (RGC), leading to loss of visual function. Although oxidative stress and/or alteration of mitochondrial (mt) dynamics induced by elevated intraocular pressure (IOP) are associated with this neurodegenerative disease, the mechanisms that regulate mt dysfunction-mediated glaucomatous neurodegeneration are poorly understood. Using a mouse model of glaucoma, DBA/2J (D2), which spontaneously develops elevated IOP, as well as an in vitro RGC culture system, we show here that oxidative stress, as evidenced by increasing superoxide dismutase 2 (SOD2) and mt transcription factor A (Tfam) protein expression, triggers mt fission and loss by increasing dynamin-related protein 1 (DRP1) in the retina of glaucomatous D2 mice as well as in cultured RGCs exposed to elevated hydrostatic pressure in vitro. DRP1 inhibition by overexpressing DRP1 K38A mutant blocks mt fission and triggers a subsequent reduction of oxidative stress, as evidenced by decreasing SOD2 and Tfam protein expression. DRP1 inhibition promotes RGC survival by increasing phosphorylation of Bad at serine 112 in the retina and preserves RGC axons by maintaining mt integrity in the glial lamina of glaucomatous D2 mice. These findings demonstrate an important vicious cycle involved in glaucomatous neurodegeneration that starts with elevated IOP producing oxidative stress; the oxidative stress then leads to mt fission and a specific form of mt dysfunction that generates further oxidative stress, thus perpetuating the cycle. Our findings suggest that DRP1 is a potential therapeutic target for ameliorating oxidative stress-mediated mt fission and dysfunction in RGC and its axons during glaucomatous neurodegeneration. Thus, DRP1 inhibition may provide a new therapeutic strategy for protecting both RGCs and their axons in glaucoma and other optic neuropathies.

Purpose: To describe a case of optic nerve head tubercular granuloma, unresponsive to conventional therapy (antitubercular drugs and systemic steroids), successfully treated with anti-vascular endothelial growth factor (VEGF) intravitreal injections in addition to systemic drugs., Methods: Case report., Results: A 44-year-old patient was referred to our clinic for progressive vision decrease in his left eye during the preceding 4 months. A large granuloma infiltrating optic nerve head was visible at funduscopic examination along with diffuse intraocular inflammation. Workup for granulomatous uveitis supported the diagnosis of presumed intraocular tuberculosis. However, the large granulomatous lesion did not show a good response to conventional therapy for tubercular uveitis (antitubercular drugs and systemic steroids). Anti-VEGF (bevacizumab) intravitreal injections were performed as an adjunct to the ongoing therapy. After 2 injections, the patient showed an almost complete regression of the lesion (demonstrated by optical coherence tomography) and a restoration of vision., Conclusions: Anti-VEGF intravitreal injections should be considered in the treatment of large tubercular granulomatous lesions in addition to conventional systemic therapy. Optical coherence tomography could be a suitable tool for studying and following optic nerve head granulomas.

The present study demonstrates the effect of neovibsanin B on the synthesis and deposition of ECM proteins and the signalling pathways used in optic nerve head (ONH) astrocytes and lamina cribrosa (LC) cells. For investigation of the signalling pathway used by neovibsanin B, ONH cells were treated with neovibsanin B. Western blot and immunostaining analyses were used to examine the phosphorylation of proteins involved in Smad and non-Smad signalling pathway. The results revealed that ONH cells on treatment with neovibsanin B showed enhanced synthesis of extracellular matrix (ECM) proteins. Neovibsanin B induced phosphorylation of canonical signalling proteins, Smad2/3. However phosphorylation of non-canonical signalling proteins, extracellular signal-regulated kinases, p38, and c-Jun N-terminal kinases (JNK) 1/2 remained unaffected. There was also increase in co-localization of pSmad2/3 with Co-Smad4 in the nucleus of ONH astrocytes and LC cells indicating activation of the canonical Smad signalling pathway. Treatment of ONH cells with SIS3, inhibitor of Smad3 phosphorylation reversed the neovibsanin B stimulated ECM expression as well as activation of canonical pathway signalling molecules. In addition, inhibition of Smad2 or Smad3 using small interfering RNA (siRNA) also suppressed neovibsanin B stimulated ECM protein synthesis in ONH astrocytes and LC cells. Thus neovibsanin B utilizes the canonical Smad signalling pathway to stimulate ECM synthesis in human ONH cells. The neovibsanin B induced ECM synthesis and activation of the canonical Smad signalling pathway may be due to its effect on transforming growth factor-β2 (TGF-β2). However, further studies are under process to understand the mechanism.

Introduction: Glaucoma is a neurodegenerative disease with heterogeneous causes that result in retinal ganglionic cell (RGC) death. The discovery of ocular antihypertensives has shifted glaucoma therapy, largely, from surgery to medical intervention. Indeed, several intraocular pressure (IOP)-lowering drugs, with different mechanisms of action and RGC protective property, have been developed., Areas Covered: In this review, the authors discuss the main new class of kinase inhibitors used as glaucoma treatments, which lower IOP by enhancing drainage and/or lowering production of aqueous humor. The authors include novel inhibitors under preclinical evaluation and investigation for their anti-glaucoma treatment. Additionally, the authors look at treatments that are in clinics now and which may be available in the near future., Expert Opinion: Treatment of glaucoma remains challenging because the exact cause is yet to be delineated. Neuroprotection to the optic nerve head is undisputable. The novel Rho-associated kinase inhibitors have the capacity to lower IOP and provide optic nerve and RGC protection. In particular, the S-isomer of roscovitine has the capacity to lower IOP and provide neuroprotection. Combinations of selected drugs, which can provide maximal and sustained IOP-lowering effects as well as neuroprotection, are paramount to the prevention of glaucoma progression. In the near future, microRNA intervention may be considered as a potential therapeutic target.

Background: Glaucoma is a progressive optic nerve degenerative disease that often leads to blindness. Local inflammatory responses are implicated in the pathology of glaucoma. Although inflammatory episodes outside the CNS, such as those due to acute systemic infections, have been linked to central neurodegeneration, they do not appear to be relevant to glaucoma. Based on clinical observations, we hypothesized that chronic subclinical peripheral inflammation contributes to neurodegeneration in glaucoma., Methods: Mouthwash specimens from patients with glaucoma and control subjects were analyzed for the amount of bacteria. To determine a possible pathogenic mechanism, low-dose subcutaneous lipopolysaccharide (LPS) was administered in two separate animal models of glaucoma. Glaucomatous neurodegeneration was assessed in the retina and optic nerve two months later. Changes in gene expression of toll-like receptor 4 (TLR4) signaling pathway and complement as well as changes in microglial numbers and morphology were analyzed in the retina and optic nerve. The effect of pharmacologic blockade of TLR4 with naloxone was determined., Findings: Patients with glaucoma had higher bacterial oral counts compared to control subjects (p<0.017). Low-dose LPS administration in glaucoma animal models resulted in enhancement of axonal degeneration and neuronal loss. Microglial activation in the optic nerve and retina as well as upregulation of TLR4 signaling and complement system were observed. Pharmacologic blockade of TLR4 partially ameliorated the enhanced damage., Conclusions: The above findings suggest that the oral microbiome contributes to glaucoma pathophysiology. A plausible mechanism by which increased bacterial loads can lead to neurodegeneration is provided by experiments in animal models of the disease and involves activation of microglia in the retina and optic nerve, mediated through TLR4 signaling and complement upregulation. The finding that commensal bacteria may play a role in the development and/or progression of glaucomatous pathology may also be relevant to other chronic neurodegenerative disorders.

As adenosine 5'-triphosphate (ATP) released from astrocytes can modulate many neural signaling systems, the triggers and pathways for this ATP release are important. Here, the ability of mechanical strain to trigger ATP release through pannexin channels and the effects of sustained strain on pannexin expression were examined in rat optic nerve head astrocytes. Astrocytes released ATP when subjected to 5% of equibiaxial strain or to hypotonic swelling. Although astrocytes expressed mRNA for pannexins 1-3, connexin 43, and VNUT, pharmacological analysis suggested a predominant role for pannexins in mechanosensitive ATP release, with Rho kinase contribution. Astrocytes from panx1(-/-) mice had reduced baseline and stimulated levels of extracellular ATP, confirming the role for pannexins. Swelling astrocytes triggered a regulatory volume decrease that was inhibited by apyrase or probenecid. The swelling-induced rise in calcium was inhibited by P2X7 receptor antagonists A438079 and AZ10606120, in addition to apyrase and carbenoxolone. Extended stretch of astrocytes in vitro upregulated expression of panx1 and panx2 mRNA. A similar upregulation was observed in vivo in optic nerve head tissue from the Tg-MYOC(Y437H) mouse model of chronic glaucoma; genes for panx1, panx2, and panx3 were increased, whereas immunohistochemistry confirmed increased expression of pannexin 1 protein. In summary, astrocytes released ATP in response to mechanical strain, with pannexin 1 the predominant efflux pathway. Sustained strain upregulated pannexins in vitro and in vivo. Together, these findings provide a mechanism by which extracellular ATP remains elevated under chronic mechanical strain, as found in the optic nerve head of patients with glaucoma., (© 2014 Wiley Periodicals, Inc.)

Purpose: To investigate the neuroprotective effects of sphingosine-1-phosphate (S1P) analogue fingolimod (FTY720) in experimental glaucoma in rats., Methods: A unilateral chronic ocular hypertensive model was established by injections of microbeads into the anterior eye chamber of adult Sprague-Dawley rats. Fingolimod was administered to one group of rats intraperitoneally every week for 3 months. The scotopic threshold response (STR) was recorded to assess the function of the inner retina. Changes in cell density in the ganglion cell layer (GCL) were evaluated by hematoxylin and eosin staining on retinal sections and axonal count of the optic nerve was performed using Bielschowsky's silver staining. Effects of drug treatment on activation of Akt and Erk1/2 were evaluated using Western blotting by assessing phosphorylation levels of these proteins. The expression of S1P receptors in the optic nerve head region was also evaluated using Western blotting and immunohistochemistry., Results: Administration of FTY720 reduced the loss of STR amplitude in glaucomatous eyes (P < 0.05). Counting and plotting the cell numbers/axonal density showed significant neural preservation in the GCL and the optic nerve (P < 0.05). An increased phosphorylation level of Akt and Erk1/2 following FTY720 administration was observed. Both S1P1 and S1P5 receptors were found to be expressed in the retina and the expression of S1P1R was upregulated in experimentally-induced glaucoma., Conclusions: This study demonstrates, for the first time, that FTY720 could act as a neuroprotective agent to protect retinal ganglion cells in experimental glaucoma. Administration of this drug significantly reduces the structural and functional loss of the inner retina elicited indicating that it may potentially be used to attenuate neuronal loss and optic nerve damage in glaucomatous patients., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: We investigated whether intravitreal infusion solution containing epinephrine affects optic nerve head (ONH) blood flow during vitreous surgeries., Methods: The subjects were 22 patients with epimacular membrane or idiopathic macular hole. During vitreous surgery, ONH blood flow was examined before and 10 minutes after intravitreal infusion of solution containing epinephrine, via a laser speckle flowgraphy (LSFG) technique modified for acquiring measurements in a supine position. Epinephrine concentration was set at 1.0 mg/500 mL (1:500,000) or 0.5 mg/500 mL (1:1,000,000), with each concentration assigned to 11 consecutive patients. Relative pupil diameter, IOP, blood pressure, and pulse rate also were measured., Results: A significant reduction in blood flow throughout the ONH was induced by intravitreal infusion of epinephrine at 1:500,000, but not at 1:1,000,000. Blood flow in ONH tissue was diminished at both concentrations, while that in vessels of the ONH was not altered significantly by either concentration. Both epinephrine concentrations induced significant pupillary dilatation, but no significant changes in IOP, blood pressure, or pulse rate., Conclusions: This study suggests that epinephrine, used in combination with intravitreal infusion solution, may decrease ONH blood flow during vitreous surgeries, as indicated by measurements obtained via a modified LSFG technique. Attention must be paid to the effects of intravitreal infusion of epinephrine on ocular circulation, particularly ONH blood flow.

Purpose: To investigate the clinical value of assessment of peripapillary retinal nerve fibre layer (RNFL) thickness with OCT in addition to the evaluation of retinal function measured by full-field electroretinography (ff-ERG) in patients with suspected vigabatrin (VGB)-attributed visual field defects., Methods: Visual fields from adult patients in our clinical follow-up program for VGB medication were analysed. Twelve patients with suspected VGB-attributed visual field defects were selected for the study. They were re-examined with computerized kinetic perimetry, ff-ERG and OCT (2D circle scan)., Results: Constricted visual fields were found in all patients. Comparative analysis of ff-ERG parameters showed reduced b-wave amplitudes for the isolated and the combined rod and cone responses (p < 0.0001). The a-wave, reflecting photoreceptor activity, was reduced (p = 0.001), as well as the summed amplitude of oscillatory potentials (p = 0.029), corresponding to inner retinal function. OCT measurements demonstrated attenuation of the RNFL in nine of 12 patients, most frequently superiorly and/or inferiorly. No temporal attenuation was found. Significant positive correlations were found between the total averaged RNFL thickness, superior and inferior RNFL thickness and reduced ff-ERG parameters. Positive correlations were also found between RNFL thickness and isopter areas., Conclusion: OCT measurements can detect attenuation of the RNFL in patients exposed to VGB medication. RNFL thickness correlates with reduced ff-ERG parameters and isopter areas of constricted visual fields, indicating that VGB is retino-toxic on several levels, from photoreceptors to ganglion cells. The study also supports previous studies, suggesting that OCT measurement of the RNFL thickness may be of clinical value in monitoring patients on vigabatrin therapy., (© 2013 The Authors. Acta Ophthalmologica © 2013 Acta Ophthalmologica Scandinavica Foundation.)

A 35-year-old female was referred to our hospital with bilateral loss of vision of two days duration. She gave history of consumption of about 150 ml of neem oil five days back.Examination revealed no perception of light in both eyes. Both pupils were dilated and sluggishly reacting to light. Her fundus examination showed bilateral hyperemic, edematous discs and also edema extending along the superior and inferior temporal vascular arcade. Magnetic resonance imaging (MRI) scan showed bilateral putaminal regions with altered signal, hypointensities in T1-weighted images, hyperintensities on T2-weighted, images and hyperintense on Fluid Attenuation Inversion Recovery (FLAIR) images suggestive of cytotoxic edema due to tissue hypoxia. Her vision improved to 20/200 in both eyes with treatment after two months. This is the first case report of such nature in the literature to the best of our knowledge.

Purpose: To evaluate the effect of bevacizumab, a VEGF inhibitor, on optic nerve edema and retinal ganglion cell (RGC) loss in a mouse model of optic nerve crush (ONC)., Methods: Two hundred C57BL/6 wild-type mice were anesthetized. Right ONC was induced in 150 mice, of which half (n = 75) received an intravitreal injection of bevacizumab immediately thereafter and half (n = 75) did not. The remaining 50 received only bevacizumab. The left eyes served as a control. Findings were analyzed by fluorescein angiography (days 0, 1, 3), histologic and immunohistochemical tests (days 1, 3, 4, 21), and quantitative real-time PCR., Results: Angiography revealed a reduction in postinjury disc leakage following bevacizumab injection (days 1, 3), confirmed with IgG staining. On PCR, expression of HO-1 and SOD-1 mRNA increased following ONC and further increased with bevacizumab. VEGF gene expression decreased following bevacizumab injection without ONC, remained at baseline after ONC, and increased slightly after ONC+bevacizumab. Histologically, there was a 38% RGC loss 21 days after ONC alone, which dropped to 14% with bevacizumab treatment; it was close to 15% with bevacizumab alone. Mean (SEM) microvascular perfusion in the optic nerve 4 days after ONC was significantly higher in the bevacizumab-treated (85% ± 10%) than the vehicle-treated (33% ± 13%) animals., Conclusions: Bevacizumab treatment following ONC induction exerts a protective effect, manifested by reduced optic nerve head edema. The underlying mechanism probably involves a lesser interruption of axonal transport. Reduced expression of antioxidative and ischemic genes may contribute to RGC preservation.

Purpose: We examined the signaling mechanisms involved in δ-opioid-receptor agonist, SNC-121-mediated attenuation of TNF-α-induced matrix metalloproteinase-2 (MMP-2) secretion from human optic nerve head (ONH) astrocytes., Methods: Human ONH astrocytes were treated with SNC-121 (1 μmol/L) for 15 minutes followed by TNF-α (25 ng/mL) treatment for 6 or 24 hours. Cells were pretreated with inhibitors of p38 mitogen-activated protein (MAP) kinase (SB-203580) or NF-κB (Helenalin) prior to TNF-α treatment. Changes in phosphorylation and expression of p38 MAP kinase, IκBα, NF-κB, and MMP-2 were measured by Western blotting. Translocation of NF-κB was determined by immunocytochemistry., Results: TNF-α treatment increased MMP-2 secretion from ONH astrocytes to 236% ± 17% and 142% ± 8% at 6 and 24 hours, respectively; while SNC-121 treatment reduced MMP-2 secretion to 149% ± 11% and 108% ± 7% at 6 and 24 hours, respectively. The SNC-121-mediated inhibitory response was blocked by the δ-opioid-receptor antagonist naltrindole. TNF-α treatment resulted in a sustained phosphorylation of p38 MAP kinase up to 24 hours (226% ± 15% over control levels), which was reduced to 150% ± 20% by SNC-121 treatment. TNF-α treatment increased the expression of NF-κB to 179% ± 21% and 139% ± 6% at 6 and 24 hours, respectively, which was significantly blocked by SNC-121 treatment. Furthermore, TNF-α-induced MMP-2 secretion was blocked by 100% and 78% in the presence of SB-203580 and Helenalin, respectively., Conclusions: Evidence is provided that SNC-121 attenuated TNF-α-induced MMP-2 secretion from ONH astrocytes. Data also supported the idea that p38 MAP kinase and NF-κB played central roles in TNF-α-induced MMP-2 secretion, and both were negatively regulated by SNC-121.

The connective tissue plates of the lamina cribrosa (LC) region are continuously exposed to a mechanically dynamic environment. To study how the LC cells respond to these mechanical forces, we measured the mechano-sensitive calcium dependent maxi-K(+) ion channel current in the cell membrane of LC cells of glaucoma and normal subjects. Primary culture LC cells from 7 normal and 7 age matched glaucoma donors were studied. Perfusion of cells with hypotonic solution was used to stretch the cell membrane. Whole-cell patch-clamp technique was used to measure the basal (non stretched) and hypotonic stretch-induced changes in maxi-K(+) ion channel activity in normal and glaucoma LC cells. The role of membrane-type Ca(2+) entry channel inhibition (verapamil) and internal Ca(2+) store re-uptake blockade (2-APB) on maxi-K(+) activity was also examined. Basal and stretched-induced maxi-K(+) current were significantly elevated in the glaucoma LC cells compared to normal controls (p < 0.05). In normal LC cells hypotonic stretch elevated the mean maxi-K(+) current from 18.5 ± 5.7 pA/pF (at Vp = +100 mV) to 88.4 ± 12.4 pA/pF (P < 0.05), and from 39.5 ± 7.3 pA/pF to 133.1 ± 18.5 pA/pF in glaucoma LC cells (P < 0.02). Verapamil and 2-APB significantly reduced basal maxi-K(+) current in glaucoma LC cells (33.1 ± 8.2 pA/pF to 17.9 ± 5.6 pA/pF; and 32.2 ± 8.3 pA/pF to 17.3 ± 5.4 pA/pF, P < 0.05, respectively) but not in normal LC cells (P > 0.05). Following hypotonic stretch, verapamil and 2-APB significantly (P < 0.05) reduced the maxi-K(+) current in both normal and glaucoma LC cells. Baseline and hypotonic stretch induced Ca(2+)-dependent maxi-K(+) channel activity are elevated in LC cells of glaucoma patients, which may result from the abnormally high levels of intracellular calcium in glaucoma LC cells., (Copyright © 2013. Published by Elsevier Ltd.)

Purpose: We determined whether administration of a nitric oxide synthase (NOS) inhibitor alters optic nerve head blood flow (ONHBF) regulation during isometric exercise in healthy subjects., Methods: Our study was done in a randomized, placebo-controlled, double-masked, three-way crossover design. A total of 18 healthy subjects was randomized to receive either placebo, phenylephrine, or an inhibitor of NOS (L-NMMA) on three different study days. ONHBF was measured with laser Doppler flowmetry while the study participants performed isometric exercise (squatting). This was done before drug administration and during infusion of the study drugs. Mean arterial pressure (MAP) and IOP were measured noninvasively, and ocular perfusion pressure (OPP) was calculated as 2/3 MAP - IOP., Results: The response in ONHBF to isometric exercise was less pronounced than the response in OPP, indicating for some autoregulatory capacity in the ONH. Administration of L-NMMA significantly decreased ONHBF at rest (P < 0.01). In contrast, inhibition of NOS did not alter the pressure-flow relationship in the ONH during an experimental increase in OPP compared to phenylephrine and placebo (P = 0.37 between groups)., Conclusions: The data of our study support previous findings that ONHBF is autoregulated during an experimental increase in OPP. Nitric oxide has an important role in basal ONHBF regulation, but seems not to be involved in the autoregulatory response during an increase in OPP induced by isometric exercise. (ClinicalTrials.gov number, NCT00806741.).

Purpose was to study efficiency and safety of mexidol in combined therapy in patients with primary open-angle glaucoma (POAG). 94 patients (185 eyes) at the age of 18-75 years old with POAG I-III stages were divided into 3 groups: 50 patients received combined therapy of mexidol 100 mg and picamilon 150 mg, 22 patients received combined therapy of mexidol 300 mg and picamilon 150 mg, 22 patients received only picamilon 150 mg. All medicine was administered qd during 14 or 21 days. Examination included standard ophthalmologic methods, perimetry, electroretinography, retinal and optic nerve heard arterial blood flow. Improvement of visual acuity, perimetric, electrofisiological indicies and increased blood flow velocity of central retinal artery were registrated. Combined mexidol therapy allows improving results in treatment of patients with POAG.

Background: Multikinase inhibitors (MKI) interfere effectively at different levels of the neovascularisation cascade. Early clinical and experimental data suggest that MKIs represent a promising novel approach for the treatment of neovascular age-related macular degeneration (AMD). However, so far little is known about the biocompatibility of MKIs regarding human ocular cells. This in vitro study investigates and compares the biocompatibility of three MKIs, axitinib, pazopanib, and sorafenib regarding ocular cells of the anterior and posterior segments, as well as organ-cultured donor corneas., Methods: Primary human optic nerve head astrocytes (ONHA), trabecular meshwork cells (TMC), and retinal pigment epithelium (RPE), human corneal endothelial and lens epithelial cells (CEC and LEC) were treated with different concentrations of axitinib, pazopanib, or sorafenib (0.1 to 100 µg/mL). To simulate oxidative stress, the cells were additionally co-incubated with 400 µM hydrogen peroxide. Induction of cell death and cellular viability were examined by live-dead assay and tetrazolium dye reduction assay (MTT). In addition, the influence of the three substances on human corneal endothelium was evaluated in seropositive donor corneas in organ culture by phase contrast microscopy., Results: Up to a concentration of 7.5 mg/mL of the substances tested in any cell type examined, no toxic effects were found. Even after 10 days of incubation of organ-cultured donor corneas with 7.5 µg/mL, axitinib, pazopanib, or sorafenib, no evidence for endothelial toxicity was found., Conclusion: All three MKIs tested, axitinib, pazopanib, and sorafenib showed a good biocompatibility on the investigated ocular cells. Even under conditions of oxidative stress, there were no toxic effects up to a concentration of 7.5 µg/mL. Only at higher concentrations, there was a dose-dependent decrease in cellular viability and pronounced induction of cell death. These effects on cellular viability and induction of cell death appeared to be stronger with pazopanib, followed by sorafenib, than with axitinib., (Georg Thieme Verlag KG Stuttgart · New York.)

Endothelin-1 (ET-1) is an important regulator of vascular tone in the eye. It appears to play a role in ocular disease because of its strong vasoconstrictor action, its role in intraocular pressure homeostasis, and its neurotoxic potential. We have previously shown that ET-1 is involved in choroidal red cell flux (RCF) regulation during isometric exercise in healthy humans. In the present study we hypothesized that ET-1 also plays a role in optic nerve head (ONH) RCF regulation during isometric exercise. To test this hypothesis, we performed a randomized, double-masked, placebo-controlled, two-way crossover study in 15 healthy volunteers. Subjects were randomized to receive intravenous infusions of the specific endothelin type A receptor antagonist BQ-123 and placebo on two different study days. During these infusion periods, subjects performed squatting for 6 min to increase ocular perfusion pressure (OPP). ONH RCF was assessed with laser-Doppler flowmetry, and OPP was calculated from mean arterial pressure and intraocular pressure. BQ-123 did not change OPP or ONH RCF at baseline. The relative increase in OPP during isometric exercise was comparable between both groups (between 84 and 88%, P = 0.76 between groups; P < 0.001 vs. baseline). Isometric exercise increased ONH RCF during placebo and BQ-123, but the increase was more pronounced when the endothelin type-A receptor antagonist was administered (placebo, 27.3 ± 5.4%; and BQ-123, 39.2 ± 4.4%; P = 0.007 between groups). The present data indicate that ET-1 regulates red cell flux in the ONH beyond the autoregulatory range.