• Zhenxing Xie, Mang Xu, Jie Xie, Tao Liu, Xie Xu, Wei Gao, Zhanfei Li, Xiangjun Bai, and Xinghua Liu.
• Trauma Center/Department of Emergency and Trauma Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095, Jiefang Avenue, Wuhan, Hubei Province, China.
• Shock. 2022 May 1; 57 (5): 694-702.

AbstractSepsis-associated encephalopathy (SAE) often manifests in severe diffuse cerebral dysfunction due to an aberrant systemic immune response to infection. The underlying pathophysiology of SAE is not entirely understood but is likely a multifactorial process that involves disruption in cell death mechanism. Ferroptosis is a novel form of programmed cell death characterized by iron accumulation and lipid peroxidation, leading to inflammatory cascade and glutamate release. We hypothesized that ferroptosis is involved in the glutamate-mediated excitotoxic neuron injury during the uncontrolled neural inflammatory process of SAE. Inhibiting ferroptosis with ferrostatin-1 (Fer-1) could alleviate glutamate excitotoxicity and reduce neuron death of SAE, potentially improving prognosis. We found that in the cecal ligation and puncture (CLP) sepsis model, ferroptosis occurred increasingly in the cerebrum, characterized by glutathione-dependent antioxidant enzyme glutathione peroxidase 4 (GPX4) inactivation, transferrin upregulation, mitochondria shrink and malondialdehyde (MDA) increased. Fer-1 treatment downregulated cerebral ferroptosis and alleviated glutamate excitotoxicity via dampening system xc-(SXC) and glutamate receptor N-methyl-D-asperate receptor subunit 2. Combined with an observed reduction in calcium transporter PLCG and PLCB activation, these processes ultimately protected the integrities of synapses and neurons during SAE. Fer-1 treatment also rescued sepsis-induced nuclear autophagy and improved the behaviors of tail suspension test and novel object recognition test in septic mice. Conclusively, our results suggested that inhibition of ferroptosis could attenuate glutamate excitotoxicity and SAE outcomes.Copyright © 2022 by the Shock Society.

22 keywords...

hide…