Department of Ophthalmology, The Second Xiangya Hospital of Central South University, Changsha, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, China.
Chinese People's Liberation Army Medical School, Beijing, China.
Int Immunopharmacol. 2023 May;118:109976. doi: 10.1016/j.intimp.2023.109976. Epub 2023 Mar 14.
Glaucoma, one of the most common ocular neurodegenerative diseases worldwide, is characterized by retinal ganglion cell (RGC) loss. There is a large body of literature that describes the neuroprotective role of melatonin against neurodegenerative diseases by regulating neuroinflammation, although the exact mechanism through which melatonin acts on RGC is still uncertain. This study assessed the protective effects of melatonin using a NMDA-induced RGC injury model, and studied the possible mechanisms involved in this process. Melatonin promoted RGC survival, improved retinal function, and inhibited the apoptosis and necrosis of retinal cells. To understand the mechanism of the neuroprotective effects of melatonin on RGC, microglia and inflammation-related pathways were assessed after melatonin administration and microglia ablation. Melatonin promoted RGC survival by suppressing microglia-derived proinflammatory cytokines, in particular TNFα, which in turn inhibited the activation of p38 MAPK pathway. Inhibiting TNFα or manipulating p38 MAPK pathway protected damaged RGC. Our results suggest that melatonin protects against NMDA-induced RGC injury by inhibiting the microglial TNFα-RGC p38 MAPK pathway. It should be considered a candidate neuroprotective therapy against retinal neurodegenerative diseases.
青光眼是全球最常见的眼部神经退行性疾病之一，其特征是视网膜神经节细胞（RGC）的丧失。有大量文献描述了褪黑素通过调节神经炎症对神经退行性疾病的神经保护作用，尽管褪黑素作用于 RGC 的具体机制尚不确定。本研究使用 NMDA 诱导的 RGC 损伤模型评估了褪黑素的保护作用，并研究了该过程中涉及的可能机制。褪黑素促进 RGC 存活，改善视网膜功能，并抑制视网膜细胞的凋亡和坏死。为了了解褪黑素对 RGC 的神经保护作用的机制，在褪黑素给药和小胶质细胞消融后评估了小胶质细胞和炎症相关途径。褪黑素通过抑制小胶质细胞衍生的促炎细胞因子，特别是 TNFα，从而抑制 p38 MAPK 通路的激活，促进 RGC 的存活。抑制 TNFα或操纵 p38 MAPK 通路可保护受损的 RGC。我们的结果表明，褪黑素通过抑制小胶质细胞 TNFα-RGC p38 MAPK 通路来抵抗 NMDA 诱导的 RGC 损伤。它应被视为针对视网膜神经退行性疾病的候选神经保护治疗方法。
