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Ester Hydrolysis Differentially Reduces Aconitine-Induced Anti-hypersensitivity and Acute Neurotoxicity: Involvement of Spinal Microglial Dynorphin Expression and Implications for Aconitum Processing
Aconitines, including bulleyaconitine A, probably the most bioactive and abundant alkaloids in Aconitum plant, are a group of diester C19-diterpenoid alkaloids with one acetylester group attached to C8 of the diterpenoid skeleton and one benzoylester group to C14. Hydrolysis of both groups is involv...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2016
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5051147/ https://www.ncbi.nlm.nih.gov/pubmed/27761113 http://dx.doi.org/10.3389/fphar.2016.00367 |
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author | Li, Teng-Fei Gong, Nian Wang, Yong-Xiang |
author_facet | Li, Teng-Fei Gong, Nian Wang, Yong-Xiang |
author_sort | Li, Teng-Fei |
collection | PubMed |
description | Aconitines, including bulleyaconitine A, probably the most bioactive and abundant alkaloids in Aconitum plant, are a group of diester C19-diterpenoid alkaloids with one acetylester group attached to C8 of the diterpenoid skeleton and one benzoylester group to C14. Hydrolysis of both groups is involved in the processing of Aconitum, a traditional Chinese medicinal approach. We recently demonstrated that bulleyaconitine A produced anti-hypersensitivity, which was mediated by stimulation of spinal microglial dynorphin A expression. This study aimed to elucidate whether the acetylester and benzoylester groups are involved in aconitine-induced dynorphin A expression, anti-hypersensitivity, neurotoxicity in neuropathic rats. Intrathecal administration of aconitine and benzoylaconine (but not aconine) attenuated mechanical allodynia and heat hyperalgesia, with normalized ED(50) values of 35 pmol and 3.6 nmol, respectively. Aconitine and benzoylaconine anti-allodynia was completely blocked by the microglial inhibitor, dynorphin A antiserum, and κ-opioid receptor antagonist. Aconitine and benzoylaconine, but not aconine, stimulated dynorphin A expression in cultured primary spinal microglia, with EC(50) values of 32 nM and 3 μM, respectively. Intrathecal aconitine, benzoylaconine and aconine induced flaccid paralysis and death, with normalized TD(50) values of 0.5 nmol, 0.2 μmol, and 1.6 μmol, respectively. The TD(50)/ED(50) ratios of aconitine and benzolyaconine were 14:1 and 56:1. Our results suggest that both the C8-acetyl and C14-benzoyl groups are essential for aconitine to stimulate spinal microglial dynorphin A expression and subsequent anti-hypersensitivity, which can be separated from neurotoxicity, because both benzoylaconine and aconine differentially produced anti-hypersensitivity and neurotoxicity due to their different stimulatory ability on dynorphin A expression. Our results support the scientific rationale for Aconitum processing, but caution should be taken to avoid overprocessing and excess hydrolysis of benzolyaconine to aconine. |
format | Online Article Text |
id | pubmed-5051147 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-50511472016-10-19 Ester Hydrolysis Differentially Reduces Aconitine-Induced Anti-hypersensitivity and Acute Neurotoxicity: Involvement of Spinal Microglial Dynorphin Expression and Implications for Aconitum Processing Li, Teng-Fei Gong, Nian Wang, Yong-Xiang Front Pharmacol Pharmacology Aconitines, including bulleyaconitine A, probably the most bioactive and abundant alkaloids in Aconitum plant, are a group of diester C19-diterpenoid alkaloids with one acetylester group attached to C8 of the diterpenoid skeleton and one benzoylester group to C14. Hydrolysis of both groups is involved in the processing of Aconitum, a traditional Chinese medicinal approach. We recently demonstrated that bulleyaconitine A produced anti-hypersensitivity, which was mediated by stimulation of spinal microglial dynorphin A expression. This study aimed to elucidate whether the acetylester and benzoylester groups are involved in aconitine-induced dynorphin A expression, anti-hypersensitivity, neurotoxicity in neuropathic rats. Intrathecal administration of aconitine and benzoylaconine (but not aconine) attenuated mechanical allodynia and heat hyperalgesia, with normalized ED(50) values of 35 pmol and 3.6 nmol, respectively. Aconitine and benzoylaconine anti-allodynia was completely blocked by the microglial inhibitor, dynorphin A antiserum, and κ-opioid receptor antagonist. Aconitine and benzoylaconine, but not aconine, stimulated dynorphin A expression in cultured primary spinal microglia, with EC(50) values of 32 nM and 3 μM, respectively. Intrathecal aconitine, benzoylaconine and aconine induced flaccid paralysis and death, with normalized TD(50) values of 0.5 nmol, 0.2 μmol, and 1.6 μmol, respectively. The TD(50)/ED(50) ratios of aconitine and benzolyaconine were 14:1 and 56:1. Our results suggest that both the C8-acetyl and C14-benzoyl groups are essential for aconitine to stimulate spinal microglial dynorphin A expression and subsequent anti-hypersensitivity, which can be separated from neurotoxicity, because both benzoylaconine and aconine differentially produced anti-hypersensitivity and neurotoxicity due to their different stimulatory ability on dynorphin A expression. Our results support the scientific rationale for Aconitum processing, but caution should be taken to avoid overprocessing and excess hydrolysis of benzolyaconine to aconine. Frontiers Media S.A. 2016-10-05 /pmc/articles/PMC5051147/ /pubmed/27761113 http://dx.doi.org/10.3389/fphar.2016.00367 Text en Copyright © 2016 Li, Gong and Wang. http://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) or licensor 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 Li, Teng-Fei Gong, Nian Wang, Yong-Xiang Ester Hydrolysis Differentially Reduces Aconitine-Induced Anti-hypersensitivity and Acute Neurotoxicity: Involvement of Spinal Microglial Dynorphin Expression and Implications for Aconitum Processing |
title | Ester Hydrolysis Differentially Reduces Aconitine-Induced Anti-hypersensitivity and Acute Neurotoxicity: Involvement of Spinal Microglial Dynorphin Expression and Implications for Aconitum Processing |
title_full | Ester Hydrolysis Differentially Reduces Aconitine-Induced Anti-hypersensitivity and Acute Neurotoxicity: Involvement of Spinal Microglial Dynorphin Expression and Implications for Aconitum Processing |
title_fullStr | Ester Hydrolysis Differentially Reduces Aconitine-Induced Anti-hypersensitivity and Acute Neurotoxicity: Involvement of Spinal Microglial Dynorphin Expression and Implications for Aconitum Processing |
title_full_unstemmed | Ester Hydrolysis Differentially Reduces Aconitine-Induced Anti-hypersensitivity and Acute Neurotoxicity: Involvement of Spinal Microglial Dynorphin Expression and Implications for Aconitum Processing |
title_short | Ester Hydrolysis Differentially Reduces Aconitine-Induced Anti-hypersensitivity and Acute Neurotoxicity: Involvement of Spinal Microglial Dynorphin Expression and Implications for Aconitum Processing |
title_sort | ester hydrolysis differentially reduces aconitine-induced anti-hypersensitivity and acute neurotoxicity: involvement of spinal microglial dynorphin expression and implications for aconitum processing |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5051147/ https://www.ncbi.nlm.nih.gov/pubmed/27761113 http://dx.doi.org/10.3389/fphar.2016.00367 |
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