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EphA1 aggravates neuropathic pain by activating CXCR4/RhoA/ROCK2 pathway in mice

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Abstract

Neuropathic pain is a refractory disease with limited treatment options due to its complex mechanisms. Whereas erythropoietin-producing hepatocyte A1 (EphA1) mediates the production of inflammatory factors that are important in the progression of neurological diseases, its role and molecular mechanisms in neuropathic pain remain unclear. In the present study, we established a mouse model of chronic constriction injury (CCI). EphA1 expression was observed to be progressively upregulated at the mRNA and protein levels with the progression of the disease. Subsequently, knockdown of EphA1 expression levels using adenovirus short hairpin RNA (AAV-shEphA1) revealed an increase in mechanical stimulation withdrawal threshold (PWT) and withdrawal latency (PWL) when EphA1 expression was decreased, accompanied by improved dorsal root ganglion injury, increased leukocytosis, decreased microglia, and decreased levels of pro-inflammatory factors. For the underlying mechanism, it was found that EphA1 regulates the activity of the RhoA/ROCK2 pathway by modulating the level of CXCR4. Inhibition of CXCR4 and RhoA/ROCK2 could effectively alleviate the promoting effect of EphA1 upregulation on neuropathic pain. In conclusion, our study suggests that depletion of EphA1 ameliorates neuropathic pain by modulating the CXCR4/RhoA/ROCK2 signaling pathway, and targeting EphA1 may be a potential clinical treatment for neuropathic pain.

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Data availability

The authors declare that all data supporting the findings of this study are available within the paper, and any raw data can be obtained from the corresponding author upon request.

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Funding

This work was supported by the Research Project of the China Medical Association of Minorities (Grant No. 2021Z1063-520701).

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Author notes

  1. Qi Li and Rui Li contributed equally to work and should be considered co-first authors.

Authors and Affiliations

  1. Department of Rehabilitation Medicine, Tianjin Hospital, Tianjin University, Tianjin, 300211, China

    Qi Li & Xiaolei Chu

  2. Academy of Medical Engineering and Translational Medicine, Tianjin University, 92, Weijin Road, Nankai District, Tianjin, 300072, China

    Qi Li, Lei Zhang & Long Chen

  3. Traditional Chinese Medicine Department, Guizhou Provincial People’s Hospital, Guiyang, 550002, Guizhou Province, China

    Rui Li

  4. Key Laboratory of Molecular Biology, Guizhou Medical University, Guiyang, 550004, Guizhou Province, China

    Xiaoxi Zhu

  5. School of Basic Medical Science, Guizhou Medical University, Guiyang, 550004, Guizhou Province, China

    Xiaoqiong An & Ming Chen

  6. Academy of the Society of Sport and Health Sciences, Tianjin University of Sport, Tianjin, 301617, China

    Mingwei Gao

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  1. Qi Li
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Contributions

QL and RL contributed to the study’s conception and design. QL, RL, XC, XA, MC, LZ, MG and XZ performed material preparation and experiments. QL, RL, XC, XA, MC, LZ, MG and XZ performed data collection and analysis. The first draft of the manuscript was written by QL, RL, and LC, and all authors commented on previous versions. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Long Chen.

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Ethical approval was obtained from the Laboratory Animal Ethics Committee of Guizhou Medical University.

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Li, Q., Li, R., Zhu, X. et al. EphA1 aggravates neuropathic pain by activating CXCR4/RhoA/ROCK2 pathway in mice. Human Cell 36, 1416–1428 (2023). https://doi.org/10.1007/s13577-023-00911-9

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  • DOI: https://doi.org/10.1007/s13577-023-00911-9

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