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Intrathecal Fumagillin Alleviates Chronic Neuropathy-Induced Nociceptive Sensitization and Modulates Spinal Astrocyte-Neuronal Glycolytic and Angiogenic Proteins

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Abstract

Nociceptive sensitization is accompanied by the upregulation of glycolysis in the central nervous system in neuropathic pain. Growing evidence has demonstrated glycolysis and angiogenesis to be related to the inflammatory processes. This study investigated whether fumagillin inhibits neuropathic pain by regulating glycolysis and angiogenesis. Fumagillin was administered through an intrathecal catheter implanted in rats with chronic constriction injury (CCI) of the sciatic nerve. Nociceptive, behavioral, and immunohistochemical analyses were performed to evaluate the effects of the inhibition of spinal glycolysis-related enzymes and angiogenic factors on CCI-induced neuropathic pain. Fumagillin reduced CCI-induced thermal hyperalgesia and mechanical allodynia from postoperative days (POD) 7 to 14. The expression of angiogenic factors, vascular endothelial growth factor (VEGF) and angiopoietin 2 (ANG2), increased in the ipsilateral lumbar spinal cord dorsal horn (SCDH) following CCI. The glycolysis-related enzymes, pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA) significantly increased in the ipsilateral lumbar SCDH following CCI on POD 7 and 14 compared to those in the control rats. Double immunofluorescence staining indicated that VEGF and PKM2 were predominantly expressed in the astrocytes, whereas ANG2 and LDHA were predominantly expressed in the neurons. Intrathecal infusion of fumagillin significantly reduced the expression of angiogenic factors and glycolytic enzymes upregulated by CCI. The expression of hypoxia-inducible factor-1α (HIF-1α), a crucial transcription factor that regulates angiogenesis and glycolysis, was also upregulated after CCI and inhibited by fumagillin. We concluded that intrathecal fumagillin may reduce the expression of ANG2 and LDHA in neurons and VEGF and PKM2 in the astrocytes of the SCDH, further attenuating spinal angiogenesis in neuropathy-induced nociceptive sensitization. Hence, fumagillin may play a role in the inhibition of peripheral neuropathy-induced neuropathic pain by modulating glycolysis and angiogenesis.

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Data Availability

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

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Acknowledgements

The illustrations (Fig. 8) were created using BioRender.com.

Funding

This study was supported by National Science and Technology Council, Taiwan, 109-2314-B-075-045-MY3, and Taipei Veterans General Hospital, Taiwan, V113C-056.

Author information

Author notes

  1. Zhi-Hong Wen and Zong-Sheng Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, 804201, Taiwan

    Zhi-Hong Wen

  2. Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan

    Zhi-Hong Wen & Hao-Jung Cheng

  3. Division of Pain Management, Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan

    Zong-Sheng Wu, Shih-Hsuan Tang, Wei-Nung Teng, Fu-Wei Su & Chun-Sung Sung

  4. College of Ocean Food and Biological Engineering, Jimei University, **amen, 361021, China

    Shi-Ying Huang

  5. Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung, 80284, Taiwan

    Nan-Fu Chen

  6. Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, 804201, Taiwan

    Nan-Fu Chen

  7. School of Medicine, National Yang-Ming Chiao Tung University, Taipei, 112304, Taiwan

    Wei-Nung Teng, Fu-Wei Su & Chun-Sung Sung

Authors
  1. Zhi-Hong Wen
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  2. Zong-Sheng Wu
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  3. Hao-Jung Cheng
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  4. Shi-Ying Huang
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  5. Shih-Hsuan Tang
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  6. Wei-Nung Teng
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  7. Fu-Wei Su
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  8. Nan-Fu Chen
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  9. Chun-Sung Sung
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Contributions

ZHW and CSS designed the experiments; ZHW and CSS supervised the design and course of the experiments; HJC, SYH and SHT performed the experiments; SYH, WNT, NFC, FWS and CSS performed the analyses and interpretation of the experiments; ZHW, ZSW and CSS wrote the manuscript; ZHW and CSS reviewed and edited the manuscript. All of the authors read and approved the final manuscript.

Corresponding author

Correspondence to Chun-Sung Sung.

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Ethics Approval

All animal experiments were approved by the Institutional Animal Care and Use Committee of National Sun Yat-sen University (Approval No. IACUC-111-37).

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The authors declare no competing interests.

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Wen, ZH., Wu, ZS., Cheng, HJ. et al. Intrathecal Fumagillin Alleviates Chronic Neuropathy-Induced Nociceptive Sensitization and Modulates Spinal Astrocyte-Neuronal Glycolytic and Angiogenic Proteins. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04254-w

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  • DOI: https://doi.org/10.1007/s12035-024-04254-w

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