N-Acetyl Serotonin Provides Neuroprotective Effects by Inhibiting Ferroptosis in the Neonatal Rat Hippocampus Following Hypoxic Brain Injury

Abstract

Hypoxic-ischemic encephalopathy is the main cause of infant brain damage, perinatal death, and chronic neonatal disability worldwide. Ferroptosis is a new form of cell death that is closely related to hypoxia-induced brain damage. N-Acetyl serotonin (NAS) exerts neuroprotective effects, but its effects and underlying mechanisms in hypoxia-induced brain damage remain unclear. In the present study, 5-day-old neonatal Sprague-Dawley rats were exposed to hypoxia for 7 days to establish a hypoxia model. Histochemical staining was used to measure the effects of hypoxia on the rat hippocampus. The hippocampal tissue in the hypoxia group showed significant atrophy. Hypoxia significantly increased the levels of prostaglandin-endoperoxide synthase 2 (PTGS2) and the iron metabolism-related protein transferrin receptor 1 (TfR1) and decreased the levels of glutathione peroxidase 4 (GPX4). These changes resulted in mitochondrial damage, causing neuronal ferroptosis in the hippocampus. More importantly, NAS may improve mitochondrial function and alleviate downstream ferroptosis and damage to the hippocampus following hypoxia. In conclusion, we found that NAS could suppress neuronal ferroptosis in the hippocampus following hypoxic brain injury. These discoveries highlight the potential use of NAS as a treatment for neuronal damage through the suppression of ferroptosis, suggesting new treatment strategies for hypoxia-induced brain damage.

Keywords: Ferroptosis; Hypoxia-induced brain injury; Hypoxic-ischemic encephalopathy; N-Acetyl serotonin.