Ferroptosis contributes to hypoxic–ischemic brain injury in neonatal rats: Role of the SIRT1/Nrf2/GPx4 signaling pathway. (2nd October 2022)

• Record Type: Journal Article
• Authors: Li, Chang; Wu, Ziyi; Xue, Hang; Gao, Qiushi; Zhang, Yahan; Wang, Changming; Zhao, Ping
• Is Part Of: CNS neuroscience & therapeutics. Volume 28:Number 12(2022)
• Page Start: 2268
• Page End: 2280
• Publication Date: 2022-10-02
• Subjects: ferroptosis -- glutathione peroxidase 4 -- hypoxic–ischemic brain injury -- learning and memory impairments -- resveratrol; Neuropharmacology -- Periodicals; Central nervous system -- Diseases -- Effect of drugs on -- Periodicals; 612.8
• DOI: 10.1111/cns.13973
• Languages: English
• ISSNs: 1755-5930

Abstract

Abstract: Aims: Hypoxic–ischemic brain injury (HIBI) often results in cognitive impairments. Herein, we investigated the roles of ferroptosis in HIBI and the underlying signaling pathways. Methods: Ferrostatin‐1 (Fer‐1) or resveratrol (Res) treatments were administered intracerebroventricularly 30 min before HIBI in 7‐day‐old rats. Glutathione peroxidase 4 (GPx4) expression, malondialdehyde (MDA) concentration, iron content, mitochondrial morphology, and the expression of silent information regulator factor 2‐related enzyme 1 (SIRT1) and nuclear factor erythroid‐2‐related factor 2 (Nrf2) were measured after HIBI. Additionally, the weight ratio of left/right hemisphere, brain morphology, Nissl staining, and the Morris water maze test were conducted to estimate brain damage. Results: At 24‐h post‐HIBI, GPx4 expression was decreased, and MDA concentration and iron content were increased in the hippocampus. HIBI led to mitochondrial atrophy, brain atrophy/damage, and resultant learning and memory impairments, which were alleviated by Fer‐1‐mediated inhibition of ferroptosis. Furthermore, Res‐mediated SIRT1 upregulation increased Nrf2 and GPx4 expression, thereby attenuating ferroptosis, reducing brain atrophy/damage, and improving learning and memory abilities. Conclusion: The results demonstrated that during HIBI, ferroptosis occurs via the SIRT1/Nrf2/GPx4 signaling pathway, suggesting it as a potential therapeutic target for inhibiting ferroptosis and ameliorating HIBI‐induced cognitive impairments. Abstract : Ferroptosis occurs in a neonatal rat model of HIBI. Ferroptosis inhibition via Fer‐1 administration attenuates brain atrophy and learning and memory impairments. Activation of SIRT1/Nrf2/GPx4 signaling following Res treatment represents a potential therapeutic strategy for inhibiting ferroptosis and ameliorating HIBI‐induced learning and memory impairments.