Amelioration of white matter injury through mitigating ferroptosis following hepcidin treatment after spinal cord injury

Abstract

Abstract Spinal cord injury (SCI) usually introduces permanent or long-lasting neurological impairments. Maintaining the integrity of limited number of white matter bundles (5–10%) preserves wholly or partially locomotor following SCI. Considering that the basic structure of white matter bundles is axon wrapped by oligodendrocytes, promoting oligodendrocytes survival might be a feasible strategy for reducing white matter injury (WMI) after SCI. Oligodendrocytes are rich in unsaturated fatty acid, and susceptible to ferroptosis-induced damage. Hence, exploring method to reduce ferroptosis is supposed to expedite oligodendrocytes survival, thereafter mitigating WMI to facilitate functional recovery post-SCI. Here, the results indicated the administration of hepcidin reduced iron accumulation to promote oligodendrocytes survival and to decrease spinal cord atrophy, thereafter facilitating functional recovery. Then, the WMI was evidently decreased due to attenuating ferroptosis. Subsequently, the results uncovered that the expression of divalent metal transporter 1 (DMT1) and transferrin receptor 1 (TfR1) was expressed in CC1+ cells. The expression level of DMT1 and TfR1 was significantly increased, while this phenomenon was obviously neutralized with the administration of hepcidin in the epicenter of spinal cord after SCI. Afterward, the application of hepcidin downregulated reactive oxygen species (ROS) overload, which was evidently increased with the treatment of 20 µM FeCl3, thereafter increasing cell viability and reducing lactate dehydrogenase (LDH) activity through downregulating the expression of DMT1 and TfR1 to inhibit ferroptosis in oligodendrocyte progenitor cells (OPCs). The present study provides evidence that the application of hepcidin expedites oligodendrocytes survival to alleviate WMI via minimizing the expression of DMT1 and TfR1.