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Naringenin relieves Paclitaxel-induced pain via inhibiting CGRP production and DRG neuron sensitization and enhances Paclitaxel's anti-tumor action
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  • Yuhao Xu,
  • Zongsheng Jiang,
  • Yu Zhang,
  • Ziyi Wu,
  • Linbin Xu,
  • Chengjiang Fan,
  • Chen Pan,
  • Changqing Mei,
  • Qingge Chen,
  • Yang Xi,
  • Xiaowei Chen
Yuhao Xu
Ningbo University
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Zongsheng Jiang
Ningbo University
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Yu Zhang
Ningbo University
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Ziyi Wu
Ningbo University
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Linbin Xu
Ningbo University
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Chengjiang Fan
Ningbo University
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Chen Pan
Ningbo University
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Changqing Mei
Ningbo University
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Qingge Chen
Huatuo Traditional Chinese Medicine Hospital, BoZhou, Anhui
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Yang Xi
Ningbo University
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Xiaowei Chen
Ningbo University

Corresponding Author:[email protected]

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Abstract

Background and Purposes: Chemotherapy-induced peripheral neuropathy commonly causes neuropathic pain. The pathogenesis of CIPN is unclear, and effective therapies are also lacking. Naringenin, a dihydroflavonoid compound in Rutaceae plants and citrus fruits, has anti-inflammatory, antioxidant, and anti-tumor activities. However, its effect on chemotherapy-induced pain has not been investigated. Experimental Approach: We used Paclitaxel (PTX) to establish a mouse model of chemotherapy-induced pain. Mechanical and thermal pain thresholds, glial activation, calcitonin gene-related peptide (CGRP) expression, c-fos expression, phosphorylation of nuclear factor κB (NF-κB), dorsal root ganglion (DRG) neuron excitability, and cell survival of pancreatic, colorectal, and gastric cancer cell lines were measured. Key Results: Systemic application of Naringenin reduced the mechanical and thermal pain hypersensitivity induced by PTX. Naringenin reduced the activation of glial cells in both DRGs and the spinal dorsal horn of PTX-treated mice. Naringenin decreased the PTX-enhanced CGRP expression in DRG and spinal neurons. Naringenin reversed the PTX-enhanced c-fos expression and excitability of DRG neurons. Naringenin downregulated PTX-elevated NF-κB phosphorylation in the spinal cord. Additionally, co-administration of Naringenin with PTX enhanced the inhibitory effect of PTX on pancreatic and colorectal cancer cell growth, whereas the application of Naringenin alone inhibited the survival of pancreatic cancer cells. Conclusion and Implications: Naringenin alleviates PTX-induced pain and may facilitate PTX’s anti-tumor effect. The mechanism involves the inhibition of glial activation, CGRP production, and neuronal sensitization in PTX-treated mice. Our study suggests the multiple beneficial actions of Naringenin in chemotherapy by mitigating side effects and inhibiting tumor growth.
16 Jun 2023Submitted to British Journal of Pharmacology
17 Jun 2023Assigned to Editor
17 Jun 2023Submission Checks Completed
17 Jun 2023Review(s) Completed, Editorial Evaluation Pending
25 Jun 2023Reviewer(s) Assigned
17 Aug 2023Editorial Decision: Revise Minor