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Hemorrhage-Induced Sphingosine Kinase 1 Contributes to Ferroptosis-Mediated Secondary Brain Injury in Intracerebral Hemorrhage

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Abstract

The pathogenic processes of brain injury after intracerebral hemorrhage (ICH) have not yet been fully elucidated. Increasing evidence suggests that ferroptosis activation aggravates injury after ICH, but the underlying mechanism remains unclear. Sphingosine kinase 1 (Sphk1) is a key enzyme in the regulation of sphingosine metabolism involved in the ferroptosis pathway, but its role in ICH needs clarification. In this study, transcriptional changes in ICH patients were assessed by microarray data, exposing Sphk1 as a highly upregulated gene during ICH. Furthermore, Sphk1 chemical inhibitors and siRNA were used to inhibit ICH-induced Sphk1 upregulation in in vivo and in vitro models, showing that Sphk1 inhibition after protects against ferroptosis and attenuates secondary brain injury and cell death. Mechanistically, this study unveiled that sphingosine kinase 1/sphingosine 1-phosphate/extracellular-regulated protein kinases/phosphorylated extracellular-regulated protein kinases (Sphk1/S1p/ERK/p-ERK) pathway is responsible for regulation of ferroptosis leading to secondary brain injury and cell death following ICH. Collectively, this study demonstrates that ferroptosis is closely associated with ICH, and that Sphk1 has a critical role in this lethal process. These results suggest a novel unique and effective therapeutic approach for ICH prevention and treatment.

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Data Availability

The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.

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Acknowledgements

We would like to thank Dr. John Hugh Snyder (Genesis Technology Communication (Beijing), Co., Ltd.) for the linguistic assistance during the preparation of this manuscript.

Funding

This work was supported by Grant Number 2018GXNSFBA138046 from the Youth Fund of the Guangxi Natural Science Foundation and the Guangxi Science and Technology Project (Grant Number Guike AD18281013). Grant Number 2020GXNSFAA259036, Grant Number 2017GXNSFBA198001, and Grant Number 2018GXNSFAA138110 were from the Fund of the Guangxi Natural Science Foundation. This work was also supported by the National Natural Science Foundation of China (No. 81760541).

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  1. Xiaojun Diao and Qi Cui contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410000, China

    Xiaojun Diao & Qinghua Li

  2. Guangxi Clinical Research Center for Neurological Diseases, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin, 541004, China

    Xiaojun Diao, Ning Tian, Zixian Zhou, Wenjing Xiang, Qinghua Li & Rujia Liao

  3. Laboratory of Neuroscience, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin, 541004, China

    Qi Cui, Ning Tian, Zixian Zhou, Wenjing Xiang, Qinghua Li & Rujia Liao

  4. Department of Neurology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin, 541004, China

    Qi Cui & Xiaohui Lin

  5. Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guilin Medical University, Guilin, 541004, China

    Zixian Zhou, Wenjing Xiang, Qinghua Li & Rujia Liao

  6. Department of Pharmacology, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin, 541004, China

    Yanlin Jiang & Jungang Deng

  7. Department of Neurosurgery, Affiliated Hospital of Guilin Medical University, Guilin Medical University, Guilin, 541004, China

    Hongzhan Liao

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Contributions

X.J.D. and Q.C. performed the experiments, analyzed the data, and wrote the paper. N.T. Z.X.Z., W.J.X., Y.L.J., J.G.D., and H.Z.L. contributed to some parts of the experiments. X.H.L. and Q.H.L. designed the experiment and provided advice on the interpretation of the data. R.J.L. conceived of and designed the experiment, analyzed and interpreted the data, provided financial support, and wrote the paper.

Corresponding authors

Correspondence to Qinghua Li or Rujia Liao.

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All animal procedures were approved by the Guilin Medical University Animal Experimentation Committee (approval number GLMC201805008).

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Fig. S1

The experimental design in this study

High resolution image (TIF 205 KB)

Fig. S2

Sphk1 inhibition reducing apoptosis after ICH. Representative images and quantification of the number of apoptotic cells at seven days after 5C administration in ICH model mice. The white arrows indicate typical apoptotic bodies. n = 4-6 per group. *p<0.05 and **p<0.01. Data are presented as mean ± S.E.M.

High resolution image (TIF 4817 KB)

Fig. S3

Sphk1 inhibition have no effect on autophagy process after ICH. Representative western blot bands and quantitative analyses of p62 and microtubule-associated protein light chain 3 (LC3)-II at seven days after 5C administration in ICH model mice. n = 3-4 per group. Data are presented as mean ± S.E.M.

High resolution image (TIF 424 KB)

Table S1

The primary antibodies and secondary antibodies used in this study (DOCX 15 KB)

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Diao, X., Cui, Q., Tian, N. et al. Hemorrhage-Induced Sphingosine Kinase 1 Contributes to Ferroptosis-Mediated Secondary Brain Injury in Intracerebral Hemorrhage. Mol Neurobiol 59, 1381–1397 (2022). https://doi.org/10.1007/s12035-021-02605-5

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