The effects of peroxisome proliferator-activated receptor (PPAR)β/δ ophthalmic solution were investigated in a rat corneal alkali burn model. After alkali injury, GW501516 (PPARβ/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-1β, 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 PPARβ/δ ligand suppressed inflammation and promoted neovascularization in the corneal wound healing process. These results will help to elucidate the role of PPARβ/δ in the field of ophthalmology.

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.

The effects of each subtype-selective peroxisome proliferator activated receptor (PPAR) agonist (α, β/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 PPARβ/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.

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.

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.

Objectives: The objective of this study is to investigate the two-year continuous efficacy, risk factors, and safety profile of selective laser trabeculoplasty (SLT) in Japanese individuals diagnosed with normal-tension glaucoma (NTG) who underwent SLT as either a first-line or second-line treatment. Methods: A retrospective chart review was conducted of patients with NTG who underwent SLT as either an initial or secondary therapy at 26 medical institutions in Japan between January 2020 and December 2021 with a 2-year follow-up. The primary endpoint was a reduction in the rate of intraocular pressure (IOP) over 2 years after SLT. To estimate the time-varying effect of IOP reduction, a linear mixed-effects model was employed. The secondary endpoints were numerical IOP reduction, treatment success rates shown by a Kaplan–Meier analysis, and complications. Success was defined as an outflow pressure improvement rate (ΔOP) ≥ 20% (definition A) or an IOP reduction rate ≥ 20% (definition B) without further treatment. A Cox proportional hazards regression analysis was used to identify the risk factors to successful SLT treatment. The study was registered with UMIN-CTR (ID: UMIN R000064045). Results: A total of 230 eyes from 230 individuals participated in this study, with 148 eyes receiving SLT as an initial (first-line) therapy and 82 eyes undergoing SLT as a secondary (second-line) intervention. In the first-line group, the mean IOP dropped from 16.7 ± 2.3 mmHg to 13.7 ± 2.4 mmHg at two years post-treatment, reflecting a 16.8% reduction. In the second-line group, the average IOP declined from 15.9 ± 2.5 mmHg to 13.2 ± 2.0 mmHg, marking a 14.4% decrease over the same period. The treatment success rate according to definition A (ΔOP ≥ 20%) was 73.7% at 2 years. Analysis using a linear mixed-effects model identified time (p < 0.001), age (p = 0.044), baseline IOP (p < 0.001), and central corneal thickness (CCT) (p < 0.001) as statistically significant contributors to IOP reduction following SLT. However, neither the Group (first-line vs. second-line) variable (p = 0.386) nor the Time × Group interaction (p = 0.298) reached statistical significance. A lower baseline IOP and a thicker CCT were confirmed as significant predictors of SLT treatment failure. Conclusions: Both initial and secondary SLT treatments for NTG proved to be effective and safe over a two-year period, although the extent of IOP reduction was smaller in cases with a lower baseline IOP. Our findings indicate that the IOP-lowering effect of SLT in NTG is influenced by pretreatment IOP levels, aligning with previous studies on primary open-angle glaucoma and ocular hypertension. However, in contrast to those earlier findings, our research identified pretreatment central corneal thickness as a statistically significant factor influencing SLT efficacy in NTG. These results support the role of SLT as a reliable and safe therapeutic option for managing NTG.