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

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 () and Wolfgang Liedtke ()
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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
Jorge Busciglio: University of California at Irvine
Ru-Rong Ji: Duke University Medical Center
Wolfgang Liedtke: Duke University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26270-3

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