Trimebutine prevents corneal inflammation in a rat alkali burn model.

Alkaline burns to the cornea lead to loss of corneal transparency, which is essential for normal vision. We used a rat corneal alkaline burn model to investigate the effect of ophthalmic trimebutine solution on healing wounds caused by alkaline burns. Trimebutine, an inhibitor of the high-mobility group box 1-receptor for advanced glycation end products, when topically applied to the burned cornea, suppressed macrophage infiltration in the early phase and neutrophil infiltration in the late phase at the wound site. It also inhibited neovascularization and myofibroblast development in the late phase. Furthermore, trimebutine effectively inhibited interleukin-1ß expression in the injured cornea. It reduced scar formation by decreasing the expression of type III collagen. These findings suggest that trimebutine may represent a novel therapeutic strategy for corneal wounds, not only through its anti-inflammatory effects but also by preventing neovascularization.

Disulfiram Ophthalmic Solution Inhibited Macrophage Infiltration by Suppressing Macrophage Pseudopodia Formation in a Rat Corneal Alkali Burn Model.

FROUNT is an intracellular protein that promotes pseudopodia formation by binding to the chemokine receptors CCR2 and CCR5 on macrophages. Recently, disulfiram (DSF), a drug treatment for alcoholism, was found to have FROUNT inhibitory activity. In this study, we investigated the effect of DSF eye drops in a rat corneal alkali burn model. After alkali burn, 0.5% DSF eye drops (DSF group) and vehicle eye drops (Vehicle group) were administered twice daily. Immunohistochemical observations and real-time reverse transcription-polymerase chain reaction (RT-PCR) analyses were performed at 6 h and 1, 4, and 7 days after alkali burn. Results showed a significant decrease in macrophage accumulation in the cornea in the DSF group, but no difference in neutrophils. RT-PCR showed decreased expression of macrophage-associated cytokines in the DSF group. Corneal scarring and neovascularization were also suppressed in the DSF group. Low-vacuum scanning electron microscopy imaging showed that macrophage length was significantly shorter in the DSF group, reflecting the reduced extension of pseudopodia. These results suggest that DSF inhibited macrophage infiltration by suppressing macrophage pseudopodia formation.

Prophylactic Instillation of Hydrogen-Rich Water Decreases Corneal Inflammation and Promotes Wound Healing by Activating Antioxidant Activity in a Rat Alkali Burn Model.

Many studies have demonstrated the therapeutic effects of hydrogen in pathological conditions such as inflammation; however, little is known about its prophylactic effects. The purpose of this study is to investigate the prophylactic effects of hydrogen-rich water instillation in a rat corneal alkali burn model. Hydrogen-rich water (hydrogen group) or physiological saline (vehicle group) was instilled continuously to the normal rat cornea for 5 min. At 6 h after instillation, the cornea was exposed to alkali. The area of corneal epithelial defect (CED) was measured every 6 h until 24 h after alkali exposure. In addition, at 6 and 24 h after injury, histological and immunohistochemical observations were made and real-time reverse transcription polymerase chain reaction (RT-PCR) was performed to investigate superoxide dismutase enzyme (SOD)1, SOD2, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) mRNA expression. CED at 12 h and the number of inflammatory infiltrating cells at 6 h after injury were significantly smaller in the hydrogen group than the vehicle group. Furthermore, SOD1 expression was significantly higher in the hydrogen group than the vehicle group at both 6 and 24 h, and the number of PGC-1α-positive cells was significantly larger in the hydrogen group than the vehicle group at 6 h after injury. In this model, prophylactic instillation of hydrogen-rich water suppressed alkali burn-induced inflammation, likely by upregulating expression of antioxidants such as SOD1 and PGC-1α. Hydrogen has not only therapeutic potential but also prophylactic effects that may suppress corneal scarring following injury and promote wound healing.

A Patient with Primary Open-Angle Glaucoma with Re-Elevated Nocturnal Sitting Intraocular Pressure after Restarting Medical Therapy due to a Bleb Failure.

We describe the case of a primary open-angle glaucoma patient with re-elevated nocturnal sitting intraocular pressure (IOP) after restarting medical therapy due to a failing bleb. IOP was markedly higher than diurnal IOP during multiple-drug therapy in both eyes, but it did not increase in the left eye with a functional bleb without medical therapy after trabeculectomy with adjuvant mitomycin. However, nocturnal sitting IOP was re-elevated after restarting multiple-drug therapy due to a failing bleb, while diurnal IOP was maintained at a low level.

Brain-derived Neurotrophic Factor in the Aqueous Humor of Glaucoma Patients.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) may be involved in the pathogenesis of glaucoma. BDNF concentrations reported in previous studies have varied widely, and the concentration of BDNF in aqueous humor is unknown. In this study, BDNF concentrations in the aqueous humor of glaucoma patients and control patients were measured with ELISA kits. METHODS: This prospective, observational study examined BDNF levels in aqueous humor in 62 eyes of 43 patients who underwent cataract surgery or trabeculectomy (11 glaucoma patients and 32 non-glaucoma cataract patients as controls). BDNF concentrations were examined by 4 different enzyme-linked immunosorbent assay (ELISA) techniques. RESULTS: The mean ± SD patient age was 72.0 ± 10.1 (range 35 to 87) years. Two of the techniques detected no BDNF in aqueous humor in any samples (n=3 and n=9, respectively); the average value was less than zero. An ultrasensitive ELISA kit did not yield reliable measurements. Finally, in an even more sensitive ELISA (Simoa-HD1), performed by an outside contractor, 25 (54.3%) eyes were below the detection limit, including 20 (55.6%) control and 5 (50%) glaucoma cases. For eyes with detectable BDNF, the overall BDNF concentration was 0.158 pg/mL (n=21): 0.196 pg/mL (n=16) in controls and 0.034 pg/mL (n=5) in glaucoma cases. CONCLUSIONS: BDNF level in aqueous humor varies widely.

Changes in the Ganglion Cell Complex after Inner Limiting Membrane Peeling for Epiretinal Membrane in Glaucoma Patients.

BACKGROUND: Epiretinal membrane (ERM) is a disease that affects the vitreoretinal interface and causes metamorphopsia, anorthopia, and decreased visual acuity. In this study, ERM patients who underwent internal limiting membrane (ILM) peeling were classified as those with glaucoma (Group G) and a control group (Group C). Changes in ganglion cell complex (GCC) thickness were compared between these groups to investigate whether such changes had an effect on progression of glaucoma from structural change. METHODS: This was a retrospective, observational study that included 27 eyes of 27 patients. Group C included 22 eyes, and Group G included 5 eyes. Patients underwent ILM peeling, and cataract surgery was combined with vitrectomy for 16 phakic eyes; 2 phakic eyes and 9 aphakic eyes were treated only with vitrectomy. GCC thickness was measured preoperatively and at 2 weeks and 1, 3, and 6 months postoperatively, and these values and the rates of thinning were compared between the two groups. RESULTS: The mean age of patients was 66.7±12.8 years (range 30-84 years). There was no significant difference between groups in the thickness of the GCC or its rate of thinning after ILM peeling. CONCLUSIONS: The present results suggest that this procedure does not cause structural exacerbation of glaucoma in glaucoma patients. Although further studies of the functional effects of ILM peeling are required, the present results suggest that there is no significant difference between the two groups.

Cystoid Macular Edema Associated with Omidenepag Isopropyl in Phakic Eyes after Laser Iridotomy: A Case Report.

Decreased vision and cystoid macular edema (CME) developed in phakic eyes of a patient who underwent laser iridotomy after changing the glaucoma eye drops from carteolol 2% long-acting ophthalmic solution to omidenepag isopropyl 0.002%. CME completely disappeared at approximately 2 months after discontinuation of omidenepag isopropyl in conjunction with the use of bromfenac sodium 0.1%.

Effects of Selective Peroxisome Proliferator Activated Receptor Agonists on Corneal Epithelial Wound Healing.

The effects of each subtype-selective peroxisome proliferator activated receptor (PPAR) agonist (α, ß/δ, γ) on corneal epithelial wound healing were investigated using a rat corneal alkali burn model. After the alkali burn, each PPAR agonist or vehicle ophthalmic solution was instilled topically onto the rat's cornea. Corneal epithelial healing processes were evaluated by fluorescein staining. Pathological analyses and real-time reverse transcription polymerase chain reactions were performed to evaluate Ki67 (proliferative maker) expression and inflammatory findings. The area of the corneal epithelial defect at 12 h and 24 h after the alkali burn was significantly smaller in each PPAR group than in the vehicle group. Ki67 mRNA expression was increased in the PPARß/δ group, whereas mRNA expressions of inflammatory cytokines were suppressed in all of the PPAR agonist groups. Nuclear factor kappa B (NF-κB) was the most suppressed in the PPARγ group. The accelerated corneal epithelial healing effects of each PPAR ligand were thought to be related to the promotion of proliferative capacity and inhibition of inflammation.

Serum Brain-Derived Neurotrophic Factor in Glaucoma Patients in Japan: An Observational Study.

PURPOSE: The aim of this study was to measure serum levels of brain-derived neurotrophic factor (BDNF) in Japanese patients with primary open angle glaucoma (POAG) and normal tension glaucoma (NTG). METHODS: This was a prospective observational study of serum BDNF levels in 78 patients who underwent cataract surgery or trabeculectomy (27 glaucoma patients and 51 non-glaucoma cataract patients as controls). Patient age was 68.8 ± 11.1 years (mean ± standard deviation; range 35-86 years). The numbers of patients with POAG and NTG were 16 and 11, respectively. POAG was diagnosed by intraocular pressure measurement, gonioscopy, optic nerve head change, and presence of a visual field defect. RESULTS: Serum BDNF concentration was significantly lower in the glaucoma group (including both POAG and NTG) than in the control group (7.2 ± 3.6 ng/mL vs. 12.2 ± 9.3 ng/mL, p=0.004). Serum BDNF concentration was lower in early glaucoma than in moderate glaucoma. There was no correlation between serum BDNF concentration and age. When patients with NTG and POAG were compared, serum BDNF concentration was lower in the former. Serum BDNF concentration was not significantly correlated with glaucoma parameters, including optical coherence tomography and visual field defects. CONCLUSION: This is the first study to investigate serum BDNF concentration in glaucoma patients in Japan. Future studies should evaluate the role of BDNF as a potential biomarker of glaucoma.

Combination of Peroxisome Proliferator-Activated Receptor (PPAR) Alpha and Gamma Agonists Prevents Corneal Inflammation and Neovascularization in a Rat Alkali Burn Model.

Peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ) agonists have anti-inflammatory and anti-neovascularization effects, but few reports have tested the combination of PPARα and PPARγ agonists. In this study, we investigated the therapeutic effects of ophthalmic solutions of agonists of PPARα, PPARγ, and the combination in a rat corneal alkali burn model. After alkali injury, an ophthalmic solution of 0.05% fenofibrate (PPARα group), 0.1% pioglitazone (PPARγ group), 0.05% fenofibrate + 0.1% pioglitazone (PPARα+γ group), or vehicle (vehicle group) was topically instilled onto the rat's cornea twice a day. After instillation, upregulation was seen of PPAR mRNA corresponding to each agonist group. Administration of agonists for PPARα, PPARγ, and PPARα+γ suppressed inflammatory cells, neovascularization, and fibrotic changes. In addition, the PPARγ agonist upregulated M2 macrophages, which contributed to wound healing, whereas the PPARα agonist suppressed immature blood vessels in the early phase. Administration of PPARα+γ agonists showed therapeutic effects in corneal wound healing, combining the characteristics of both PPARα and PPARγ agonists. The results indicate that the combination of PPARα and γ agonists may be a new therapeutic strategy.

Peroxisome Proliferator-Activated Receptor Beta/Delta Agonist Suppresses Inflammation and Promotes Neovascularization.

The effects of peroxisome proliferator-activated receptor (PPAR)ß/δ ophthalmic solution were investigated in a rat corneal alkali burn model. After alkali injury, GW501516 (PPARß/δ agonist) or vehicle ophthalmic solution was topically instilled onto the rat's cornea twice a day until day 7. Pathological findings were evaluated, and real-time reverse transcription polymerase chain reaction was performed. GW501516 strongly suppressed infiltration of neutrophils and pan-macrophages, and reduced the mRNA expression of interleukin-6, interleukin-1ß, tumor necrosis factor alpha, and nuclear factor-kappa B. On the other hand, GW501516 promoted infiltration of M2 macrophages, infiltration of vascular endothelial cells associated with neovascularization in the wounded area, and expression of vascular endothelial growth factor A mRNA. However, 7-day administration of GW501516 did not promote neovascularization in uninjured normal corneas. Thus, the PPARß/δ ligand suppressed inflammation and promoted neovascularization in the corneal wound healing process. These results will help to elucidate the role of PPARß/δ in the field of ophthalmology.