Lee Jae Rim, Jeong Kwang Won
College of Pharmacy, Gachon Research Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea.
Korean J Physiol Pharmacol. 2023 Sep 1;27(5):449-456. doi: 10.4196/kjpp.2023.27.5.449.
-methyl--aspartate (NMDA) receptors are ionic glutamine receptors involved in brain development and functions such as learning and memory formation. NMDA receptor inhibition is associated with autophagy activation. In this study, we investigated whether the NMDA receptor antagonists, memantine and ifenprodil, induce autophagy in human retinal pigment epithelial cells (ARPE-19) to remove Nretinylidene- -retinylethanolamine (A2E), an intracellular lipofuscin component. Fluorometric analysis using labeled A2E (A2E-BDP) and confocal microscopic examination revealed that low concentrations of NMDA receptor antagonists, which did not induce cytotoxicity, significantly reduced A2E accumulation in ARPE-19 cells. In addition, memantine and ifenprodil activated autophagy in ARPE-19 cells as measured by microtubule-associated protein 1A/1B-light chain3-II formation and phosphorylated p62 protein levels. Further, to understand the correlation between memantine- and ifenprodil-mediated A2E degradation and autophagy, autophagy-related 5 (ATG5) was depleted using RNA interference. Memantine and ifenprodil failed to degrade A2E in ARPE-19 cells lacking ATG5. Taken together, our study indicates that the NMDA receptor antagonists, memantine and ifenprodil, can remove A2E accumulated in cells via autophagy activation in ARPE-19 cells.
N-甲基-D-天冬氨酸（NMDA）受体是离子型谷氨酰胺受体，参与大脑发育以及学习和记忆形成等功能。NMDA受体抑制与自噬激活相关。在本研究中，我们调查了NMDA受体拮抗剂美金刚和艾芬地尔是否会在人视网膜色素上皮细胞（ARPE-19）中诱导自噬，以清除细胞内脂褐素成分N-视黄叉基-N-视黄基乙醇胺（A2E）。使用标记的A2E（A2E-BDP）进行荧光分析和共聚焦显微镜检查显示，低浓度的NMDA受体拮抗剂（不会诱导细胞毒性）可显著减少ARPE-19细胞中A2E的积累。此外，通过微管相关蛋白1A/1B轻链3-II的形成和磷酸化p62蛋白水平测定，美金刚和艾芬地尔可激活ARPE-19细胞中的自噬。此外，为了了解美金刚和艾芬地尔介导的A2E降解与自噬之间的相关性，使用RNA干扰使自噬相关5（ATG5）缺失。在缺乏ATG5的ARPE-19细胞中，美金刚和艾芬地尔无法降解A2E。综上所述，我们的研究表明，NMDA受体拮抗剂美金刚和艾芬地尔可通过激活ARPE-19细胞中的自噬来清除细胞内积累的A2E。
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