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Ferroptosis is involved in the development of neuropathic pain and allodynia

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Abstract

Neuropathic pain (NP) is chronic, intractable, and typically not alleviated using analgesics. Ferroptosis is a new type of cell death characterized by mitochondrial damage, oxidative stress, and mitochondrial dysfunction, affecting specific types of synaptic plasticity in the spinal cord. Here, we evaluated the role of ferroptosis in NP using chronic contractile injury (CCI) in rats. The CCI and control groups were subjected to sciatic nerve ligation. The mechanical withdrawal threshold and thermal withdrawal reflex latency were used to detect changes in mechanical pain threshold and thermal pain threshold in rats, respectively. Notably, CCI caused mechanical and thermal stimulation of the injured hind paw, reduced levels of glutathione peroxidase 4 (GPX4), and increased acyl-CoA synthetase long-chain family member 4 (ACSL4). Treatment with the ferroptosis inhibitor ferrostatin-1 (10 mg/kg) 1 h after surgery upregulated GPX4 expression and downregulated ACSL4 expression, whereas the ferroptosis inducer, erastin (10 mg/kg), exerted opposite effects. Treatment with ferrostatin-1 upregulated NeuN expression and downregulated GPX4 expression, whereas erastin reversed these effects. CCI increased the number of damaged mitochondria and decreased the mean planar mitochondrial area, and treatment with erastin further exacerbated these effects. The iron ion content in the spinal cords of CCI-induced rats increased. Treatment with ferrostatin-1 decreased, whereas treatment with erastin increased iron ion content in the CCI-induced rat model. Taken together, our results showed that ferroptosis is involved in the development of NP in male rats by blocking neuron and astrocyte activation in the spinal dorsal horn.

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Acknowledgements

We thank the Deputy Chief Physician, Jiang Ning, the Central Laboratory of the Second Hospital of Tianjin Medical University for assistance with experimental techniques.

Funding

Tianjin Natural Science Foundation supported this research project (Grant No. 18JCQNJC13100).

Author information

Author notes

  1. Huixing Wang, Xiaodong Huo, and Chenyang Han contributed equally to this work.

Authors and Affiliations

  1. Pain Management Center, Second Hospital of Tianjin Medical University, Tianjin, 300211, People’s Republic of China

    Huixing Wang, Chenyang Han, Bo Li, Jingzhi Liu, Wenting Ma, Quanbo Li & Kemei Shi

  2. Department of Oncology, Second Hospital of Tianjin Medical University, Tianjin, 300211, People’s Republic of China

    Xiaodong Huo

  3. Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin Research Institute of Anesthesiology, Tianjin, 300211, People’s Republic of China

    Hongguang Chen & Yonghao Yu

  4. The Central Laboratory, Second Hospital of Tianjin Medical University, Tianjin, 300211, People’s Republic of China

    Jiang Ning

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  1. Huixing Wang
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Contributions

HW, XH, and CH jointly participated in the experimental design, experimental operation, and writing. JN guided the design and writing. HC, BL, JL, and WM participated in the design and performed experiments. QL and YY performed experiments. KS provided experimental ideas and guided the writing of the paper.

Corresponding author

Correspondence to Kemei Shi.

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The authors declare that there are no conflicts of interest regarding the publication of this paper.

Ethics approval

All procedures involved in this experiment were approved by the Animal Clinical Committee of Tianjin Medical University (Approval: DWLI-20181010) and were performed in accordance with the National Institutes of Health Laboratory Animal Care and Use Guidelines (National Institutes of Health Institute Publication 85-23, revised in 1996).

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Wang, H., Huo, X., Han, C. et al. Ferroptosis is involved in the development of neuropathic pain and allodynia. Mol Cell Biochem 476, 3149–3161 (2021). https://doi.org/10.1007/s11010-021-04138-w

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  • DOI: https://doi.org/10.1007/s11010-021-04138-w

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