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

Yuji Nakano,Takeshi Arima,Hiroshi Takahashi,Yutaro Tobita,Masaaki Uchiyama,Akira Shimizu

doi:10.3390/ijms21145093

Yuji Nakano, Takeshi Arima + Show 4 more

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https://doi.org/10.3390/ijms21145093

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Abstract

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.

Highlights

Transparency of the cornea is an essential factor for normal vision
Recent studies have shown their roles in lipid metabolism and in the control of inflammation, angiogenesis, and fibrosis [6,7]
We previously showed anti-inflammatory and anti-neovascularization effects by PPARα and PPARγ agonists in a rat corneal alkali burn model [8,9]

Summary

Introduction

Transparency of the cornea is an essential factor for normal vision. An alkali burn can cause severe damage to the corneal surface, resulting in loss of its transparency [1,2]. Suppression of scar formation and neovascularization during corneal wound healing is important for a good visual outcome. PPARs have three isoforms—PPAR alpha (α), PPAR beta/delta (β/δ), and PPAR gamma (γ), and they are important factors in adipocyte differentiation and lipid metabolism [5]. Recent studies have shown their roles in lipid metabolism and in the control of inflammation, angiogenesis, and fibrosis [6,7]. We previously showed anti-inflammatory and anti-neovascularization effects by PPARα and PPARγ agonists in a rat corneal alkali burn model [8,9]

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