Pemafibrate exerts therapeutic effects on retinal damages induced by transient elevation of intraocular pressure via multiple protective pathways

Abstract

Purpose : Retinal ischemia-reperfusion injury (I/R) is a general cause of vision loss, and no effective treatment is available for retinal I/R. Pemafibrate, a peroxisome proliferator-activated receptor α (PPARα) modulator, was suggested as a promising therapeutic in ischemic retinopathies. However, its roles have not been clearly unraveled in retinal I/R. In this study, we investigated therapeutic effects of pemafibrate against retinal dysfunction in an experimental model of retinal I/R by transient elevation of intraocular pressure (IOP).

Methods : Adult male mice (5–7 weeks old; C57BL/6) were orally given to pemafibrate (0.5 mg/kg) for 4 days, followed by retinal I/R (IOP: 90–99 mmHg; 40 minutes). Mice were continuously given to pemafibrate (0.5 mg/kg) once every day until the end of experiments, 5 days after retinal I/R. Retinal functional changes were measured using electroretinography (ERG). Then, the retina, liver, and serum samples were used for western blotting (WB), qPCR, immunohistochemistry (IHC, sagittal-sectioning, and flat-mounting), or ELISA analysis.

Results : Retinal dysfunction and retinal ganglion cell (RGC) loss stained by NeuN were prevented by pemafibrate administration (ERG, a-wave and b-wave: 1.7-fold and 1.5-fold increase, p < 0.05; IHC, RGC: 1.7-fold increase, p < 0.001). Pemafibrate administration increased hepatic PPARα target gene expressions (qPCR, p < 0.05) and serum levels of fibroblast growth factor 21 (FGF21; ELISA, 20.3-fold increase, p < 0.01), one of the neuroprotective molecules in the eye. Retinal inflammation stained by Isolectin GS-IB4 and pathological gliosis stained by GFAP were reduced by pemafibrate administration (IHC, GS-IB4: 0.26-fold decrease, p < 0.01; GFAP: 0.76-fold decrease, p < 0.05). Furthermore, pemafibrate administration altered expressions in hypoxia-response genes (qPCR, p < 0.05) via hypoxia-inducible factor-1α (HIF-1α; WB, 0.70-fold decrease, p < 0.01) pathway and pro-apoptotic and anti-apoptotic genes such as c-Jun, Nrf2, and Ho-1 (qPCR, p < 0.05) in the ischemic retina.

Conclusions : Our data suggest possibilities of therapeutic effects of pemafibrate on ischemic retinal degeneration via multiple protective pathways.

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