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Endoplasmic Reticulum Stress Promotes Neuronal Damage in Neonatal Hypoxic-Ischemic Brain Damage by Inducing Ferroptosis

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Abstract

Hypoxic-ischemic brain damage (HIBD) poses a significant risk of neurological damage in newborns. This study investigates the impact of endoplasmic reticulum stress (ERS) on neuronal damage in neonatal HIBD and its underlying mechanisms. HIBD neonatal rat model was constructed and pre-treated with 4-phenylbutiric acid (4-PBA). Nissl and TUNEL staining were utilised to assess neuronal damage and apoptosis in rat brains. HIBD cell model was established by inducing oxygen-glucose deprivation (OGD) in rat H19-7 neurons, which were then pre-treated with Thapsigargin (TG), Ferrostatin-1 (Fer-1), or both. Cell viability and apoptosis of H19-7 neurons were analysed using cell counting kit-8 assay and TUNEL staining. GRP78-PERK-CHOP pathway activity and glutathione peroxidase-4 (GPX4) expression in rat brains and H19-7 neurons were assessed using Western blot. Ferroptosis-related indicators, including glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and iron content, were measured using commercial kits in both rat brains and H19-7 neurons. GRP78-PERK-CHOP pathway was overactivated in HIBD neonatal rats’ brains, which was mitigated by 4-PBA treatment. 4-PBA treatment demonstrated a reduction in neuronal damage and apoptosis in HIBD-affected neonatal rat brains. Furthermore, it attenuated ferroptosis in rats by increasing GPX4, GSH and SOD while decreasing MDA and iron content. In the OGD-induced H19-7 neurons, Fer-1 treatment counteracted the suppressive effects of TG on viability, the exacerbation of apoptosis, the promotion of ferroptosis and the activation of the GRP78-PERK-CHOP pathway. Overall, ERS facilitates neuronal damage in neonatal HIBD by inducing ferroptosis. Consequently, the suppression of ERS may represent a promising therapeutic strategy for treating neonatal HIBD.

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Data Availability

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

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Funding

Ningxia Natural Science Foundation, the role of endoplasmic reticulum stress in the regulation of brain injury in hypoxic-ischemic rats (2022AAC03705).

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  1. Peking University First Hospital Ningxia Women and Children’s Hospital (Ningxia Hui Autonomous Region Maternal and Child Health Hospital), 127 Hupan Road, Jinfeng District, Yinchuan City, Ningxia, 750001, China

    Yongjia Ji, Huili Liu, Fang Niu, Bo Kang, Xiu Luo, Hua Yang, Zhen Tian & Juan Yang

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Correspondence to Yongjia Ji.

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Ji, Y., Liu, H., Niu, F. et al. Endoplasmic Reticulum Stress Promotes Neuronal Damage in Neonatal Hypoxic-Ischemic Brain Damage by Inducing Ferroptosis. Mol Biotechnol (2024). https://doi.org/10.1007/s12033-024-01095-9

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