Ferroptosis Contributes to Hypoxic-Ischemic Brain Injury in Neonatal Rats: Role of the SIRT1/Nrf2/GPx4 Signaling Pathway

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 The 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 modeling. Additionally, the weight ratio of left/right hemispheres and brain morphology were determined and Nissl staining was conducted to reflect brain damage. The Morris water maze test was used to assess cognitive function. Results At 24 h after HIBI, GPx4 expression was decreased and MDA concentration and iron content were increased in the hippocampi. HIBI led to mitochondrial atrophy, brain atrophy/damage, and resultant learning and memory impairments, which were alleviated by inhibiting ferroptosis using Fer-1. Furthermore, the upregulation of SIRT1 expression by Res treatment increased the expression of Nrf2 and GPx4, which in turn attenuated ferroptosis, reducing brain atrophy/damage and improving learning and memory abilities. Conclusion Our results demonstrated the occurrence of ferroptosis during HIBI via the SIRT1/Nrf2/GPx4 signaling pathway. Thus, this pathway represents a potential therapeutic target for the inhibition of ferroptosis and amelioration of HIBI-induced cognitive impairments.