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

Zhi-Hong Wen; Zong-Sheng Wu; Hao-Jung Cheng; Shi-Ying Huang; Shih-Hsuan Tang; Wei-Nung Teng; Fu-Wei Su; Nan-Fu Chen; Chun-Sung Sung

doi:10.1007/s12035-024-04254-w

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

Mol Neurobiol. 2024 Jun 5. doi: 10.1007/s12035-024-04254-w. Online ahead of print.

Authors

Zhi-Hong Wen^#^{1

2}, Zong-Sheng Wu^#³, Hao-Jung Cheng², Shi-Ying Huang⁴, Shih-Hsuan Tang³, Wei-Nung Teng^{3

5}, Fu-Wei Su^{3

5}, Nan-Fu Chen^{6

7}, Chun-Sung Sung^{8

9}

Affiliations

¹ Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, 804201, Taiwan.
² Institute of Biopharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan.
³ Division of Pain Management, Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan.
⁴ College of Ocean Food and Biological Engineering, Jimei University, Xiamen, 361021, China.
⁵ School of Medicine, National Yang-Ming Chiao Tung University, Taipei, 112304, Taiwan.
⁶ Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung, 80284, Taiwan.
⁷ Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, 804201, Taiwan.
⁸ Division of Pain Management, Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, 112201, Taiwan. cssung@vghtpe.gov.tw.
⁹ School of Medicine, National Yang-Ming Chiao Tung University, Taipei, 112304, Taiwan. cssung@vghtpe.gov.tw.

^# Contributed equally.

PMID: 38837104
DOI: 10.1007/s12035-024-04254-w

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.

Keywords: Angiogenesis; Glycolysis; Lactate dehydrogenase A; Neuropathic pain; Pyruvate kinase M2.

Abstract

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