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Monoamine Oxidase Inhibition by Major Tanshinones from Salvia miltiorrhiza and Selective Muscarinic Acetylcholine M(4) Receptor Antagonism by Tanshinone I
Monoamine oxidases (MAOs) and muscarinic acetylcholine receptors (mAChRs) are considered important therapeutic targets for Parkinson’s disease (PD). Lipophilic tanshinones are major phytoconstituents in the dried roots of Salvia miltiorrhiza that have demonstrated neuroprotective effects against dop...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301926/ https://www.ncbi.nlm.nih.gov/pubmed/34356625 http://dx.doi.org/10.3390/biom11071001 |
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author | Prajapati, Ritu Park, Se Eun Seong, Su Hui Paudel, Pradeep Fauzi, Fazlin Mohd Jung, Hyun Ah Choi, Jae Sue |
author_facet | Prajapati, Ritu Park, Se Eun Seong, Su Hui Paudel, Pradeep Fauzi, Fazlin Mohd Jung, Hyun Ah Choi, Jae Sue |
author_sort | Prajapati, Ritu |
collection | PubMed |
description | Monoamine oxidases (MAOs) and muscarinic acetylcholine receptors (mAChRs) are considered important therapeutic targets for Parkinson’s disease (PD). Lipophilic tanshinones are major phytoconstituents in the dried roots of Salvia miltiorrhiza that have demonstrated neuroprotective effects against dopaminergic neurotoxins and the inhibition of MAO-A. Since MAO-B inhibition is considered an effective therapeutic strategy for PD, we tested the inhibitory activities of three abundant tanshinone congeners against recombinant human MAO (hMAO) isoenzymes through in vitro experiments. In our study, tanshinone I (1) exhibited the highest potency against hMAO-A, followed by tanshinone IIA and cryptotanshinone, with an IC(50) less than 10 µM. They also suppressed hMAO-B activity, with an IC(50) below 25 µM. Although tanshinones are known to inhibit hMAO-A, their enzyme inhibition mechanism and binding sites have yet to be investigated. Enzyme kinetics and molecular docking studies have revealed the mode of inhibition and interactions of tanshinones during enzyme inhibition. Proteochemometric modeling predicted mAChRs as possible pharmacological targets of 1, and in vitro functional assays confirmed the selective M(4) antagonist nature of 1 (56.1% ± 2.40% inhibition of control agonist response at 100 µM). These findings indicate that 1 is a potential therapeutic molecule for managing the motor dysfunction and depression associated with PD. |
format | Online Article Text |
id | pubmed-8301926 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-83019262021-07-24 Monoamine Oxidase Inhibition by Major Tanshinones from Salvia miltiorrhiza and Selective Muscarinic Acetylcholine M(4) Receptor Antagonism by Tanshinone I Prajapati, Ritu Park, Se Eun Seong, Su Hui Paudel, Pradeep Fauzi, Fazlin Mohd Jung, Hyun Ah Choi, Jae Sue Biomolecules Article Monoamine oxidases (MAOs) and muscarinic acetylcholine receptors (mAChRs) are considered important therapeutic targets for Parkinson’s disease (PD). Lipophilic tanshinones are major phytoconstituents in the dried roots of Salvia miltiorrhiza that have demonstrated neuroprotective effects against dopaminergic neurotoxins and the inhibition of MAO-A. Since MAO-B inhibition is considered an effective therapeutic strategy for PD, we tested the inhibitory activities of three abundant tanshinone congeners against recombinant human MAO (hMAO) isoenzymes through in vitro experiments. In our study, tanshinone I (1) exhibited the highest potency against hMAO-A, followed by tanshinone IIA and cryptotanshinone, with an IC(50) less than 10 µM. They also suppressed hMAO-B activity, with an IC(50) below 25 µM. Although tanshinones are known to inhibit hMAO-A, their enzyme inhibition mechanism and binding sites have yet to be investigated. Enzyme kinetics and molecular docking studies have revealed the mode of inhibition and interactions of tanshinones during enzyme inhibition. Proteochemometric modeling predicted mAChRs as possible pharmacological targets of 1, and in vitro functional assays confirmed the selective M(4) antagonist nature of 1 (56.1% ± 2.40% inhibition of control agonist response at 100 µM). These findings indicate that 1 is a potential therapeutic molecule for managing the motor dysfunction and depression associated with PD. MDPI 2021-07-08 /pmc/articles/PMC8301926/ /pubmed/34356625 http://dx.doi.org/10.3390/biom11071001 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Prajapati, Ritu Park, Se Eun Seong, Su Hui Paudel, Pradeep Fauzi, Fazlin Mohd Jung, Hyun Ah Choi, Jae Sue Monoamine Oxidase Inhibition by Major Tanshinones from Salvia miltiorrhiza and Selective Muscarinic Acetylcholine M(4) Receptor Antagonism by Tanshinone I |
title | Monoamine Oxidase Inhibition by Major Tanshinones from Salvia miltiorrhiza and Selective Muscarinic Acetylcholine M(4) Receptor Antagonism by Tanshinone I |
title_full | Monoamine Oxidase Inhibition by Major Tanshinones from Salvia miltiorrhiza and Selective Muscarinic Acetylcholine M(4) Receptor Antagonism by Tanshinone I |
title_fullStr | Monoamine Oxidase Inhibition by Major Tanshinones from Salvia miltiorrhiza and Selective Muscarinic Acetylcholine M(4) Receptor Antagonism by Tanshinone I |
title_full_unstemmed | Monoamine Oxidase Inhibition by Major Tanshinones from Salvia miltiorrhiza and Selective Muscarinic Acetylcholine M(4) Receptor Antagonism by Tanshinone I |
title_short | Monoamine Oxidase Inhibition by Major Tanshinones from Salvia miltiorrhiza and Selective Muscarinic Acetylcholine M(4) Receptor Antagonism by Tanshinone I |
title_sort | monoamine oxidase inhibition by major tanshinones from salvia miltiorrhiza and selective muscarinic acetylcholine m(4) receptor antagonism by tanshinone i |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301926/ https://www.ncbi.nlm.nih.gov/pubmed/34356625 http://dx.doi.org/10.3390/biom11071001 |
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