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

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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.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by the Shandong Provincial Natural Science Foundation of China (Grant No. ZR2015PH036), the China Scholarship Council (Grant No. 201706225023), and the China Postdoctoral Science Foundation (Grant No. 2021M691944). Xiaomei Yang has received research support from the Shandong Provincial Natural Science Foundation of China, the China Scholarship Council and the China Postdoctoral Science Foundation.

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Authors and Affiliations

  1. Department of Anesthesiology, Qilu Hospital of Shangdong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong, China

    Xiaomei Yang, Yue Yang & Chunling Wang

  2. Department of Anesthesiology, School of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, 250012, Shandong, China

    Xiaomei Yang & Kangping Lu

  3. Biomedical Isotope Research Center, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China

    Feng Gao

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  1. Xiaomei Yang
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  2. Yue Yang
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Contributions

All authors contributed to the study conception and design. Material preparation, investigation, data collection, and analysis were performed by Xiaomei Yang, Yue Yang, Feng Gao, and Kangping Lu. Project administration and supervision was performed by Chunling Wang. The first draft of the manuscript was written by Chunling Wang and Yue Yang. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Chunling Wang.

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The animal study protocol was approved by the Ethics Committee of Qilu Hospital of Shandong University (protocol code: ECAESDUSM 2012029).

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Xiaomei Yang and Yue Yang contributed to the study equally, and both are co-first authors.

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Yang, X., Yang, Y., Gao, F. et al. N-Acetyl Serotonin Provides Neuroprotective Effects by Inhibiting Ferroptosis in the Neonatal Rat Hippocampus Following Hypoxic Brain Injury. Mol Neurobiol 60, 6307–6315 (2023). https://doi.org/10.1007/s12035-023-03464-y

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