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

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 c...

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Autores principales: Yeo, Michele, Chen, Yong, Jiang, Changyu, Chen, Gang, Wang, Kaiyuan, Chandra, Sharat, Bortsov, Andrey, Lioudyno, Maria, Zeng, Qian, Wang, Peng, Wang, Zilong, Busciglio, Jorge, Ji, Ru-Rong, Liedtke, Wolfgang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551327/
https://www.ncbi.nlm.nih.gov/pubmed/34707084
http://dx.doi.org/10.1038/s41467-021-26270-3
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author Yeo, Michele
Chen, Yong
Jiang, Changyu
Chen, Gang
Wang, Kaiyuan
Chandra, Sharat
Bortsov, Andrey
Lioudyno, Maria
Zeng, Qian
Wang, Peng
Wang, Zilong
Busciglio, Jorge
Ji, Ru-Rong
Liedtke, Wolfgang
author_facet Yeo, Michele
Chen, Yong
Jiang, Changyu
Chen, Gang
Wang, Kaiyuan
Chandra, Sharat
Bortsov, Andrey
Lioudyno, Maria
Zeng, Qian
Wang, Peng
Wang, Zilong
Busciglio, Jorge
Ji, Ru-Rong
Liedtke, Wolfgang
author_sort Yeo, Michele
collection PubMed
description 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.
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spelling pubmed-85513272021-10-29 Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission Yeo, Michele Chen, Yong Jiang, Changyu Chen, Gang Wang, Kaiyuan Chandra, Sharat Bortsov, Andrey Lioudyno, Maria Zeng, Qian Wang, Peng Wang, Zilong Busciglio, Jorge Ji, Ru-Rong Liedtke, Wolfgang Nat Commun Article 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. Nature Publishing Group UK 2021-10-27 /pmc/articles/PMC8551327/ /pubmed/34707084 http://dx.doi.org/10.1038/s41467-021-26270-3 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Yeo, Michele
Chen, Yong
Jiang, Changyu
Chen, Gang
Wang, Kaiyuan
Chandra, Sharat
Bortsov, Andrey
Lioudyno, Maria
Zeng, Qian
Wang, Peng
Wang, Zilong
Busciglio, Jorge
Ji, Ru-Rong
Liedtke, Wolfgang
Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission
title Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission
title_full Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission
title_fullStr Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission
title_full_unstemmed Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission
title_short Repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission
title_sort repurposing cancer drugs identifies kenpaullone which ameliorates pathologic pain in preclinical models via normalization of inhibitory neurotransmission
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551327/
https://www.ncbi.nlm.nih.gov/pubmed/34707084
http://dx.doi.org/10.1038/s41467-021-26270-3
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