Yu Zhengxi, Wu Dingwei, Shi Tengbin, Chen Dehui, Feng Hao, Chen Huina, Lin Hailin, Sun Lei, Liu Wenge
Department of Orthopedics, Fujian Medical University Union Hospital, No.29 Xin Quan Road, Fuzhou, 350001, Fujian, China.
Department of Minimally Invasive Spinal Surgery, The Affiliated Hospital of Putian University, Putian, 351100, Fujian, China.
Mol Neurobiol. 2025 Jul 20. doi: 10.1007/s12035-025-05226-4.
Spinal cord injury (SCI) is one of the most devastating and catastrophic types of injury, with high rates of mortality and disability. Ferroptosis has become the target of many major incurable human diseases. By inhibiting ferroptosis, melatonin (MT) can reduce the damage in various organs, but the protective effect of MT on SCI has not been reported yet. The modified Ellen's method was used to establish an SCI rat model. The protective effect of MT on spinal cord neurons and the recovery of motor function were observed. In in vitro experiments, an oxygen-glucose deprivation/reoxygenation (OGD/R) model was established by using mouse hippocampal neuron (HT22) cells to simulate spinal cord ischemia-reperfusion injury. A ferroptosis model directly induced by Erastin was also used. The nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor ML 385 was used to further detect the mechanism through which MT inhibits ferroptosis and protects neuronal cells. Our study demonstrates that in rats, melatonin can promote the recovery of behavior and injured tissue after SCI. Under the electron microscope, MT inhibited neuron ferroptosis, rescued damaged mitochondria, and partially restored the mitochondrial structure. ML385, an Nrf2 inhibitor, reversed the effects of MT. Overall, MT may alleviate early SCI by inhibiting ferroptosis through activating the Nrf2/heme oxygenase-1(HO-1)/glutathione peroxidase 4 (GPX 4) pathway.
脊髓损伤（SCI）是最具毁灭性和灾难性的损伤类型之一，死亡率和致残率很高。铁死亡已成为许多主要的人类不治之症的靶点。通过抑制铁死亡，褪黑素（MT）可以减少各个器官的损伤，但MT对SCI的保护作用尚未见报道。采用改良的埃伦方法建立SCI大鼠模型。观察MT对脊髓神经元的保护作用及运动功能的恢复情况。在体外实验中，利用小鼠海马神经元（HT22）细胞建立氧糖剥夺/复氧（OGD/R）模型，模拟脊髓缺血再灌注损伤。还使用了由埃拉斯汀直接诱导的铁死亡模型。采用核因子红细胞2相关因子2（Nrf2）抑制剂ML 385进一步检测MT抑制铁死亡并保护神经元细胞的机制。我们的研究表明，在大鼠中，褪黑素可以促进SCI后行为和受损组织的恢复。在电子显微镜下，MT抑制神经元铁死亡，挽救受损的线粒体，并部分恢复线粒体结构。Nrf2抑制剂ML385逆转了MT的作用。总体而言，MT可能通过激活Nrf2/血红素加氧酶-1（HO-1）/谷胱甘肽过氧化物酶4（GPX 4）途径抑制铁死亡，从而减轻早期SCI。
