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Monoclonal Antibody Targeting CGRP Relieves Cisplatin-Induced Neuropathic Pain by Attenuating Neuroinflammation

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Abstract

Chemotherapy-induced neuropathic pain (CIPN) is a common side effect of antitumor chemotherapeutic agents. It describes a pathological state of pain related to the cumulative dosage of the drug, significantly limiting the efficacy of antitumor treatment. Sofas strategies alleviating CIPN still lack. Calcitonin gene-related peptide (CGRP) is a neuropeptide involved in many pathologic pains. In this study, we explored the effects of CGRP blocking on CIPN and potential mechanisms. Total dose of 20.7 mg/kg cisplatin was used to establish a CIPN mouse model. Mechanical and thermal hypersensitivity was measured using von Frey hairs and tail flick test. Western blot and immunofluorescence were utilized to evaluate the levels of CGRP and activated astrocytes in mouse spinal cord, respectively. In addition, real-time quantitative PCR (RT-qPCR) was used to detect the level of inflammatory cytokines such as IL-6, IL-1β, and NLRP3 in vitro and in vivo. There are markedly increased CGRP expression and astrocyte activation in the spinal cord of mice following cisplatin treatment. Pretreatment with a monoclonal antibody targeting CGRP (ZR8 mAb) effectively reduced cisplatin-induced mechanical hypersensitivity and thermal nociceptive sensitization and attenuated neuroinflammation as marked by downregulated expression of IL-6, IL-1β, and NLRP3 in the mice spinal cord and spleen. Lastly, ZR8 mAb does not interfere with the antitumor effects of cisplatin in tumor-bearing mice. Our findings indicate that neutralizing CGRP with monoclonal antibody could effectively alleviate CIPN by attenuating neuroinflammation. CGRP is a promising therapeutic target for CIPN.

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Data Availability

All data generated or analyzed during this study are included in this published article.

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Funding

This study was supported by the China Science and Technology STI 2030—Major Projects (2021ZD0201600), National Natural Science Foundation of China (82171753, 82301992).

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Authors and Affiliations

  1. Navy Clinical College, The Fifth School of Clinical Medicine, Anhui Medical University, Hefei, Anhui Province, 230032, China

    Shun Xie & Taiqian Gong

  2. Department of Thoracic Surgery, The Sixth Medical Center of Chinese, PLA General Hospital, Beijing, 100048, China

    Shun Xie, Jiale Zhang, Yanxin Dong & Taiqian Gong

  3. Department of Neuroimmune and Antibody Engineering, Beijing Institute of Basic Medical Sciences, Beijing, 100048, China

    Shun Xie, Zhenfang Gao, Cong Xing, Lanyin Wang, Zhiding Wang, Yuxiang Li, Ge Li & Gencheng Han

  4. Joint National Laboratory for Antibody Drug Engineering, The First Affiliated Hospital of Henan University, School of Medicine, Henan University, Kaifeng, 475004, China

    Cong Xing

Authors
  1. Shun Xie
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  2. Zhenfang Gao
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  3. Jiale Zhang
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  4. Cong Xing
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  5. Yanxin Dong
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  9. Ge Li
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  10. Gencheng Han
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Contributions

All authors contributed to the conceptualization and design of the study, S.X. performed all experiments and wrote the main manuscript, Z.G. assisted in designing the experiments, graphing and writing part of the manuscript, J.Z. analyzed the data and wrote part of the manuscript, C.X and Y.D. assisted with part of the experiments and data analysis, L.W. assisted with part of the experiments, Z.W., Y.L. and G.L. help analyze data, G.H. provided the main funding and carried out the corrections to the manuscript, and T.G. designed the main experiments and participated in the corrections to the manuscript.

Corresponding authors

Correspondence to Gencheng Han or Taiqian Gong.

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Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. The Animal Ethics Committee of the Beijing Institute of Basic Medical Sciences, Beijing, China, approved the experiments (IACUC-DWZX-2022–546).

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The authors declare no competing interests.

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Xie, S., Gao, Z., Zhang, J. et al. Monoclonal Antibody Targeting CGRP Relieves Cisplatin-Induced Neuropathic Pain by Attenuating Neuroinflammation. Neurotox Res 42, 8 (2024). https://doi.org/10.1007/s12640-023-00685-w

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