Normal tension glaucoma (NTG) is referred to as a progressive degenerative disorder of the retinal ganglion cells (RGCs), resulting in nonreversible visual defects, despite intraocular pressure levels within the statistically normal range. Current therapeutic strategies for NTG yield limited benefits. Excitatory amino acid carrier 1 (EAAC1) knockout (EAAC1^−/−) in mice has been shown to induce RGC degeneration without elevating intraocular pressure, mimicking pathological characteristics of NTG. In this study, we explored whether daily oral administration of melatonin could block RGCs loss and prevent retinal morphology and function defects associated with EAAC1 deletion. We also explored the molecular mechanisms underlying EAAC1 deletion-induced RGC degeneration and the neuroprotective effects of melatonin. Our RNA sequencing and in vivo data indicated EAAC1 deletion caused elevated oxidative stress, activation of apoptosis and cellular senescence pathways, and neuroinflammation in RGCs. However, melatonin administration efficiently prevented these detrimental effects. Furthermore, we investigated the potential role of apoptosis- and senescence-related redox-sensitive factors in EAAC1 deletion-induced RGCs degeneration and the neuroprotective effects of melatonin administration. We observed remarkable upregulation of p53, whereas NRF2 and Sirt1 expression were significantly decreased in EAAC1^−/− mice, which were prevented by melatonin treatment, suggesting that melatonin exerted its neuroprotective effects possibly through modulating NRF2/p53/Sirt1 redox-sensitive signaling pathways. Overall, our study provided a solid foundation for the application of melatonin in the management of NTG.

中文翻译：

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褪黑激素通过抑制细胞凋亡和衰老来防止 EAAC1 缺失诱导的视网膜神经节细胞变性

正常眼压性青光眼 (NTG) 被称为视网膜神经节细胞 (RGC) 的进行性退行性疾病，尽管眼压水平在统计正常范围内，但仍会导致不可逆的视觉缺陷。目前 NTG 的治疗策略效果有限。小鼠中兴奋性氨基酸载体 1 (EAAC1) 敲除 (EAAC1 ^−/− ) 已被证明可诱导 RGC 变性而不升高眼内压，模拟 NTG 的病理特征。在这项研究中，我们探讨了每日口服褪黑激素是否可以阻止 RGC 损失并预防与 EAAC1 缺失相关的视网膜形态和功能缺陷。我们还探讨了 EAAC1 缺失引起的 RGC 变性的分子机制以及褪黑激素的神经保护作用。我们的 RNA 测序和体内数据表明 EAAC1 缺失导致氧化应激升高、细胞凋亡和细胞衰老途径激活以及 RGC 中的神经炎症。然而，褪黑激素的施用有效地防止了这些有害影响。此外，我们研究了细胞凋亡和衰老相关的氧化还原敏感因子在 EAAC1 缺失诱导的 RGC 退化中的潜在作用以及褪黑激素的神经保护作用。^{我们观察到 p53 显着上调，而 NRF2 和 Sirt1 表达在 EAAC1 −/−}小鼠中显着降低，而褪黑激素治疗可以阻止这种情况，表明褪黑激素可能通过调节 NRF2/p53/Sirt1 氧化还原敏感信号通路发挥其神经保护作用。总的来说，我们的研究为褪黑素在 NTG 治疗中的应用奠定了坚实的基础。