Pemafibrate prevents retinal neuronal cell death in NMDA-induced excitotoxicity via inhibition of p-c-Jun expression

Naoki Fujita,Chihiro Tsukahara,Hitoshi Takagi,Yasushi Kitaoka,Ibuki Arizono,Kana Sase

doi:10.1007/s11033-020-06032-y

Naoki Fujita, Chihiro Tsukahara + Show 4 more

Open Access

https://doi.org/10.1007/s11033-020-06032-y

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Abstract

Excitotoxicity is involved in the retinal neuronal cell death in diabetic retinopathy. Although fenofibrate has been shown to ameliorate the progression of diabetic retinopathy, the effect of pemafibrate, which is highly selective for peroxisome proliferator-activated receptor α on retinal neuronal cell death has not been documented. Here, we investigated whether pemafibrate exerts a beneficial effect against retinal ganglion cell (RGC) death induced by N-methyl-D-aspartate (NMDA) in rats. Experiments were performed on adult male Wistar rats that received an intravitreal injection of 20 nmol NMDA. Fluoro-Gold labeled RGC morphometry showed that oral intake of pemafibrate once a day for 7 days resulted in significant protection on RGC death induced by NMDA. Phosphorylated c-Jun protein, which is involved in apoptosis, was upregulated after NMDA exposure, and this increase was significantly lessened by the systemic pemafibrate treatment. Phosphorylated c-Jun immunopositive cells were colocalized with Thy-1 immunopositive cells, and the increased these cells were ameliorated by the pemafibrate treatment. An increase in TUNEL-positive cells was significantly suppressed by the pemafibrate treatment. Phosphorylated c-Jun immunopositive cells were colocalized with TUNEL-positive cells, and they were decreased by pemafibrate treatment. These results suggest that the RGC protection achieved with pemafibrate appears to be associated with inhibition of phosphorylated c-Jun and its anti-apoptotic effect.

Highlights

Peroxisome proliferator-activated receptors (PPARs) are involved in the body’s energy metabolism and are classified into three subtypes: PPAR-α, PPAR-β, and PPAR-γ
Using retrograde labeling with Fluoro-Gold, we found a significant decrease in the number of retinal ganglion cell (RGC) in the NMDA vitreous injection group compared to the control group (Fig. 2)
The number of RGCs at the center in the control group was 2963 ± 349/mm2, while the number was 962 ± 65/mm2 in the NMDA group. This decrease was significantly ameliorated in the systemic pemafibrate treatment group (RGC number was 1350 ± 61/mm2; p < 0.05; Fig. 2b)

Summary

Introduction

Peroxisome proliferator-activated receptors (PPARs) are involved in the body’s energy metabolism and are classified into three subtypes: PPAR-α, PPAR-β, and PPAR-γ. PPAR-α has been shown to inhibit oxidative stress and degeneration in retinal neuronal cells in retinopathy model mice induced by high oxygen [4]. Fenofibrate is a PPAR-α agonist that has been used in the treatment of dyslipidemia. I.e., the Fenofibrate Intervention and Event Lowering in Diabetes trial [8] and the Action to Control Cardiovascular Risk in Diabetes trial [9,10,11], have shown that administration of fenofibrate inhibits the diabetic retinopathy progression [8,9,10,11]. A recent study has shown that fenofibrate reduces reactive oxygen species formation and ameliorates diabetic retinopathy [12]. Pemafibrate has been used as a novel treatment for fibrate dyslipidemia, and recently it has become clear that it has various functions in vivo activities [13, 14]. It has been reported to be safer than fenofibrate [15] and to be highly selective for PPAR-α [16]

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