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Metformin Relieves Bortezomib-Induced Neuropathic Pain by Regulating AMPKa2-Mediated Autophagy in the Spinal Dorsal Horn

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Abstract

Chemotherapy-induced neuropathic pain is a major clinical problem with limited treatment options. Here, we show that metformin relieves bortezomib (BTZ)-evoked induction and maintenance of neuropathic pain by preventing the reduction in the expression of Beclin-1, an autophagy marker, in the spinal dorsal horn. Application of rapamycin or 3-methyladenine, autophagy inducer and inhibitor, respectively, affected the mechanical allodynia differently. Co-application of 3-methyladenine and metformin partially inhibited the effect of metformin in recovering Beclin-1 expression and in reducing the pain behavior in rats subjected to BTZ treatment. BTZ treatment also reduced the expression of AMPKa2 in the dorsal horn, which was recovered by metformin treatment. Overexpression of AMPKa2 attenuated the BTZ-evoked reduction in Beclin-1 expression and mechanical allodynia, whereas intrathecal injection of AMPKa2 siRNA decreased the Beclin-1 expression and induced mechanical allodynia in naive rats. Moreover, BTZ treatment increased the GATA3 expression in the dorsal horn, and GATA3 siRNA attenuated the AMPKa2 downregulation and mechanical allodynia induced by BTZ. Chromatin immunoprecipitation further showed that BTZ induced an increased recruitment of GATA3 to multiple sites in the AMPKa2 promoter region. Furthermore, decreased acetylation and increased methylation of histone H3 in the AMPKa2 promoter in the spinal dorsal horn was detected after BTZ treatment. Our findings suggest that metformin may regulate AMPKa2-mediated autophagy in the dorsal horn and alleviate the behavioral hypersensitivity induced by BTZ.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This study was funded by National Natural Science Foundation of China (31970936, 81801103 and 81971048), Natural Science Foundation of Guangdong (2019A1515010871 and 2019A1515110716), Shanghai Pujiang Program (2020PJD059) and Youth Cultivation Project for Special Basic Medical Research of the First Affiliated Hospital of Naval Medical University (2021JCQN02).

Funding

This work was supported by National Natural Science Foundation of China (31970936, 81801103 and 81971048), Natural Science Foundation of Guangdong (2019A1515010871 and 2019A1515110716), Shanghai Pujiang Program (2020PJD059) and Youth Cultivation Project for Special Basic Medical Research of the First Affiliated Hospital of Naval Medical University (2021JCQN02).

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Author notes

  1. Meng Liu and Yu-Ting Zhao have contributed equally to this work.

Authors and Affiliations

  1. Zhongshan Medical School and Guangdong Province Key Laboratory of Brain Function and Disease, Sun Yat-Sen University, Zhongshan Rd. 2, Guangzhou, China

    Meng Liu, Yu-Ting Zhao, Ting Xu, Wen-Jun Xin & Su-Yan Lin

  2. Department of Anesthesia and Pain Medicine, Guangzhou First People’s Hospital, Guangzhou, China

    Meng Liu

  3. Department of Anesthesia, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, China

    You-You Lv

  4. Department of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China

    Dai Li & Yuan-Chang Xiong

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  1. Meng Liu
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Contributions

ML: Investigation, Writing—Original Draft. YTZ: Investigation, Formal analysis. YYL: Investigation, Formal analysis. TX: Formal analysis. DL: Formal analysis. YCX: Visualization, Supervision. WJX: Visualization, Supervision. SYL: Conceptualization, Supervision, Writing—Review & Editing.

Corresponding author

Correspondence to Su-Yan Lin.

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The authors have no relevant financial or non-financial interests to disclose.

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All experimental protocols were approved by the Local Animal Care Committee and carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Liu, M., Zhao, YT., Lv, YY. et al. Metformin Relieves Bortezomib-Induced Neuropathic Pain by Regulating AMPKa2-Mediated Autophagy in the Spinal Dorsal Horn. Neurochem Res 47, 1878–1887 (2022). https://doi.org/10.1007/s11064-022-03571-7

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  • DOI: https://doi.org/10.1007/s11064-022-03571-7

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