Department of Spine, Orthopaedic Center, Guangdong Second Provincial General Hospital, Guangzhou, 510000, PR China; Orthopaedic Center, Zhaoqing Central People's Hospital, Zhaoqing, 526040, PR China.
Department of Spine, Orthopaedic Center, Guangdong Second Provincial General Hospital, Guangzhou, 510000, PR China.
Chem Biol Interact. 2023 Aug 25;381:110556. doi: 10.1016/j.cbi.2023.110556. Epub 2023 May 23.
Spinal cord injury (SCI) is a destructive neurological disorder that causes impaired mobility, sensory, and autonomic dysfunctions. The loss of oligodendrocyte progenitor cells (OPCs), which can differentiate into mature oligodendrocytes and re-myelinate damaged axons, is related to poorer recovery for SCI patients. However, inhibiting OPCs loss has always been a difficult problem to overcome. In this study, we demonstrated the anti-ferroptosis effects of quercetin as a mechanism in erastin-induced OPC ferroptosis. Quercetin ameliorated erastin-induced ferroptosis in OPCs, as indicated by decreased iron concentration, reactive oxygen species (ROS) production, and increased content of glutathione (GSH) as well as more normal mitochondria morphology. Compared with erastin-induced OPCs, the myelin basic protein (MBP)-positive myelin and NF200-positive axonal was remarkably increased in quercetin-treated OPCs. Furthermore, quercetin ameliorated the erastin-induced ferroptosis as well as the myelin and axon loss of OPCs by downregulating transferrin. Transfected OPCs with transferrin overexpression plasmids significantly abrogated the protective role of quercetin in OPC ferroptosis. Using ChIP-qPCR, a direct interaction of transferrin with its upstream gene Id2 was found. The overexpression of Id2 reversed the effect of quercetin on OPC ferroptosis. In vivo study found that quercetin greatly decreased the area of injury, and enhanced the BBB score after SCI. Furthermore, in the SCI model, quercetin significantly downregulated Id2 and transferrin expression, while significantly up-regulated GPX4 and PTGS2 expression. In conclusion, quercetin prevents the ferroptosis of OPCs by inhibiting the Id2/transferrin pathway. These findings highlight quercetin as an anti-ferroptosis agent for the treatment or prevention of spinal cord injury.
脊髓损伤（SCI）是一种破坏性的神经系统疾病，会导致运动、感觉和自主功能障碍。少突胶质前体细胞（OPC）的丢失与 SCI 患者的恢复较差有关，这些细胞可以分化为成熟的少突胶质细胞并重新髓鞘化受损的轴突。然而，抑制 OPC 丢失一直是一个难以克服的问题。在这项研究中，我们证明了槲皮素作为一种机制在依马替尼诱导的 OPC 铁死亡中的抗铁死亡作用。槲皮素改善了依马替尼诱导的 OPC 铁死亡，表现为铁浓度降低、活性氧（ROS）产生减少、谷胱甘肽（GSH）含量增加以及线粒体形态更加正常。与依马替尼诱导的 OPC 相比，在槲皮素处理的 OPC 中，髓鞘碱性蛋白（MBP）阳性的髓鞘和 NF200 阳性的轴突明显增加。此外，槲皮素通过下调转铁蛋白改善了依马替尼诱导的 OPC 铁死亡以及 OPC 髓鞘和轴突的丢失。转染转铁蛋白过表达质粒的 OPC 显著削弱了槲皮素在 OPC 铁死亡中的保护作用。使用 ChIP-qPCR 发现转铁蛋白与它的上游基因 Id2 有直接相互作用。Id2 的过表达逆转了槲皮素对 OPC 铁死亡的作用。体内研究发现，槲皮素在 SCI 后大大减少了损伤面积，提高了 BBB 评分。此外，在 SCI 模型中，槲皮素显著下调了 Id2 和转铁蛋白的表达，同时显著上调了 GPX4 和 PTGS2 的表达。总之，槲皮素通过抑制 Id2/转铁蛋白途径来防止 OPC 的铁死亡。这些发现强调了槲皮素作为一种抗铁死亡剂，可用于治疗或预防脊髓损伤。
