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Identification of Koumine as a Translocator Protein 18 kDa Positive Allosteric Modulator for the Treatment of Inflammatory and Neuropathic Pain

Koumine is an alkaloid that displays notable activity against inflammatory and neuropathic pain, but its therapeutic target and molecular mechanism still need further study. Translocator protein 18 kDa (TSPO) is a vital therapeutic target for pain treatment, and recent research implies that there ma...

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Autores principales: Xiong, Bojun, Jin, Guilin, Xu, Ying, You, Wenbing, Luo, Yufei, Fang, Menghan, Chen, Bing, Huang, Huihui, Yang, Jian, Lin, Xu, Yu, Changxi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264504/
https://www.ncbi.nlm.nih.gov/pubmed/34248642
http://dx.doi.org/10.3389/fphar.2021.692917
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author Xiong, Bojun
Jin, Guilin
Xu, Ying
You, Wenbing
Luo, Yufei
Fang, Menghan
Chen, Bing
Huang, Huihui
Yang, Jian
Lin, Xu
Yu, Changxi
author_facet Xiong, Bojun
Jin, Guilin
Xu, Ying
You, Wenbing
Luo, Yufei
Fang, Menghan
Chen, Bing
Huang, Huihui
Yang, Jian
Lin, Xu
Yu, Changxi
author_sort Xiong, Bojun
collection PubMed
description Koumine is an alkaloid that displays notable activity against inflammatory and neuropathic pain, but its therapeutic target and molecular mechanism still need further study. Translocator protein 18 kDa (TSPO) is a vital therapeutic target for pain treatment, and recent research implies that there may be allostery in TSPO. Our previous competitive binding assay hint that koumine may function as a TSPO positive allosteric modulator (PAM). Here, for the first time, we report the pharmacological characterization of koumine as a TSPO PAM. The results imply that koumine might be a high-affinity ligand of TSPO and that it likely acts as a PAM since it could delay the dissociation of (3)H-PK11195 from TSPO. Importantly, the allostery was retained in vivo, as koumine augmented Ro5-4864-mediated analgesic and anti-inflammatory effects in several acute and chronic inflammatory and neuropathic pain models. Moreover, the positive allosteric modulatory effect of koumine on TSPO was further demonstrated in cell proliferation assays in T98G human glioblastoma cells. In summary, we have identified and characterized koumine as a TSPO PAM for the treatment of inflammatory and neuropathic pain. Our data lay a solid foundation for the use of the clinical candidate koumine to treat inflammatory and neuropathic pain, further demonstrate the allostery in TSPO, and provide the first proof of principle that TSPO PAM may be a novel avenue for the discovery of analgesics.
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spelling pubmed-82645042021-07-09 Identification of Koumine as a Translocator Protein 18 kDa Positive Allosteric Modulator for the Treatment of Inflammatory and Neuropathic Pain Xiong, Bojun Jin, Guilin Xu, Ying You, Wenbing Luo, Yufei Fang, Menghan Chen, Bing Huang, Huihui Yang, Jian Lin, Xu Yu, Changxi Front Pharmacol Pharmacology Koumine is an alkaloid that displays notable activity against inflammatory and neuropathic pain, but its therapeutic target and molecular mechanism still need further study. Translocator protein 18 kDa (TSPO) is a vital therapeutic target for pain treatment, and recent research implies that there may be allostery in TSPO. Our previous competitive binding assay hint that koumine may function as a TSPO positive allosteric modulator (PAM). Here, for the first time, we report the pharmacological characterization of koumine as a TSPO PAM. The results imply that koumine might be a high-affinity ligand of TSPO and that it likely acts as a PAM since it could delay the dissociation of (3)H-PK11195 from TSPO. Importantly, the allostery was retained in vivo, as koumine augmented Ro5-4864-mediated analgesic and anti-inflammatory effects in several acute and chronic inflammatory and neuropathic pain models. Moreover, the positive allosteric modulatory effect of koumine on TSPO was further demonstrated in cell proliferation assays in T98G human glioblastoma cells. In summary, we have identified and characterized koumine as a TSPO PAM for the treatment of inflammatory and neuropathic pain. Our data lay a solid foundation for the use of the clinical candidate koumine to treat inflammatory and neuropathic pain, further demonstrate the allostery in TSPO, and provide the first proof of principle that TSPO PAM may be a novel avenue for the discovery of analgesics. Frontiers Media S.A. 2021-06-24 /pmc/articles/PMC8264504/ /pubmed/34248642 http://dx.doi.org/10.3389/fphar.2021.692917 Text en Copyright © 2021 Xiong, Jin, Xu, You, Luo, Fang, Chen, Huang, Yang, Lin and Yu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Xiong, Bojun
Jin, Guilin
Xu, Ying
You, Wenbing
Luo, Yufei
Fang, Menghan
Chen, Bing
Huang, Huihui
Yang, Jian
Lin, Xu
Yu, Changxi
Identification of Koumine as a Translocator Protein 18 kDa Positive Allosteric Modulator for the Treatment of Inflammatory and Neuropathic Pain
title Identification of Koumine as a Translocator Protein 18 kDa Positive Allosteric Modulator for the Treatment of Inflammatory and Neuropathic Pain
title_full Identification of Koumine as a Translocator Protein 18 kDa Positive Allosteric Modulator for the Treatment of Inflammatory and Neuropathic Pain
title_fullStr Identification of Koumine as a Translocator Protein 18 kDa Positive Allosteric Modulator for the Treatment of Inflammatory and Neuropathic Pain
title_full_unstemmed Identification of Koumine as a Translocator Protein 18 kDa Positive Allosteric Modulator for the Treatment of Inflammatory and Neuropathic Pain
title_short Identification of Koumine as a Translocator Protein 18 kDa Positive Allosteric Modulator for the Treatment of Inflammatory and Neuropathic Pain
title_sort identification of koumine as a translocator protein 18 kda positive allosteric modulator for the treatment of inflammatory and neuropathic pain
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264504/
https://www.ncbi.nlm.nih.gov/pubmed/34248642
http://dx.doi.org/10.3389/fphar.2021.692917
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