Effect of palmitoylethanolamide on degeneration of a human-derived retinal pigment epithelial cell induced by all-trans retinal
Authors:   Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Engineering and Research Center of Eye Regenerative Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China; Department of Ophthalmology, Xiang&#x2019;an Hospital of Xiamen University, Xiamen 361102, Fujian Province, China; Xiamen University Affiliated Xiamen Eye Center, Xiamen 361102, Fujian Province, China, Han Yun , He Dan-Xue ,   Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Engineering and Research Center of Eye Regenerative Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China, Yu Chao-Feng ,   Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Engineering and Research Center of Eye Regenerative Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China, Tao Lei ,   Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Engineering and Research Center of Eye Regenerative Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China, Liao Chun-Yan ,   Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Engineering and Research Center of Eye Regenerative Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China, Cai Bin-Xiang ,   Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Engineering and Research Center of Eye Regenerative Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China, Liu Zu-Guo ,   Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Engineering and Research Center of Eye Regenerative Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China; Department of Ophthalmology, Xiang&#x2019;an Hospital of Xiamen University, Xiamen 361102, Fujian Province, China; Xiamen University Affiliated Xiamen Eye Center, Xiamen 361102, Fujian Province, China, Qiu Yan ,   Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Engineering and Research Center of Eye Regenerative Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China; Department of Ophthalmology, Xiang&#x2019;an Hospital of Xiamen University, Xiamen 361102, Fujian Province, China; Xiamen University Affiliated Xiamen Eye Center, Xiamen 361102, Fujian Province, China, Wu Ya-Lin ,   Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Engineering and Research Center of Eye Regenerative Medicine, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China; Department of Ophthalmology, Xiang&#x2019;an Hospital of Xiamen University, Xiamen 361102, Fujian Province, China; Xiamen University Affiliated Xiamen Eye Center, Xiamen 361102, Fujian Province, China
Published: February 2023

AIM: To study the effect of palmitoylethanolamide (PEA) on apoptosis of retinal pigment epithelial (RPE) cells induced by all-trans retinal (atRAL) and to explore the possible molecular mechanism.
METHODS: CellTiter 96® Aqueous One Solution Cell Proliferation Assay (MTS) was used to detect the effect of PEA on human-derived retinal epithelial cells (ARPE-19) viability induced by atRAL. A Leica DMi8 inverted microscope was used to observe cell morphology. Reactive oxygen species (ROS) production was evaluated with 2’,7’-dichlorodihydrof-luorescein diacetate (H2DCFDA) staining and fluorescence microscopy. Expression of c-Jun N-terminal kinase (JNK), phosphorylated JNK (p-JNK), c-Jun, phosphorylated c-Jun (p-c-Jun), Bak, cleaved caspase-3, C/EBP homologous protein (CHOP), and binding (Bip) protein levels were tested by Western blot. Abca4-/-Rdh8-/- mice, mouse models of atRAL clearance defects which displays some symbolic characteristics of dry age-related macular degeneration (AMD) and Stargardt disease (STGD1). In the animal models, PEA was injected intraperitoneally. The full-field electroretinogram was used to detect visual function under scotopic conditions traced from mice. Optical coherence tomography showed reconstitution or thickening of the retinal pigment epithelium layer. Effect of PEA on fundus injury induced by light in Abca4-/-Rdh8-/- mice was observed by fundus photography.
RESULTS: PEA ameliorated ARPE-19 cells apoptosis and inhibited ROS (including mitochondrial ROS) production induced by atRAL. PEA improved the retinal functional, prohibited both RPE and photoreceptor from death, ameliorates light-induced fundus impairment in Abca4-/-Rdh8-/- mice. In vitro and in vivo, PEA inhibited JNK, p-JNK, c-Jun, p-c-Jun, Bak, cleaved caspase-3, CHOP, and Bip protein levels induced by all-trans retinal in ARPE-19 cells.
CONCLUSION: PEA has effect on treating RPE cells apoptosis in retinopathy caused by atRAL accumulation. PEA is a potential treatment strategy for dry AMD and STGD1. The molecular mechanism is affecting the ROS-JNK-CHOP signaling pathway partly.