2. Academic Validation
  3. Overexpression of GPX4 attenuates cognitive dysfunction through inhibiting hippocampus ferroptosis and neuroinflammation after traumatic brain injury

Overexpression of GPX4 attenuates cognitive dysfunction through inhibiting hippocampus ferroptosis and neuroinflammation after traumatic brain injury

  • Free Radic Biol Med. 2023 Apr 25;204:68-81. doi: 10.1016/j.freeradbiomed.2023.04.014.
Jiang Fang 1,  Qiang Yuan 1,  Zhuoying Du 1,  Quan Zhang 1,  Lei Yang 2,  Meihua Wang 2,  Weijian Yang 1,  Cong Yuan 1,  Jian Yu 1,  Gang Wu 1,  Jin Hu 3
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China; Neurosurgical Institute of Fudan University, Shanghai Clinical Medical Center of Neurosurgery, Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, China.
  • 2 Department of Neurosurgery & Neurocritical Care, Huashan Hospital, Fudan University, Shanghai, China.
  • 3 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China; Neurosurgical Institute of Fudan University, Shanghai Clinical Medical Center of Neurosurgery, Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, China. Electronic address: [email protected].
PMID: 37105419 DOI: 10.1016/j.freeradbiomed.2023.04.014
Abstract

Ferroptosis is a newly discovered form of regulated cell death that is triggered primarily by lipid peroxidation. A growing body of evidence has implicated Ferroptosis in the pathophysiology of traumatic brain injury (TBI). However, none of these studies focused its role on TBI-induced hippocampal injury. Here, we demonstrated that the distinct ferroptotic signature was detected in the injured hippocampus at the early stage of TBI. Besides, a prominent pro-ferroptosis environment was detected in the ipsilateral hippocampus after TBI, including elevated levels of arachidonic acid (AA), ACLS4, and ALXO15, and deficiency of GPX4. Subsequently, we used AAV-mediated Gpx4 overexpression to counteract Ferroptosis in the hippocampus, and found that TBI-induced cognitive deficits were significantly alleviated after Gpx4 overexpression. Biochemical results also confirmed that TBI-induced hippocampal Ferroptosis and synaptic damage were partially reversed by Gpx4 overexpression. In addition, Gpx4 overexpression inhibited TBI-induced neuroinflammation and peripheral macrophage infiltration. Interestingly, the results of transwell migration assay showed that ferroptotic neurons increased CCL2 expression and promoted iBMDM cell migration. However, this effect was inhibited by CCL2 antagonist, RS102895. These data suggested that inhibition of Ferroptosis may be as a potential strategy to ameliorate TBI-induced cognitive deficits through blockade of hippocampal Ferroptosis and neuroinflammation.

Keywords

Cognitive impairment; Ferroptosis; Hippocampus; Neuroinflammation; Traumatic brain injury.

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