Department of Ophthalmology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China; Department of Ophthalmology, National Regional Medical Center, Binghai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Fujian Institute of Ophthalmology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Provincial Clinical Medical Research Center of Eye Diseases and Optometry, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
The School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, China.
Int Immunopharmacol. 2024 Jun 15;134:112193. doi: 10.1016/j.intimp.2024.112193. Epub 2024 May 8.
Retinal neurodegenerative diseases are a category of refractory blinding eye conditions closely associated with oxidative stress induced by mitochondrial dysfunction in retinal cells. SARM1, a core driver molecule leading to axonal degeneration, possesses NAD enzyme (NADase) activity. However, the role of the SARM1-NAD axis in oxidative stress-induced retinal cell death remains unclear. Here, we employed the SARM1 NADase inhibitor DSRM-3716 and established a glucose oxidase (GOx)-induced oxidative stress cell model. We found that compared to the GOx group, the DSRM-3716 pre-treated group reduced the hydrolysis of NAD, inhibited the elevation of oxidative stress markers induced by GOx, decreased mitochondrial dysfunction, lowered the phosphorylation level of JNK, and attenuated the occurrence of pyroptosis in retinal and nerve cells, thereby providing protection for neurite growth. Further utilization of the JNK activator Anisomycin activated JNK, revealed that the JNK/c-Jun pathway down-regulated NMNAT2 expression. Consequently, it reduced cellular NAD synthesis, exacerbated mitochondrial dysfunction and cell pyroptosis, and reversed the protective effect of DSRM-3716 on cells. In summary, the inhibition of SARM1 NADase activity substantially mitigates oxidative damage to retinal cells and mitochondrial damage. Additionally, JNK simultaneously serves as both an upstream and downstream regulator in the SARM1-NAD axis, regulating retinal cell pyroptosis and neurite injury. Thus, this study provides new insights into the pathological processes of retinal cell oxidative stress and identifies potential therapeutic targets for retinal neurodegenerative diseases.
视网膜神经退行性疾病是一类难治性致盲眼病，与视网膜细胞中线粒体功能障碍引起的氧化应激密切相关。SARM1 是导致轴突退化的核心驱动分子，具有 NAD 酶（NADase）活性。然而，SARM1-NAD 轴在氧化应激诱导的视网膜细胞死亡中的作用尚不清楚。在这里，我们使用了 SARM1 NADase 抑制剂 DSRM-3716，并建立了葡萄糖氧化酶（GOx）诱导的氧化应激细胞模型。我们发现，与 GOx 组相比，DSRM-3716 预处理组降低了 NAD 的水解，抑制了 GOx 诱导的氧化应激标志物的升高，减少了线粒体功能障碍，降低了 JNK 的磷酸化水平，并减轻了视网膜和神经细胞中细胞焦亡的发生，从而为神经突生长提供了保护。进一步利用 JNK 激活剂 Anisomycin 激活 JNK，表明 JNK/c-Jun 通路下调了 NMNAT2 的表达。因此，它减少了细胞内 NAD 的合成，加剧了线粒体功能障碍和细胞焦亡，并逆转了 DSRM-3716 对细胞的保护作用。总之，抑制 SARM1 NADase 活性可显著减轻视网膜细胞的氧化损伤和线粒体损伤。此外，JNK 同时作为 SARM1-NAD 轴的上游和下游调节剂，调节视网膜细胞焦亡和神经突损伤。因此，本研究为视网膜细胞氧化应激的病理过程提供了新的见解，并确定了视网膜神经退行性疾病的潜在治疗靶点。
