Evaluation of the Effect of Topical and Oral Peroxisome Proliferator-activated Receptor α (PPARα) agonist on Corneal Nerve Regeneration in Diabetic Mice.

Abstract

Purpose : To investigate the potential stimulation effect of topical and oral fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, on corneal nerve regeneration in diabetes mellitus.

Methods : A total of 108 Ins2Akita mice were divided into 4 groups (n=54 eyes/group): negative control (NC), positive control (PC), topical fenofibrate (TF) and oral fenofibrate (OF) treatment groups. All the mice underwent a 2-weekly clinical evaluation including slit-lamp examination, in vivo confocal microscopy (IVCM), corneal sensitivity, and tear enzyme-linked immunosorbent assay analysis. Mice were euthanized after 6-week and 12-week treatment, and were subjected to immunohistochemistry staining; corneal whole-mount staining, and western blot (WB) analysis.

Results : After 12-weeks of treatment, corneal PPARα protein expression evaluated by WB increased by 2.67-folds and 1.52-folds in the TF and OF groups, respectively. IVCM evaluation showed that the corneal nerve fibre density (CNFD) and corneal nerve fibre length (CNFL) significantly improved in the TF (9.2 to 16.8 fibres/mm² (p=0.01) and 3.9 to 6.2 mm/mm² (p=0.04), respectively) and OF groups (10.3 to 14.7 fibres/mm² (p=0.02) and 3.7 to 5.4 mm/mm² (p=0.04), respectively; Figure 1). The area of corneal epitheliopathy reduced in the TF (58.7% to 8.9%; p<0.001) and OF groups (37.4 to 6.8%; p<0.001 Figure 2). Corneal whole mount staining with β3-tubulin demonstrated that corneal nerve parameters decreased in diabetic mice, but they improved with fenofibrate treatment. No significant difference was observed in the corneal sensitivity of different groups. The tear substance P and calcitonin gene-related peptide concentrations significantly increased in the TF (115.07 to 163.4 pg/ml (p=0.03) and 149.22 to 215.92 pg/ml (p=0.02), respectively) and OF groups (112.77 to 116.53 pg/ml (p=0.32) and 156.37 to 247.50 pg/ml (p=0.01), respectively).

Conclusions : Topical and oral fenofibrate potentially promote corneal nerves regeneration and enhance ocular surface health in diabetic corneal neuropathy.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

 

Figure 1: Representative IVCM images of sub-basal nerves showing CNFD and CNFL improved in the TF and OF groups after 12-weeks of treatment.

 

Figure 2: Representative slit-lamp images of ocular surface showing the area of corneal epitheliopathy reduced in the TF and OF groups after 12-weeks of treatment.