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 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.

Purpose. The aim of this study was to measure the serum levels of brain-derived neurotrophic factor (BDNF) in primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) patients in Japan. Methods. This was a prospective, observational study that examined serum BDNF levels in 78 patients who underwent cataract surgery or trabeculectomy (27 glaucoma patients and 51 non-glaucoma cataract patients as controls). The patients' age was 68.8 ± 11.1 years (mean ± standard deviation; range 35-86 years). The number of patients with POAG and NTG was 16 and 11, respectively. The diagnosis of POAG was done by intraocular pressure measurement, gonioscopy, optic nerve head change, and the presence of a visual field defect. Results. The 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). The serum BDNF concentration was lower in the early phase than in the moderate phases of glaucoma. There was no correlation between the serum BDNF concentration and age. When the NTG and POAG patient groups were compared, the serum BDNF concentration was lower in NTG patients than in POAG patients. No significant correlations were found between glaucoma parameters, including optical coherence tomography and visual field defects, and the serum BDNF concentration. Conclusion. This is the first study to have investigated serum BDNF concentrations in glaucoma patients in Japan. Further investigations are needed to evaluate the role of BDNF as a potential biomarker of glaucoma.

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 nonglaucoma cataract patients as controls). BDNF concentrations were examined by 4 different enzymelinked 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.

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.