Pemafibrate prevents retinal neuronal cell death in NMDA-induced excitotoxicity via inhibition of p-c-Jun expression
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ORIGINAL ARTICLE
Pemafibrate prevents retinal neuronal cell death in NMDA-induced excitotoxicity via inhibition of p-c-Jun expression Naoki Fujita1,2 · Kana Sase2 · Chihiro Tsukahara2 · Ibuki Arizono1,2 · Hitoshi Takagi2 · Yasushi Kitaoka1 Received: 25 September 2020 / Accepted: 24 November 2020 © The Author(s) 2020
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. Keywords Excitotoxicity · PPAR-α · Pemafibrate · c-Jun · NMDA · Apoptosis
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 is distributed mainly in metabolic tissue, including the heart, skeletal muscle, liver, and retina, and it is activated by free fatty acids and leukotriene B4 as physiological ligands, which play a pivotal role in fatty acid metabolism [1–3]. PPAR-α has been shown to inhibit oxidative stress and degeneration in retinal neuronal cells in retinopathy model mice induced by high oxygen [4]. Fibrates are artificial * Yasushi Kitaoka kitaoka@marianna‑u.ac.jp 1
Department of Molecular Neuroscience, St. Marianna University Graduate School of Medicine, 2‑16‑1 Sugao, Miyamae‑ku, Kaswasaki, Kanagawa 216‑8511, Japan
Department of Ophthalmology, St. Marianna University School of Medicine, 2‑16‑1 Sugao, Miyamae‑ku, Kaswasaki, Kanagawa 216‑8511, Japan
2
ligands of PPAR-α that promote the beta-oxidation of fatty acids and lower triglycerides in the blood [5–7]. PPAR-α has recently attracted attention for its anti-inflammatory effects, but the precise me
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