Department of Orthopedics, The First Affiliated Hospital Jinan University Guangzhou, 510613, China.
MOE Key Laboratory of Tumor Molecular Biology and Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes Institute of Life and Health Engineering College of Life Science and Technology Jinan University Guangzhou, 510632, China.
Biomaterials. 2022 May;284:121481. doi: 10.1016/j.biomaterials.2022.121481. Epub 2022 Apr 1.
Generation of a promising antioxidative reagent with superior biocompatibility is urgently needed to remedy spinal cord injuries (SCI), repair the damaged neurons and restrain the secondary injuries caused by inflammation-induced oxidative stress. Inhibitory elements in the injury sites and necessitous inherent neural regeneration ability were major challenges for functional recovery after spinal cord injuries. We here developed a highly bioactive iridium complex (IrFPHtz) with enhanced antioxidative activities and improved SCI therapeutic efficacy. Both in vivo and in vitro, IrFPHtz has exhibited neuroprotective and anti-inflammatory properties. Mechanically, IrFPHtz directly targets SOD1 and upregulates the expression of SOD1 to eliminate the excess Reactive Oxygen Species (ROS) production induced by SCI, and thus protecting neuron cells from further damage. As a result, IrFPHtz safeguarded the neurons and myelin sheaths against trauma, lessened glial scar conformations and facilitated the repair of neurons and long axon expansion in the glial scar. Furthermore, IrFPHtz significantly ameliorated the behavioral functions of SCI mice and promoted a satisfactory curative effect. Therefore, this study sheds light on a novel method for SCI treatment using IrFPHtz as a potential drug and implicates the clinical significance of metal complexes in diseases featuring with upregulated ROS species.
生成一种具有良好生物相容性的有前途的抗氧化试剂，对于治疗脊髓损伤（SCI）、修复受损神经元以及抑制由炎症引起的氧化应激引起的继发性损伤至关重要。损伤部位的抑制因素和内在必需的神经再生能力是脊髓损伤后功能恢复的主要挑战。我们在此开发了一种具有增强抗氧化活性和改善 SCI 治疗效果的高生物活性铱配合物（IrFPHtz）。在体内和体外，IrFPHtz 均表现出神经保护和抗炎特性。从机制上讲，IrFPHtz 直接靶向 SOD1 并上调其表达，以消除 SCI 引起的过量活性氧（ROS）产生，从而防止神经元进一步受损。结果，IrFPHtz 保护神经元和髓鞘免受创伤，减少神经胶质瘢痕形成，并促进神经元和长轴突在神经胶质瘢痕中的修复。此外，IrFPHtz 显著改善了 SCI 小鼠的行为功能，并促进了令人满意的治疗效果。因此，这项研究为使用 IrFPHtz 作为潜在药物治疗 SCI 提供了一种新方法，并暗示了金属配合物在 ROS 水平升高的疾病中的临床意义。
