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Netrin-1 Alleviates Early Brain Injury by Regulating Ferroptosis via the PPARγ/Nrf2/GPX4 Signaling Pathway Following Subarachnoid Hemorrhage

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Abstract

Subarachnoid hemorrhage (SAH) is a type of stroke with high morbidity and mortality. Netrin-1 (NTN-1) can alleviate early brain injury (EBI) following SAH by enhancing peroxisome proliferator-activated receptor gamma (PPARγ), which is an important transcriptional factor modulating lipid metabolism. Ferroptosis is a newly discovered type of cell death related to lipid metabolism. However, the specific function of ferroptosis in NTN-1-mediated neuroprotection following SAH is still unclear. This study aimed to evaluate the neuroprotective effects and the possible molecular basis of NTN-1 in SAH-induced EBI by modulating neuronal ferroptosis using the filament perforations model of SAH in mice and the hemin-stimulated neuron injury model in HT22 cells. NTN-1 or a vehicle was administered 2 h following SAH. We examined neuronal death, brain water content, neurological score, and mortality. NTN-1 treatment led to elevated survival probability, greater survival of neurons, and increased neurological score, indicating that NTN-1-inhibited ferroptosis ameliorated neuron death in vivo/in vitro in response to SAH. Furthermore, NTN-1 treatment enhanced the expression of PPARγ, nuclear factor erythroid 2-related factor 2 (Nrf2), and glutathione peroxidase 4 (GPX4), which are essential regulators of ferroptosis in EBI after SAH. The findings show that NTN-1 improves neurological outcomes in mice and protects neurons from death caused by neuronal ferroptosis. Furthermore, the mechanism underlying NTN-1 neuroprotection is correlated with the inhibition of ferroptosis, attenuating cell death via the PPARγ/Nrf2/GPX4 pathway and coenzyme Q10-ferroptosis suppressor protein 1 (CoQ10-FSP1) pathway.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank all the participants for donating samples for this study. And we thank Bullet Edits Limited for the linguistic editing and proofreading of the manuscript.

Funding

This work was supported by the Natural Science Foundation of China (no. 81871589), Jiangsu Provincial Natural Science Foundation (grant no.: BK20201140), Top Talent Support Program for Young and Middle-aged People of Wuxi Health Committee (HB2020119), and Wuxi Science and Technology Development Foundation (grant no.: N20201008).

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Author notes

  1. Junhui Chen, Yuhai Wang, Mingchang Li these authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha, Hunan Province, China

    Junhui Chen & Kun Xiong

  2. Department of Neurosurgery, Renmin Hospital of Wuhan University, No. 9 Zhangzhidong Road, Wuchang District, Wuhan, 430072, Hubei Province, China

    Junhui Chen, Mingchang Li & Qianxue Chen

  3. Department of Neurosurgery, 904th Hospital of Joint Logistic Support Force of PLA, Wuxi Clinical College of Anhui Medical University, Wuxi, 214044, China

    Junhui Chen, Yuhai Wang & Zhuanghua Liu

  4. Department of Neurosurgery, The Second Hospital of Tianjin Medical University, Tianjin, China

    Xun Zhu

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  4. Xun Zhu
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  5. Zhuanghua Liu
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  6. Qianxue Chen
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  7. Kun Xiong
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Contributions

JC, KX, and QC designed the experiments of the study. YW, ML, XZ, and KX contributed to the execution of experiments and manuscript composition. JC, ML, and ZL collected and analyzed clinical data. JC, QC, and KX performed animal and cell experiments. JC performed the statistical analysis. JC and ML compiled the figures and wrote the manuscript. All authors discussed the results, revised the manuscript, and read and approved the final manuscript.

Corresponding authors

Correspondence to Qianxue Chen or Kun Xiong.

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Competing Interests

The authors declare no competing interests.

Ethics Approval and Consent to Participate

The Institutional Animal Care and Use Committee of Wuxi Clinical College of Anhui Medical University (YXLL-2019–020) granted approval for all the procedures and mice used in the research, and all procedures were performed in compliance with the protocols stipulated by the National Institutes of Health (NIH) and Animal Research: Reporting of In Vivo Experiments (NIH publication No. 80–23, revised 1996).The serum Netrin-1 study was approved by the Renmin Hospital of Wuhan University and Anhui Medical University affiliated Wuxi Clinical College’s Clinical Research Ethics Committee (YXLL-2020111). We obtained written informed consent from the patients or family members of patients.

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We have obtained consent to publish from the participants to report patient data.

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Fig. 1

Downregulation of Nrf2 expression by siRNA transfection. a. Relative protein expressions of Nrf2 in PC12 neurons were significantly decreased in si-Nrf2-1 and si-Nrf2-2 groups by western blot analysis (n = 5; *p 0.01 vs. si-Control group; t-test; mean ± SD). b. MTT assay demonstrated that si-Nrf2 transfection did not affect cell viability. c. Microscopic analysis showed that PC12 neuron morphology was normal 48 hours after si-Nrf2 transfection. (PNG 1448 kb)

High Resolution Image (TIF 12765 KB)

Supplementary Table 1

Sequences of the primers for quantitative RT-PCR (DOC 38 KB)

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Chen, J., Wang, Y., Li, M. et al. Netrin-1 Alleviates Early Brain Injury by Regulating Ferroptosis via the PPARγ/Nrf2/GPX4 Signaling Pathway Following Subarachnoid Hemorrhage. Transl. Stroke Res. 15, 219–237 (2024). https://doi.org/10.1007/s12975-022-01122-4

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