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Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission

Author

Listed:
  • Michele Yeo

    (Duke University Medical Center)

  • Yong Chen

    (Duke University Medical Center)

  • Changyu Jiang

    (Duke University Medical Center)

  • Gang Chen

    (Duke University Medical Center)

  • Kaiyuan Wang

    (Duke University Medical Center)

  • Sharat Chandra

    (Duke University Medical Center)

  • Andrey Bortsov

    (Duke University Medical Center)

  • Maria Lioudyno

    (University of California at Irvine)

  • Qian Zeng

    (Duke University Medical Center)

  • Peng Wang

    (Duke University Medical Center)

  • Zilong Wang

    (Duke University Medical Center
    Duke University Medical Center)

  • Jorge Busciglio

    (University of California at Irvine)

  • Ru-Rong Ji

    (Duke University Medical Center
    Duke University Medical Center)

  • Wolfgang Liedtke

    (Duke University Medical Center
    Duke University Medical Center
    Duke University Medical Center
    Duke University Medical Center)

Abstract

Inhibitory GABA-ergic neurotransmission is fundamental for the adult vertebrate central nervous system and requires low chloride concentration in neurons, maintained by KCC2, a neuroprotective ion transporter that extrudes intracellular neuronal chloride. To identify Kcc2 gene expression‑enhancing compounds, we screened 1057 cell growth-regulating compounds in cultured primary cortical neurons. We identified kenpaullone (KP), which enhanced Kcc2/KCC2 expression and function in cultured rodent and human neurons by inhibiting GSK3ß. KP effectively reduced pathologic pain-like behavior in mouse models of nerve injury and bone cancer. In a nerve-injury pain model, KP restored Kcc2 expression and GABA-evoked chloride reversal potential in the spinal cord dorsal horn. Delta-catenin, a phosphorylation-target of GSK3ß in neurons, activated the Kcc2 promoter via KAISO transcription factor. Transient spinal over-expression of delta-catenin mimicked KP analgesia. Our findings of a newly repurposed compound and a novel, genetically-encoded mechanism that each enhance Kcc2 gene expression enable us to re-normalize disrupted inhibitory neurotransmission through genetic re-programming.

Suggested Citation

  • Michele Yeo & Yong Chen & Changyu Jiang & Gang Chen & Kaiyuan Wang & Sharat Chandra & Andrey Bortsov & Maria Lioudyno & Qian Zeng & Peng Wang & Zilong Wang & Jorge Busciglio & Ru-Rong Ji & Wolfgang Li, 2021. "Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26270-3
    DOI: 10.1038/s41467-021-26270-3
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    References listed on IDEAS

    as
    1. Paul T E Cusack, 2020. "On Pain," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 31(3), pages 24253-24254, October.
    2. Francesco Ferrini & Jimena Perez-Sanchez & Samuel Ferland & Louis-Etienne Lorenzo & Antoine G. Godin & Isabel Plasencia-Fernandez & Martin Cottet & Annie Castonguay & Feng Wang & Chiara Salio & Nicola, 2020. "Differential chloride homeostasis in the spinal dorsal horn locally shapes synaptic metaplasticity and modality-specific sensitization," Nature Communications, Nature, vol. 11(1), pages 1-18, December.
    3. Sangsu Bang & Christopher R. Donnelly & Xin Luo & Maria Toro-Moreno & Xueshu Tao & Zilong Wang & Sharat Chandra & Andrey V. Bortsov & Emily R. Derbyshire & Ru-Rong Ji, 2021. "Activation of GPR37 in macrophages confers protection against infection-induced sepsis and pain-like behaviour in mice," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
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