Ferritin reduction is essential for cerebral ischemia-induced hippocampal neuronal death through p53/SLC7A11-mediated ferroptosis

Abstract

Cerebral ischemia is the most common cause of hippocampal neuronal death and the most prevalent cause of stroke with high mortality rate. Ferroptosis has been suggested to affect the role of hippocampal neurons. This study explores the influence of lentivirus infection-induced ferritin overexpression in hippocampal neuronal injury and death through simulations in August Copenhagen Irish rat models. Twenty-four-hour cerebral ischemia–reperfusion injury was induced in the rats after 90-min middle cerebral artery occlusion (MCAO). Ferritin overexpression was induced through lentivirus infection. The Morris Water Maze (MWM) test and tau hyperphosphorylation test were performed on hippocampal neurons to establish a MCAO model. The effect of ferritin overexpression on hippocampal neuronal death was evaluated using hematoxylin–eosin staining and annexin V/propidium iodide flow cytometry. The MWM test revealed that MCAO modeling decreased the cognitive and locomotor capacity of the rats, whereas ferritin overexpression partially reversed the effect of MCAO. In addition, the hyperphosphorylation of tau caused by MCAO was reduced by ferritin. Pathogenic changes, impaired viability, increased apoptosis, and elevated caspase-9 cleavage in hippocampal neurons were clearly recovered by ferritin. Moreover, robust reactive oxygen species production and glutathione consumption, which was induced by MCAO modeling, were ameliorated by ferritin. Furthermore, two key modulators of ferroptosis, p53 and SLC7A11, were demonstrated to be upregulated by MCAO modeling and downregulated by ferritin. Ferritin reduction is essential for cerebral ischemia-induced hippocampal neuronal ferroptosis mediated via p53 and SLC7A11.