Fer-1 Alleviates Traumatic Brain Injury-Induced Cognitive Impairment By Inhibiting Hippocampal Ferroptosis

Abstract The hippocampus plays a pivotal role in the development of cognitive disorders induced by traumatic brain injury (TBI). Recent studies have elucidated the involvement of ferroptosis in the pathophysiological cascade of TBI. However, the specific role of ferroptosis and the therapeutic potential of ferrostatin-1 in mitigating hippocampal damage post-TBI remain unclear. In this study, we established a TBI model and conducted a series of behavioral and histomorphological experiments in mice to assess outcomes. Our assessments included evaluating ferroptosis levels using Perl's staining, measuring reactive oxygen species (ROS) accumulation via malondialdehyde assays, assessing neuronal cell death through PI staining, examining mitochondrial shrinkage with transmission electron microscopy, and analyzing the expression levels of key proteins such as glutathione peroxidase 4 (GPX4), transferrin receptor, and SLC40A1 via Western blotting. Our results revealed that TBI led to iron and lipid-ROS accumulation, disrupted iron metabolism, mitochondrial atrophy, neuronal cell death, and downregulation of GPX4 expression in the hippocampus. Importantly, administration of Ferrostatin-1 into the lateral ventricle significantly mitigated iron accumulation and neuronal cell death in the hippocampus, thereby attenuating injury and long-term cognitive impairment following TBI. This study highlights the therapeutic potential of targeting hippocampal ferroptosis as a novel treatment approach for TBI.